Genetics of Colorectal Cancer (PDQ®)–Health Professional Version
Additional cancers potentially associated with Lynch syndrome
Additional tumors are being considered as part of the spectrum of Lynch syndrome, but this is controversial. Breast and prostate cancers have been raised as possible Lynch syndrome–associated tumors such that MMR genes are now included on multigene (panel) tests for these cancers.
Breast cancer
The issue of breast cancer risk in Lynch syndrome has been controversial. Retrospective studies have been inconsistent, but several have demonstrated microsatellite instability in a proportion of breast cancers from individuals with Lynch syndrome;[434-437] one of these studies evaluated breast cancer risk in individuals with Lynch syndrome and found that it is not elevated.[437] However, the largest prospective study to date of 446 unaffected carriers of pathogenic variants from the Colon Cancer Family Registry [397] who were followed for up to 10 years reported an elevated SIR of 3.95 for breast cancer (95% CI, 1.59–8.13; P = .001).[397] The same group subsequently analyzed data on 764 carriers of MMR gene pathogenic variants with a prior diagnosis of colorectal cancer. Results showed that the 10-year risk of breast cancer following colorectal cancer was 2% (95% CI, 1%–4%) and that the SIR was 1.76 (95% CI, 1.07–2.59).[438] A series from the United Kingdom composed of clinically referred Lynch syndrome kindreds, with efforts to correct for ascertainment, showed a twofold increased risk of breast cancer in 157 MLH1carriers but not in carriers of other MMR variants.[439] Results from a meta-analysis of breast cancer risk in Lynch syndrome among 15 studies with molecular tumor testing results revealed that 62 of 122 breast cancers (51%; 95% CI, 42%–60%) in MMR pathogenic variant carriers were MMR-deficient. In addition, breast cancer risk estimates among a total of 21 studies showed an increased risk of twofold to 18-fold in eight studies that compared MMR variant carriers with noncarriers, while 13 studies did not observe statistical evidence for an association of breast cancer risk with Lynch syndrome.[440]
A number of subsequent studies have suggested the presence of higher breast cancer risks than previously published,[336,337,441,442] although this has not been consistently observed.[443] Through a study of 325 Canadian families with Lynch syndrome, primarily encompassing MLH1 and MSH2 carriers, the lifetime cumulative risk for breast cancer among MSH2 carriers was reported to be 22%.[441] Similarly, breast cancer risks were elevated in a study of 423 women with Lynch syndrome, with substantially higher risks among those with MSH6 and PMS2 pathogenic variants, compared with MLH1 and MSH2pathogenic variants.[337] In fact, breast cancer risk to age 60 years was 37.7% for PMS2, 31.1% for MSH6, 16.1% for MSH2, and 15.5% for MLH1. These findings are consistent with another study of 528 patients with Lynch syndrome–associated pathogenic variants (including MLH1, MSH2, MSH6, PMS2, and EPCAM) in which PMS2 and MSH6 variants were much more frequent among patients with only breast cancer, compared with those with only colorectal cancer (P = 2.3 x 105).[336] Additional data to support an association of MSH6 with breast cancer were provided through a study of over 10,000 cancer patients across the United States who had genetic testing.[442] Findings indicated that MSH6 was associated with breast cancer with an odds ratio (OR) of 2.59 (95% CI, 1.35–5.44). Taken together, these studies highlight how the risk profile among patients with Lynch syndrome is continuing to evolve as more individuals are tested through multigene panel testing, with representation of larger numbers of individuals with PMS2 and MSH6 pathogenic variants compared with prior studies. In the absence of definitive risk estimates, individuals with Lynch syndrome are screened for breast cancer on the basis of family history.[444]
Prostate cancer
Prostate cancer was found to be associated with Lynch syndrome in a study of 198 families from two U.S. Lynch syndrome registries in which prostate cancer had not originally been part of the family selection criteria. Prostate cancer risk in relatives of carriers of MMR gene pathogenic variants was 6.3% at age 60 years and 30% at age 80 years, versus a population risk of 2.6% at age 60 years and 18% at age 80 years, with an overall HR of 1.99 (95% CI, 1.31–3.03).[404] A 2014 meta-analysis supports this association, finding an estimated RR of 3.67 (95% CI, 2.32–6.67) for prostate cancer in men with a known MMR pathogenic variant.[445] This risk is possibly increased in those with MSH2 pathogenic variants.[406,445] Notwithstanding prevalent controversy surrounding routine prostate-specific antigen (PSA) screening, the authors suggested that screening by means of PSA and digital rectal exam beginning at age 40 years in male MMR gene carriers would be “reasonable to consider.”[404] A study of 692 men with metastatic prostate cancer unselected for family history of cancer or age at diagnosis identified germline MMR pathogenic variants in four men (0.5%).[446] Currently, molecular and epidemiologic evidence supports prostate cancer as one of the Lynch syndrome cancers. As with breast cancer,[445] additional studies are needed to define absolute risks and age distribution before surveillance guidelines for prostate cancer can be developed for carriers of MMR pathogenic variants. (Refer to the MMR Genes section in the PDQ summary on Genetics of Prostate Cancer for more information about prostate cancer and Lynch syndrome.)
Adrenocortical cancer
In a series of 114 ACC cases, of which 94 patients had a detailed family history assessment and Li-Fraumeni syndrome was excluded, three patients had family histories that were suggestive of Lynch syndrome. The prevalence of MMR gene pathogenic variants in 94 families was 3.2%, similar to the proportion of Lynch syndrome among unselected colorectal and endometrial cancer patients. In a retrospective review of 135 MMR gene pathogenic variant–positive Lynch syndrome families from the same program, two probands were found to have had a history of ACC. Of the four ACCs in which MSI testing could be performed, all were MSS. These data suggest that if Lynch syndrome is otherwise suspected in an ACC index case, an initial evaluation of the ACC using MSI or IHC testing may be misleading.[405]
Other cancers
Several additional cancers have been found to be associated with Lynch syndrome in some studies, but further investigation is warranted. Table 13 compares the risk of these cancers in the general population with that of individuals with Lynch syndrome.
Management of Lynch syndrome
Screening and surveillance in Lynch syndrome
Colon cancer screening and surveillance in Lynch syndrome
Several aspects of the biologic behavior of CRC and its precursor lesion, the adenomatous polyp, in individuals with Lynch syndrome support a different approach to CRC screening in this population as compared with those recommendations for average-risk people in the general population. At present, the recommendations for cancer screening and surveillance in Lynch syndrome take into account the differences in cancer risks as compared with those in the general population due to the causative germline deficiency in the MMR system. The following biological differences form the basis of the currently implemented screening strategies in Lynch syndrome:
- CRC and adenomas present at a younger age.CRCs in Lynch syndrome occur earlier in life than do sporadic cancers; however the age of onset varies based on which of the MMR genes is altered. (Refer to the Prevalence, clinical manifestations, and cancer risks associated with Lynch syndrome section of this summary for more information about gene-specific age of onset of CRC.)Carriers of Lynch syndrome pathogenic variants have an increased risk of developing colon adenomas and the onset of adenomas appears to occur at a younger age than in pathogenic variant–negative individuals from the same families.[447] The risk of a carrier of MMR pathogenic variants developing adenomas has been reported to be 3.6 times higher than the risk in noncarriers.[447] By age 60 years, 70% of the carriers developed adenomas, compared with 20% of noncarriers. Most of the adenomas in carriers had absence of MMR protein expression and were more likely to have dysplastic features, compared with adenomas from control subjects.[447]In one study, the mean age at diagnosis of adenoma in carriers was 43.3 years (range, 23–63.2 y), and the mean age at diagnosis of carcinoma was 45.8 years (range, 25.2–57.6 y).[447]
- There is a right-sided predominance of colon cancer.A larger proportion of Lynch syndrome CRCs (60%–70%) occur in the right colon, suggesting that sigmoidoscopy alone is not an appropriate screening strategy and that a colonoscopy provides a more complete structural examination of the colon. Evidence-based reviews of surveillance colonoscopy in Lynch syndrome have been reported.[144,448,449] The incidence of CRC throughout life is substantially higher in patients with Lynch syndrome, suggesting that the most-sensitive test available should be used. (Refer to Table 14 for available colon surveillance recommendations.)
- The adenoma-carcinoma sequence is accelerated.The progression from normal mucosa to adenoma to cancer is accelerated,[450,451] suggesting that screening should be performed at shorter intervals (every 1–2 years) and with colonoscopy.[451-454] It has been demonstrated that carriers of MMR gene pathogenic variants develop detectable adenomas at an earlier age than do noncarriers.[447,447] It is not known whether this reflects a greater prevalence of adenomas or the presence of larger adenomas with better detection in Lynch syndrome.
Evidence for the use of colonoscopy for CRC screening and surveillance in Lynch syndrome
The risk of CRC in Lynch syndrome has been studied and updated in a Finnish screening trial, which spans from the early 1980s to present.[451,455] Over the course of this trial, the design of the longitudinal study has evolved. In the earliest period, information about each individual's variant status was unknown and study participants were eligible based on fulfillment of clinical criteria; the study consisted of some people with a previous cancer or adenoma diagnosis and others without such history who were undergoing asymptomatic screening while the comparison group was composed of individuals from those same families who refused screening. Many of these people (68%) had screening with x-ray contrast/barium enema. Colonoscopy was the approach used for carriers of MMR pathogenic variants when this information was obtainable and the interval between exams was shortened from 5 years to 3 years to 2 years, based on results from the study over time.
A 15-year controlled screening trial conducted in this series demonstrated a reduction in the incidence of CRC, CRC-specific mortality, and overall mortality with colonoscopy in individuals from Lynch syndrome families.[451] Colonic screening was provided at 3-year intervals in 133 individuals from Lynch syndrome families and 119 controls from these families had no screening. Among those screened, 8 individuals (6%) developed CRC compared with 19 control subjects (16%), for a risk reduction of 62% with screening. Furthermore, all CRCs in the screened group were local, causing no deaths, while there were 9 deaths caused by CRC in the control group. There was also a benefit in overall mortality in the screened group with 10 deaths in the screened group and 26 deaths in the control group (P = .003).
The series subsequently limited its attention to subjects without prior diagnosis of adenoma or cancer. The eligible 420 carriers of pathogenic variants had a mean age of 36 years and underwent an average of 2.1 colonoscopies, with a median follow-up of 6.7 years. Adenomas were detected in 28% of subjects. Cumulative risk of one or more adenomas by age 60 years was 68.5% in men and 48.3% in women. Notably, risk of detecting cancer in those free of cancer at baseline exam, and thus regarded as interval cancers, by age 60 years was 34.6% in men and 22.1% in women. The combined cumulative risk of adenoma or cancer by age 60 years was 81.8% in men and 62.9% in women. For both adenomas and carcinomas, about one-half were located proximal to the splenic flexure. While the rates for CRC despite colonoscopy surveillance appear high, the recommended short intervals were not regularly adhered to in this nonrandomized series. These authors recommended surveillance at 2-year intervals. This is in line with most consensus guidelines (refer to Table 14), in which the appropriate colonoscopy screening interval remains every 1 to 2 years. Analysis of colonoscopic surveillance data in 242 carriers of pathogenic variants 10 years after testing shows 95% compliance in surveillance procedures for CRC and endometrial cancer. Although not all CRCs were prevented, mortality was comparable with variant-negative relatives. However, this may be attributable to the modest sample size of the study.[455]
Given that colonoscopy is the accepted measure for colon cancer surveillance, preliminary data suggest that the use of chromoendoscopy, such as with indigo carmine, may increase the detection of diminutive, histologically advanced adenomas.[456,457]
When an adenoma is detected, the question of whether to test the adenoma for MSI/IHC is raised. One study of patients with prior CRC and known MMR pathogenic variants found eight of 12 adenomas to have both MSI and IHC protein loss.[458] However, the study authors emphasized that normal MSI/IHC testing in an adenoma does not exclude Lynch syndrome. Abnormal MSI/IHC are uncommon in the smallest adenomas, and more prevalent in adenomas larger than 8 mm, which also suggests that the MMR defect is acquired in the growing adenoma.[235]
Special considerations: The impact of gene-specific variability in cancer risk on CRC screening recommendations in Lynch syndrome
Because of the variability of gene-specific CRC risks, experts in the field have proposed gene-specific screening and surveillance recommendations. For example, a European consortium [373] made a clinical recommendation for delaying the onset of colorectal and endometrial cancer screening to age 30 years, in line with their recommendation for later initiation of screening for carriers of MSH6 pathogenic variants. Additionally, a 2015 review by an ad hoc American virtual workgroup involved in the care of Lynch syndrome patients and families concluded that despite multiple studies indicating reduced penetrance in monoallelic PMS2 carriers, they could not recommend any changes to Lynch syndrome cancer surveillance guidelines for this group.[369]
While initial data may support different strategies for the initiation and surveillance of CRC and other extracolonic cancers by specific MMR gene alteration,[397] concerns related to (a) the adherence of recommendations overall by the medical community and by affected individuals [459] and (b) limitations related to specific screening modalities [460] have prevented the implementation of gene-specific guidelines until additional data are available.[95]
Extracolonic cancer screening in Lynch syndrome
Gynecologic cancer screening in Lynch syndrome
Endometrial cancer screening in Lynch syndrome
Note: A separate PDQ summary on Endometrial Cancer Screening in the general population is also available.
Cancer of the endometrium is the most common extracolonic cancer observed in Lynch syndrome families, affecting at least one female in about 50% of Lynch syndrome families. (Refer to the Endometrial cancer section of this summary for more information about gene-specific risks of endometrial cancer in carriers of MMR pathogenic variants.)
In the general population, the diagnosis of endometrial cancer is generally made when women present with symptoms including abnormal or postmenopausal bleeding. Endometrial sampling is performed to provide a histologic specimen for diagnosis. Eighty percent of women with endometrial cancer present with stage I disease and there are no data to suggest that the clinical presentation in women with Lynch syndrome differs from that in the general population.
Given their substantial increased risk of endometrial cancer, endometrial screening for women with Lynch syndrome has been suggested. Proposed modalities for screening include transvaginal ultrasound (TVUS) and/or endometrial biopsy. TVUS continues to be widely recommended without data to support its use; current NCCN guidelines suggest that there is no clear evidence to support endometrial cancer screening for Lynch syndrome.[95] Two studies have examined the use of TVUS in endometrial screening for women with Lynch syndrome.[465,466] In one study of 292 women from Lynch syndrome families or "Lynch syndrome-like/HNPCC-like" families, no cases of endometrial cancer were detected by TVUS. In addition, two interval cancers developed in symptomatic women.[465] In a second study, 41 women with Lynch syndrome were enrolled in a TVUS screening program. Of 179 TVUS procedures performed, there were 17 abnormal scans. Three of the 17 women had complex atypical hyperplasia on endometrial sampling, while 14 had normal endometrial sampling. However, TVUS failed to identify one patient who presented 8 months after a normal TVUS with abnormal vaginal bleeding, and was found to have stage IB endometrial cancer.[466] Both of these studies concluded that TVUS is neither sensitive nor specific.
A study of 175 women with Lynch syndrome, which included both endometrial sampling and TVUS, showed that endometrial sampling improved sensitivity compared with TVUS. Endometrial sampling found 11 of the 14 cases of endometrial cancer. Two of the three other cases were interval cancers that developed in symptomatic women and one case was an occult endometrial cancer found at the time of hysterectomy. Endometrial sampling also identified 14 additional cases of endometrial hyperplasia. Among the group of 14 women with endometrial cancer, ten also had TVUS screening with endometrial sampling. Four of the ten had abnormal TVUS, but six had normal TVUS.[467] While this cohort study demonstrated that endometrial sampling may have benefits over TVUS for endometrial screening, there are no data that predict that screening with any other modality has benefits for endometrial cancer survival in women with Lynch syndrome.
Some studies suggest that women with a clinical or genetic diagnosis of Lynch syndrome do not universally adopt intensive gynecologic screening.[468,469] (Refer to the Gynecologic cancer screening in Lynch syndrome section in the Psychosocial Issues in Hereditary Colon Cancer Syndromes section of this summary for more information.)
Ovarian cancer screening in Lynch syndrome
Estimates of the cumulative lifetime risk of ovarian cancer in Lynch syndrome patients range from 3.4% to 22%.[4,353,422-424] However, no studies on the effectiveness of ovarian screening are currently available for women in Lynch syndrome families. TVUS used for endometrial cancer screening has been extended to include ovarian cancer screening in clinical practice for those women who do not undergo risk-reducing surgery for gynecological cancer prevention. However, NCCN asserts that data do not support routine ovarian cancer screening for Lynch syndrome due to a lack of sensitivity and specificity of available screening modalities.[95]
Level of evidence: None assigned
Risk-reducing surgeries for the prevention of gynecologic cancers in Lynch syndrome
An effective strategy for the prevention of endometrial and ovarian cancers in Lynch syndrome families is risk-reducing surgery. A retrospective study of 315 women with pathogenic MMR gene variants compared the rate of endometrial and ovarian cancer among the women who did and did not have hysterectomy and oophorectomy. In women followed for endometrial cancer, the mean follow-up periods were 13.3 years in the surgical group and 7.4 years in the nonsurgical group; in women followed for ovarian cancer, the mean follow-up periods were 11.2 years in the surgical group and 10.6 years in the nonsurgical groups. For those women in the surgical group, no cancers were diagnosed, compared with a 33% rate of endometrial cancer and a 5.5% rate of ovarian cancer in the nonsurgical group.[470] Cost-effectiveness–analysis modeling of risk-reducing surgeries (prophylactic hysterectomy and bilateral salpingo-oophorectomy) versus nonsurgical screening in a theoretical population of carriers aged 30 years with MMR gene variants associated with Lynch syndrome revealed that prophylactic surgery was cost-effective with lower cost and yielded higher QALY.[429] A subsequent modeling study evaluated multiple screening and surgical strategies and found that annual screening initiated at age 30 years followed by risk-reducing surgery at age 40 years was the most effective strategy.[471]
Additional extracolonic cancer screening in Lynch syndrome
The decision to screen for other Lynch syndrome–associated cancers is done on an individual basis and relies on the cancers reported among FDRs and second-degree relatives with Lynch syndrome.
Gastric cancer
The lifetime risk of gastric cancer is approximately 8% for male Lynch syndrome carriers and 5% for female Lynch syndrome carriers.[425] Recent epidemiologic data report a decreasing trend in the diagnosis of gastric cancer than was previously reported, which was as high as 13%. The histologic characterization of most Lynch syndrome–associated gastric cancer is of the intestinal type and may thereby be detected using screening esophagogastroduodenoscopy (EGD).[425,472] Although there are no clear data to support surveillance for gastric, duodenal, and more distal small bowel cancers, EGD with visualization of the duodenum at the time of colonoscopy can be used in individuals with Lynch syndrome with a baseline examination performed at age 40 years. Evaluation and treatment of Helicobacter pylori infection is recommended when found. Despite limited data on appropriate surveillance intervals, there is general consensus that surveillance be performed every 3 to 5 years, particularly if there is a family history of gastric, duodenal, or more distal small bowel cancer or for those of Asian descent.[95]
Small bowel cancer
There are variable reports on the lifetime risk of small bowel cancer associated with Lynch syndrome, ranging from less than 1% to 12%.[4,359,421-423,426] Most small bowel malignancies are confined to the duodenum and the ileum, which are within endoscopic reach using EGD and colonoscopy (with dedicated ileal intubation), respectively. Other modalities to assess for small bowel lesions include CT enterography and capsule endoscopy but cost-effectiveness analyses do not support use of these evaluations for routine screening in Lynch syndrome.[424]
Urinary tract cancer
Urinary tract malignancies include those of the transitional cell type of the renal pelvis and ureters, and the bladder. The associated lifetime risk of these malignancies is variable, ranging from less than 1% to as high as 25%, with higher estimates related to pooling the cancers found in different locations within the urinary tract and including the bladder.[4,359,422,423,426,427] Studies that have evaluated urinary cytology as a potential screening modality revealed that it was associated with low sensitivity and a high false-positive rate and ultimately leads to additional evaluation that is often invasive (i.e., cystoscopy). There are currently no effective modalities used for routine screening in asymptomatic individuals with Lynch syndrome.
Pancreatic cancer
An elevated risk of pancreatic cancer among Lynch syndrome carriers has been supported by two cohort studies that adjust for ascertainment bias. One study reported a cumulative risk of pancreatic cancer of 3.7% by age 70 years and an 8.6-fold increase compared with the general population. [433] Another prospective study using data from the Colon Cancer Family Registry reported an SIR of 10.7 with cumulative risk of 0.95%.[397] Results of these studies have supported an expert consensus that recommended screening for pancreatic cancer in individuals with Lynch syndrome and an FDR with pancreatic cancer, similar to other high-risk populations with comparable risk.[473]
Of note, screening for cancers of the urinary tract, bladder, hepatobiliary system, and pancreas is not recommended beyond that for the general population; however, NCCN suggests the consideration of urothelial cancer screening for individuals with a family history of urothelial cancer or individuals with MSH2 pathogenic variants (especially males).[95]
Chemoprevention in Lynch syndrome
The Colorectal Adenoma/Carcinoma Prevention Programme (CAPP2) was a double-blind, placebo-controlled, randomized trial to determine the role of aspirin in preventing CRC in patients with Lynch syndrome who were in surveillance programs at a number of international centers.[474] The study randomly assigned 861 participants to receive aspirin (600 mg/day), aspirin placebo, resistant starch (30 g/day), or starch placebo for up to 4 years. At a mean follow-up of 55.7 months (range, 1–128 months), 53 primary CRCs developed in 48 participants (18 of 427 in the aspirin group and 30 of 434 in the aspirin placebo group). Seventy-six patients who refused randomization to the aspirin groups (because of an aspirin sensitivity or a history of peptic ulcer disease) were randomly assigned to receive resistant starch or resistant starch placebo. The intent-to-treat analysis yielded an HR for CRC of 0.63 (95% CI, 0.35–1.13; P = .12). However, five of the patients who developed CRC developed two primary colon cancers. A Poisson regression was performed to account for the effect of the multiple primary CRCs and yielded a protective effect for aspirin (incidence rate ratio [IRR], 0.56; 95% CI, 0.32–0.99; P = .05). For participants who completed at least 2 years of treatment, the per-protocol analysis yielded an HR of 0.41 (95% CI, 0.19–0.86; P = .02) and an IRR of 0.37 (0.18–0.78; P = .008). An analysis of all Lynch syndrome cancers (endometrial, ovarian, pancreatic, small bowel, gallbladder, ureter, stomach, kidney, and brain) revealed a protective effect of aspirin versus placebo (HR, 0.65; 95% CI, 0.42–1.00; P = .05). There were no significant differences in adverse events between the aspirin and placebo groups, and no serious adverse effects were noted with any treatment. The authors concluded that 600 mg of aspirin per day for a mean of 25 months substantially reduced cancer incidence in Lynch syndrome patients. CAPP2 failed to show any effect from daily resistant starch intake. A limitation of the trial is that the frequency of surveillance studies at the various centers was not reported as being standardized. Earlier CAPP2 trial results for 746 Lynch syndrome patients enrolled in the study were published in 2008 [475] and failed to show a significant preventive effect on incident colonic adenomas or carcinomas (relative risk, 1.0; 95% CI, 0.7–1.4) with a shorter mean follow-up of 29 months (range, 7–74 months). A 2015 survey of 1,858 participants in the Colon Cancer Family Registry suggested that aspirin and ibuprofen might be chemopreventive for carriers of MMR gene pathogenic variants.[476] The CAPP3 trial, which is evaluating the effect of lower doses of aspirin (blinded 100 mg, 300 mg, and 600 mg enteric-coated aspirin), began in 2013 and is expected to enroll approximately 3,000 carriers of pathogenic variants by about 2021.[477]
Despite level 1 evidence, experts believe that the evidence regarding aspirin use for the chemoprevention of Lynch syndrome is not sufficiently robust or mature to recommend its standard use.[419]
Management of Lynch syndrome-associated CRC
Surgical management of CRC in Lynch syndrome
One of the hallmark features of Lynch syndrome is the presence of synchronous and metachronous CRCs. The incidence of metachronous CRCs has been reported to be 16% at 10 years, 41% at 20 years, and 63% at 30 years after segmental colectomy.[389] Because of the increased incidence of synchronous and metachronous neoplasms, the recommended surgical treatment for a patient with Lynch syndrome with neoplastic colonic lesions is generally an extended colectomy (total or subtotal). Nevertheless, treatment has to be individualized and has often included segmental colectomy. Mathematical models suggest that there are minimal benefits of extended procedures in individuals older than 67 years, compared with the benefits seen in younger individuals with early-onset cancer. In one Markov decision analysis model, the survival advantage for a young individual with early-onset CRC undergoing an extended procedure could be up to 4 years longer than that seen in the same individual undergoing a segmental resection.[478] The recommendation for an extended procedure must be balanced with the comorbidities of the patient, the clinical stage of the disease, the wishes of the patient, and surgical expertise. No prospective or retrospective study has shown a survival advantage for patients with Lynch syndrome who underwent an extended resection versus a segmental procedure.
Two studies have shown that patients who undergo extended procedures have fewer metachronous CRCs and additional surgical procedures related to CRC than do patients who undergo segmental resections.[389,479] Balancing functional results of an extended procedure versus a segmental procedure is of paramount importance. Although the majority of patients adapt well after an abdominal colectomy, some patients will require antidiarrheal medication. A decision model compared QALYs for a patient aged 30 years undergoing an abdominal colectomy versus a segmental colectomy.[480] In this model, there was not much difference between the extended and segmental procedure, with QALYs being 0.3 years more in patients undergoing a segmental procedure than in those undergoing an extended procedure.[480]
When considering surgical options, it is important to recognize that a subtotal or total colectomy will not eliminate the rectal cancer risk. The lifetime risk of developing cancer in the rectal remnant after an abdominal colectomy has been reported to be 12% at 12 years post-colectomy.[481] In addition to the general complications of surgery are the potential risks of urinary and sexual dysfunction and diarrhea after an extended colectomy; these risks increase as the anastomosis becomes more distal. Therefore, the choice of surgery must be made on an individual basis by the surgeon and the patient.
In patients with Lynch syndrome and rectal cancer, similar surgical options (extended vs. segmental resection) and considerations must be given. Extended procedures include restorative proctocolectomy and IPAA if the sphincter can be saved, or proctocolectomy with loop ileostomy if the sphincter cannot be saved. The risk of metachronous colon cancer after segmental resection for an index rectal cancer has been reported to be between 15% and 27%.[438,482] Two retrospectives studies reported a 15% and 18% incidence of metachronous colon cancer after segmental rectal cancer–resection in patients with Lynch syndrome.[483,484] In one of the studies, the combined risk of metachronous high-risk adenomas and cancers was 51% at a median follow-up of 101.7 months after proctectomy.[484]
There are no data about fertility after surgery in Lynch syndrome patients. In female FAP patients, no difference in fecundity after abdominal colectomy and IRA has been reported, whereas there is a 54% decrease in fecundity in patients who undergo restorative proctocolectomy with IPAA compared with the general population.[485] Another study in which a questionnaire was sent to FAP patients reported a similar prevalence of fertility problems among patients who had undergone IRA, IPAA, and proctocolectomy with end ileostomy. In that study, it was reported that earlier age at the time of surgery was associated with more fertility problems.[486]
Prognostic and therapeutic implications of MSI
As discussed in previous sections, MSI is not only a molecular feature of Lynch syndrome, but is also present in 10% to 15% of sporadic cases of CRC (largely due to MLH1hypermethylation or biallelic somatic pathogenic variants in an MMR gene). Although MSI testing was initially utilized to screen patients who might harbor pathogenic MMR gene variants, it has been increasingly recognized that MSI has important prognostic and therapeutic implications. The utility of MSI testing beyond identifying Lynch syndrome has made the case for universal MSI screening more compelling, and has contributed to its widespread adoption. Several studies have suggested that stage-specific survival is better for MSI-H CRC compared with MSS cancers. Additionally, the chemotherapeutic agent 5-fluorouracil (5-FU) appears ineffective in the adjuvant treatment of resected MSI-H CRC, in contrast to MSS CRC in which this agent is widely utilized for this purpose. Finally, immunomodulation with agents such as checkpoint inhibitors appears effective in the treatment of advanced MSI-H CRC based on early phase 1 and phase 2 studies, while these agents, at least when utilized as monotherapy, show little activity in MSS CRC.
Prognosis of MSI
Although MSI-H tumors account for 15% of all sporadic CRC, they appear to be more frequent in stage II compared with stage III CRC,[489] and are even less common in metastatic disease, being present in only 3% to 4% of metastatic cases.[490] This stage distinction alludes to the possibility of a better prognosis associated with underlying MSI-H status.
Several studies subsequently confirmed the improved survival of stage II MSI-H CRC compared with MSS cases. A meta-analysis of 32 studies of 7,642 cases, including 1,277 with MSI-H, showed a combined HR estimate for overall survival (OS) associated with MSI of 0.65 (95% CI, 0.59–0.71; heterogeneity P = .16; I2 [a measure of the percentage of variation across studies that is due to heterogeneity rather than chance] = 20%).[491] However, while data were limited, tumors with MSI derived no benefit from adjuvant 5-FU (HR, 1.24; 95% CI, 0.72–2.14). Subsequent data from several large randomized clinical trials confirmed the favorable prognosis associated with MSI-H. These included the QUick And Simple And Reliable (QUASAR) trial, which explored the benefit of adjuvant 5-FU–based chemotherapy compared with surgery alone in 1,900 patients with resected stage II CRC. In this study, MSI-H tumors were associated with a recurrence risk of half that of MSS tumors (risk ratio [RR], 0.53; 95% CI, 0.40–0.70).[492] Similar results were seen in the Pan European Trial Adjuvant Colon Cancer (PETACC)-3 trial, a randomized trial of 5-FU with or without irinotecan in resected stage II or stage III CRC.[493] MSI-H status was associated with an OS odds ratio (OR) of 0.39 (95% CI, 0.24–0.65) and this advantage was seen in both stage II and stage III disease.
Consistent with other prior data, clinicopathologic analysis of 85 Lynch syndrome–associated CRCs and 67 sporadic MMR-deficient (dMMR) CRCs demonstrated a significantly superior survival among patients with Lynch syndrome, as well as younger ages at diagnosis and higher numbers of tumor-infiltrating lymphocytes (TILs).[494] Exome sequencing and neoantigen data from a subset of 16 CRC tumors (eight Lynch syndrome CRCs and eight sporadic dMMR CRCs) from this cohort suggest that somatic mutational burden and neoantigen load is significantly higher among Lynch syndrome–associated CRCs than sporadic dMMR CRCs; this was speculated to be the source of the improved survival outcomes and increased TILs.
Given the predilection for MSI-H tumors to involve the right side of the colon, there is a paucity of data on the outcome and prognosis of MSI-H tumors involving the rectum. One study suggested only 2% of rectal cancers are MSI-H.[492] A study of 62 patients with MSI-H rectal cancers from a single institution were followed for a median of 6.8 years. The 5-year rectal cancer–specific survival was 100% for stage I and stage II, 85.1% for stage III, and 60.0% for stage IV disease, suggesting the favorable prognosis associated with MSI-H may also apply to cancers involving the rectum.[482] The authors additionally reported a favorable 26% pathologic complete response (pCR) rate with 5-FU combined with radiation therapy, suggesting that 5-FU given with radiation for the locoregional treatment of rectal cancer may still be effective in the setting of MSI-H tumors. The substantial rate of pCRs demonstrated in this study also reinforces the need for adequate biopsies to assess MSI status prior to commencing treatment.
The use of adjuvant chemotherapy after surgery for CRC in Lynch syndrome
The finding of MSI in a CRC has been shown in several studies to predict the lack of benefit of adjuvant chemotherapy with 5-FU in resected stage II or stage III colon cancer.[495] This has been a controversial area historically. It was known that loss of DNA MMR activity in cultured colon cancer cells conferred resistance to DNA-damaging agents (the common mechanism of cytotoxic chemotherapy) through loss of the signal to arrest the cell cycle in response to DNA damage that cannot be repaired.[496] This led to the prediction that DNA dMMR tumors may not be fully sensitive to alkylating agents, 5-FU, and platinum-containing drugs.[497-499] Unexpectedly, in 2000, a paper was published suggesting that patients with Dukes C (stage III) CRC with MSI had a substantial survival benefit when given 5-FU–based adjuvant chemotherapy.[500] However, the patients in this analysis had not been randomized to therapy; they were selected for adjuvant chemotherapy based upon clinical status, and inadvertently, the median age in the treatment group was 13 years younger than the controls.
In 2003, however, the outcomes in a randomized controlled prospective trial of adjuvant chemotherapy in 570 colon cancer patients demonstrated no benefit from adjuvant 5-FU in the group with MSI. Moreover, there were nonsignificant trends towards increased mortality when colon cancers with MSI were treated: twofold for stage III cancers and threefold for stage II cancers.[501] Subsequently, ten studies confirmed this, as all failed to show benefit when CRC patients were given 5-FU–based chemotherapy.[495] In contrast, a meta-analysis of randomized trials of 5-FU versus observation suggested a potential benefit of 5-FU in patients with MSI stage III disease. An exploratory subset analysis suggested benefit only in those patients with Lynch syndrome–related MSI. An analysis of stage II patients was not undertaken in this study.[502]
Preclinical data suggests the addition of oxaliplatin to 5-FU can overcome the resistance to 5-FU monotherapy seen in MSI-H tumors.[503] A retrospective analysis of 433 MSI-H stage II and stage III CRC cases (both sporadic and secondary to Lynch syndrome) suggested a benefit in disease-free survival (DFS) with FOLFOX (5-FU and oxaliplatin) compared with surgery alone.[504] There was a trend towards improved DFS utilizing FOLFOX in the subset of patients with MSI due to Lynch syndrome, however, the result was not statistically significant. Additional studies have demonstrated similar survival outcomes irrespective of MSI status with adjuvant chemotherapy including FOLFOX.[505,506]
Immunotherapy
Tumors that develop via the MSI pathway have more somatic variants than tumors that develop via other pathways. This could imply that dMMR tumors may have more potential antigens (termed neoantigens) and may be more responsive to immune system manipulation than proficient MMR (pMMR) tumors. Microscopically, MSI-H tumors often exhibit abundant tumor-infiltrating lymphocytes, sometimes resulting in a Crohn-like reaction. This histologic feature has long suggested the possibility of increased tumor immune surveillance in MSI-H cancers, and is one of the main hypotheses for the better stage-specific survival seen in MSI-H compared with MSS cancers.
To test the hypothesis of efficacy of immunomodulation in MSI-H tumors, a phase 2 trial of programmed cell death-1 (PD-1) inhibition was carried out in a small cohort of patients with MSI-H or MSS cancers. Patients with metastatic disease that had failed various chemotherapy regimens were treated with pembrolizumab, an anti–PD-1 immune checkpoint inhibitor.[507] In this small phase 2 study, 32 patients with CRC (11 were dMMR, 21 were pMMR, and 9 others had noncolorectal dMMR tumors) were treated with intravenous pembrolizumab every 14 days. The immune-related response among evaluable patients was 40% (4 of 10) for dMMR CRC tumors, 0% (0 of 18) for pMMR CRC tumors, and 71% (5 of 7) for non-CRC dMMR tumors. The immune-related 20-week progression-free survival (PFS) was 78% (7 of 9) in patients with dMMR CRC tumors, 11% (2 of 18) in patients with pMMR CRC tumors, and 67% (4 of 6) in patients with non-CRC dMMR tumors. dMMR tumors had a mean of 24-fold more somatic variants than pMMR tumors. Additionally, in this study somatic variant load was associated with prolonged PFS. The authors concluded that MMR status predicted clinical benefit to immune checkpoint blockade with pembrolizumab.
A single-arm phase 2 study (CheckMate 142) of another PD-1 inhibitor, nivolumab, was performed in 74 patients with MSI-H/dMMR CRC that had progressed on prior cytotoxic chemotherapy (including 5-FU, irinotecan, and oxaliplatin).[508] Overall, 31% of patients (23 of 74) experienced an objective response to therapy, and 69% (51 of 74) had disease control for at least 12 weeks. Among patients who responded to nivolumab, the median duration of response was not reached at the time of study analysis (median follow up of 12 months). There was no significant difference in the response rates among individuals with Lynch syndrome–associated metastatic MSI-H/dMMR CRC versus non-Lynch metastatic MSI-H/dMMR CRC in this study. Twenty percent of study participants experienced grade 3 or greater toxicities, most commonly elevations in amylase and/or lipase, and there were no deaths that were attributed to nivolumab.
Based on these data, pembrolizumab 200 mg given intravenously every 3 weeks was approved by the FDA in May 2017 for the treatment of any MSI-H/dMMR metastatic cancer that is refractory to standard therapy and nivolumab 240 mg given intravenously every 2 weeks was granted accelerated approval by the FDA in August 2017 for the treatment of MSI-H/dMMR CRC that is refractory to cytotoxic chemotherapy.
In another arm of CheckMate 142, 119 individuals with metastatic dMMR CRC were treated with nivolumab plus ipilimumab.[509] The objective response rate was 55% with a 12-week disease control rate of 80%, a 12-month PFS of 71%, and a medial duration of response that was not reached. Grade 3 and grade 4 toxicities occurred in 32% of participants (most commonly increased liver function tests) and 13% of all participants discontinued therapy due to toxicity. This was a nonrandomized study, and thus questions remain as to whether the combination of immune checkpoint blockade is superior to PD-1 inhibition alone, especially given the apparent increase in toxicity with combination therapy. On the basis of these data, in July 2018 the FDA granted accelerated approval to nivolumab plus ipilimumab therapy for the treatment of dMMR/MSI-H metastatic CRC that has progressed through prior chemotherapy with a fluoropyrimidine, oxaliplatin, and irinotecan.
Vaccines in the treatment or prevention of MSI-related CRC
An alternative approach to immunotherapy in MSI-H CRC involves the use of tumor-directed vaccines. The most promising approaches thus far involve the use of tumor-related neoantigens as epitopes to increase tumor-specific T-cell immunity. Studies are currently under way in the adjuvant treatment of resected stage III CRC (NCT01461148), in patients with metastatic disease (NCT01885702), and in the prevention of CRC in patients with Lynch syndrome (NCT01885702).
Lynch syndrome–related syndromes
Lynch-like or HNPCC-like syndrome
Lynch-like syndrome may account for up to 70% of cases in which Lynch syndrome is suspected but germline testing fails to identify a pathogenic MMR gene variant.[296] Similar to the tumor phenotype seen in Lynch syndrome, CRCs manifest MSI and IHC loss of a DNA MMR protein. However, the MMR-deficient CRCs are due to biallelic somatic inactivation of DNA MMR genes,[510-512] in which a somatic variant in one allele of the MMR gene along with loss of heterozygosity of the other allele is most probable versus the presence of two somatic sequence variants. (Refer to Table 11 for more information about the tumor phenotype of Lynch-like syndrome.)
Possible explanations for the cause of Lynch-like syndrome include the following: (1) the possibility that some germline DNA variants are not detected by current testing; (2) affected individuals may have germline pathogenic variants in genes other than DNA MMR genes currently known to be associated with Lynch syndrome; or (3) there are other mechanisms that inactivate DNA MMR beyond those related to alterations in the germline.
There is growing evidence that the CRC risk among probands and families with Lynch-like syndrome are lower, with an SIR of 2.12, than in Lynch syndrome, with an SIR of 6.04.[296] Preliminary estimates reveal a lower risk of extracolonic cancers with a SIR of 1.69 in Lynch-like syndrome versus 2.81 in Lynch syndrome. In the absence of large-scale studies with longitudinal follow-up, in addition to data pertaining to the rates of neoplastic progression in Lynch-like syndrome, intensive cancer screening recommendations are currently similar to those in Lynch syndrome guidelines.
Familial colorectal cancer type X
The term familial colorectal cancer type X or FCCX was coined to refer to families who meet Amsterdam criteria but lack MSI/IHC abnormalities.[251] Approximately 50% of families that fulfill Amsterdam criteria, lack pathogenic MMR gene variants and thereby are characterized as FCCX families. Research is ongoing to determine a genetic etiology for FCCX, but for the most part it remains unknown and is thought to be a heterogeneous condition. However, differentiating between Lynch syndrome and FCCX has important implications regarding cancer risk assessment and screening recommendations for affected individuals and at-risk relatives. While the risk of CRC is increased to twice that in the general population, it is less than that in Lynch syndrome (>sixfold increase) and there is no significant risk of extracolonic malignancy. Cancer screening recommendations are therefore modified and CRC surveillance is recommended every 5 years.[251]
Special considerations: Young-onset CRC
The epidemiology of CRC with regard to age at diagnosis is shifting with individuals increasingly being diagnosed before age 50 years.[513] (Refer to the PDQ summary on Colorectal Cancer Prevention for more information about CRC incidence trends in the general population.) One study that examined the prevalence of highly penetrant pathogenic variants in 450 individuals with young-onset CRC (mean age at diagnosis, 42.5 y) and a family history including at least one FDR with colon, endometrial, breast, ovarian, and/or pancreatic cancer identified 75 germline pathogenic or likely pathogenic variants in 72 patients (16%).[333] The spectrum of variants identified included Lynch syndrome and non-Lynch syndrome–associated genes, including several genes that have not traditionally been associated with CRC (e.g., BRCA1/BRCA2, ATM, CHEK2, PALB2, and CDKN2A). Given the high frequency and variety of hereditary cancer syndromes identified, the authors suggest that multigene (panel) testing in this population may be warranted.
In the absence of additional family or personal history suggestive of Lynch syndrome, isolated cases of CRC diagnosed before age 36 years are uncommonly associated with MMR gene pathogenic variants. One study found MMR pathogenic variants in only 6.5% of such individuals,[514] whereas another study of CRC patients younger than 50 years with no more than one FDR with CRC found abnormal MSI in 21% of tumors and overrepresentation of defects in the PMS2 and MSH6 genes.[515] Therefore, isolated cases of very early-onset CRC should be offered tumor screening with MSI/IHC rather than proceeding directly to germline pathogenic variant analysis.
Advances in Endoscopic Imaging in Hereditary CRC
Performance of endoscopic therapies for adenomas in FAP and Lynch syndrome, and decision-making regarding surgical referral and planning, require accurate estimates of the presence of adenomas. In both AFAP and Lynch syndrome the presence of very subtle adenomas poses special challenges—microadenomas in the case of AFAP and flat, though sometimes large, adenomas in Lynch syndrome.
Chromoendoscopy
The need for sensitive means to endoscopically detect subtle polyps has increased with the recognition of flat adenomas and sessile serrated polyps in otherwise average-risk subjects, very attenuated adenoma phenotypes in AFAP, and subtle flat adenomas in Lynch syndrome. Modern high-resolution endoscopes improve adenoma detection yield, but the use of various vital dyes, especially indigo carmine dye-spray, has further improved detection. Several studies have shown that the improved mucosal contrast achieved with the use of indigo carmine can improve the adenoma detection rate. Whether family history is significant or not, careful clinical evaluation consisting of dye-spray colonoscopy (indigo carmine or methylene blue),[456,516-521] with or without magnification, or possibly newer imaging techniques such as narrow-band imaging,[522] may reveal the characteristic right-sided clustering of more numerous microadenomas. Upper GI endoscopy may be informative if duodenal adenomas or fundic gland polyps with surface dysplasia are found. Such findings will increase the likelihood of variant detection if APC or MUTYH testing is pursued.
In various large series of average-risk populations, subtle flat lesions were detected in about 5% to 10% of cases, including adenomas with high-grade dysplasia and invasive adenocarcinoma.[523] Some of these studies involved tandem procedures—white-light exam followed by randomization to “intensive” (> 20-minute pull-back from cecum) inspection versus chromoendoscopy—with significantly more adenomas detected in the chromoendoscopy group.[524] However, in several randomized trials, no significant difference in yield was seen.[525,526]
In a randomized trial of subjects with Lynch syndrome,[527] standard colonoscopy, with polypectomy as indicated, was followed by either indigo carmine chromoendoscopy or repeat “intensive” white-light colonoscopy (a design very nearly identical to the average-risk screening group noted above). In this series, no significant difference in adenoma yield between the chromoendoscopy and intensive white-light groups was detected. However, these patients were younger and in many cases had undergone several previous exams that might have resulted in polyp clearing.
In a German study,[528] one series of Lynch syndrome patients underwent white-light exam followed by chromoendoscopy, while a second series underwent colonoscopy with narrow-band imaging followed by chromoendoscopy. Significant differences in flat polyp detection favored chromoendoscopy in both series, although some of the detected lesions were hyperplastic. In a French series of Lynch syndrome subjects that also employed white-light exam followed by chromoendoscopy, significantly more adenomas were detected with chromoendoscopy.[457]
Fewer evaluations of chromoendoscopy have been performed in AFAP than in Lynch syndrome. One study examined four patients with presumed AFAP and fewer than 20 adenomas upon white-light examination.[529] All had more than 1,000 diminutive adenomas found on chromoendoscopy, in agreement with pathology evaluation after colectomy.
A similar role for chromoendoscopy has been suggested to evaluate the duodenum in FAP. One study from Holland that used indigo carmine dye-spray to detect duodenal adenomas showed an increase in the number and size of adenomas, including some large ones. Overall Spigelman score was not significantly affected.[530]
Small bowel imaging
Patients with PJS and JPS are at greater risk of disease-related complications in the small bowel (e.g., bleeding, obstruction, intussusception, or cancer). FAP patients, although at great risk of duodenal neoplasia, have a relatively low risk of jejunoileal involvement. The RR of small bowel malignancy is very high in Lynch syndrome, but absolute risk is less than 10%. Although the risks of small bowel neoplasia are high enough to warrant consideration of surveillance in each disease, the technical challenges of doing so have been daunting. Because of the technical challenges and relatively low prevalences, there is virtually no evidence base for small-bowel screening in Lynch syndrome.
Historically, the relative endoscopic inaccessibility of the mid and distal small bowel required radiographic measures for its evaluation, including the barium small bowel series or a variant called tube enteroclysis, in which a nasogastroduodenal tube is placed so that all of the contrast goes into the small intestine for more precise imaging. None of these measures were sensitive for small lesions. Any therapeutic undertaking required laparotomy. This entailed resection in most cases, although intraoperative endoscopy, with or without enterotomy for scope access, has been available for many years. Peroral enteroscopy (aided by stiffening overtubes with two balloons, one balloon, or spiral ribs) has been employed to overcome the technical problem of excessive looping, enabling deep jejunal access with therapeutic (polypectomy) potential.
Most data relate that PJS with double-balloon enteroscopy is the preferred method for endoscopy of the small bowel.[531] This may involve only peroral enteroscopy, although subsequent retrograde enteroscopy has been described for more complete evaluation of the total small bowel. Because these procedures are time-consuming and involve some risk of complication, deep enteroscopy is usually preceded by more noninvasive imaging, including traditional barium exams, capsule endoscopy, and CT or magnetic resonance enterography.[83]
In FAP, data from capsule endoscopy [83] show a 50% to 100% prevalence of jejunal and/or ileal polyps in patients with Spigelman stage III or stage IV duodenal involvement but virtually no such polyps in Spigelman stage I or stage II disease. All polyps were smaller than 10 mm and were not biopsied or removed. Consequently, their clinical significance remains uncertain but is likely limited, given the infrequency of jejunoileal cancer reports in FAP.
Capsule endoscopy in the small series of PJS patients described above [83] showed the presence of a similar frequency (50%–100%) of polyps, but the prevalent polyps were much larger than in FAP, were more likely to become symptomatic, and warranted endoscopic or surgical excision. Capsule studies were suggested as an appropriate replacement for radiographic studies because of the sensitivity of capsule endoscopy.
Familial CRC
An estimated 7% to 10% of people have an FDR with CRC,[532,533] and approximately twice that many have either an FDR or a second-degree relative with CRC.[533,534] A simple family history of CRC (defined as one or more close relatives with CRC in the absence of a known hereditary colon cancer) confers a twofold to sixfold increase in risk. The risk associated with family history varies greatly according to the age of onset of CRC in the family members, the number of affected relatives, the closeness of the genetic relationship (e.g., FDRs), and whether cancers have occurred across generations.[532,535] A positive family history of CRC appears to increase the risk of CRC earlier in life such that at age 45 years, the annual incidence is more than three times higher than that in average-risk people; at age 70 years, the risk is similar to that in average-risk individuals.[532] The incidence in a 35- to 40-year-old is about the same as that of an average-risk person at age 50 years. There is no evidence to suggest that CRC in people with one affected FDR is more likely to be proximal or is more rapidly progressive.
A personal history of adenomatous polyps confers a 15% to 20% risk of subsequently developing polyps [536] and increases the risk of CRC in relatives.[537] The RR of CRC, adjusted for sex and the year of birth, was 1.78 (95% CI, 1.18–2.67) for the parents and siblings of the patients with adenomas as compared with the spouse controls. The RR for siblings of patients in whom adenomas were diagnosed before age 60 years was 2.59 (95% CI, 1.46–4.58), compared with the siblings of patients who were 60 years or older at the time of diagnosis and after adjustment for the sibling's year of birth and sex, with a parental history of CRC.
While familial clusters account for approximately 20% of all CRC cases in developed countries,[538] the rare and highly penetrant Mendelian CRC diseases contribute to only a fraction of familial cases, which suggests that other genes and/or shared environmental factors may contribute to the remainder of the cancers. Two studies attempted to determine the degree to which hereditary factors contribute to familial CRCs.
The first study utilized the Swedish, Danish, and Finnish twin registries that cumulatively provided 44,788 pairs of same-sex twins (for men: 7,231 monozygotic [MZ] and 13,769 dizygotic [DZ] pairs; for women: 8,437 MZ and 15,351 DZ pairs) to study the contribution of heritable and environmental factors involved in 11 different cancers.[539] The twins included in the study all resided in their respective countries of origin into adulthood (>50 y). Cancers were identified through their respective national cancer registries in 10,803 individuals from 9,512 pairs of twins. The premise of the study was based on the fact that MZ twins share 100% and DZ twins share 50% of their genes on average for any individual twin pair. This study calculated that heritable factors accounted for 35%, shared environmental factors for 5%, and nonshared environmental factors for 60% of the risk of CRC. For CRC, the estimated heritability was only slightly greater in younger groups than in older groups. This study revealed that although nonshared environmental factors constitute the major risk of familial CRC, heredity plays a larger-than-expected role.
The second study utilized the Swedish Family-Cancer Database, which contained 6,773 CRCs in offspring and 31,100 CRCs in their parents, from 1991 to 2000.[540] The database included 253,467 pairs of spouses, who were married and lived together for at least 30 years, and who were used to control for common environmental effects on cancer risk. In the offspring of an affected parent, the overall SIR for cancer of the colon was 1.81 (95% CI, 1.62–2.02), for cancer of the rectum it was 1.74 (95% CI, 1.53–1.96), and for cancer of the colon-and-rectum combined it was 1.78 (95% CI, 1.53–1.96). The risk conferred by affected siblings was also significantly elevated. Because there was no significantly increased risk of CRC conferred between spouses, the authors concluded that heredity plays a significant role in familial CRCs; however, controls for shared environmental effects among siblings were absent in this study.
Ten percent to 15% of persons with CRC and/or colorectal adenomas have other affected family members,[532,533,535-537,541-546] but their findings do not fit the criteria for FAP, and their family histories may or may not meet clinical criteria for Lynch syndrome. Such families are categorized as having familial CRC, which is currently a diagnosis of exclusion (of known hereditary CRC disorders). The presence of CRC in more than one family member may be caused by hereditary factors, shared environmental risk factors, or even chance. Because of this etiologic heterogeneity, understanding the basis of familial CRC remains a research challenge.
Genetic studies have demonstrated a common autosomal dominant inheritance pattern for colon tumors, adenomas, and cancers in familial CRC families,[547] with a gene frequency of 0.19 for adenomas and colorectal adenocarcinomas.[546] A subset of families with MSI-negative familial colorectal neoplasia was found to link to chromosome 9q22.2-31.2.[548] A more recent study has linked three potential loci in familial CRC families on chromosomes 11, 14, and 22.[549]
Familial colorectal cancer type X (FCCX)
Families meeting Amsterdam-I criteria for Lynch syndrome who do not show evidence of defective MMR by MSI testing do not appear to have the same risk of colorectal or other cancers as those families with classic Lynch syndrome and clear evidence of defective MMR. These Amsterdam-I criteria families with intact MMR systems have been described as FCCX,[251,550-554] and it has been suggested that these families be classified as a distinct group.
The genetic etiology of FCCX remains unclear. Utilizing whole-genome linkage analysis and exome sequencing, a truncating variant in ribosomal protein S20 (RPS20), a ribosomal protein gene, was identified in four individuals with CRC from an FCCX family.[554] The variant cosegregated with CRC in the family, with a logarithm of the odds score of 3. Additionally, the variant was not identified in 292 controls. No LOH was observed in tumor samples, and in vitro analyses of mature RNA formation confirmed a model of haploinsufficiency for RPS20. No germline variants in RPS20 were found in 25 additional FCCX families studied, suggesting RPS20 variants are an infrequent cause of FCCX. The same group had previously identified variants in the bone morphogenetic protein receptor type 1A (BMPR1A) gene in affected individuals from 2 of 18 families with FCCX.[555] Additional studies are necessary to definitively confirm or refute a role for RPS20 or BMPR1A in FCCX.
Age of CRC onset in Lynch syndrome ranges from 44 years (registry series) to a mean of 52 years (population-based series).[255,303,351] There are no corresponding population-based data for FCCX because FCCX by definition requires at least one early-onset case and is not likely to lend itself to any population-based figures in the foreseeable future. Studies that have directly compared age of onset between FCCX and Lynch syndrome have suggested that the age of onset is slightly older in FCCX,[251,550,552] but the lifetime risk of cancer is substantially lower. The SIR for CRC among families with intact MMR (FCCX families) was 2.3 (95% CI, 1.7–3.0) in one large study, compared with 6.1 (95% CI, 5.7–7.2) in families with defective MMR (Lynch syndrome families).[251] The risk of extracolonic tumors was also not found to be elevated in the FCCX families, suggesting that enhanced surveillance for CRC was sufficient. Although further studies are required, tumors arising within FCCX families also appear to have a different pathologic phenotype, with fewer tumor-infiltrating lymphocytes than those in families with Lynch syndrome.[551]
Interventions for family history of CRC
There are no controlled comparisons of screening in people with a mild or modest family history of CRC. Most experts who accept that average-risk people should be screened starting at age 50 years suggest that screening should begin earlier in life (e.g., at age 35–40 y) when the magnitude of risk is comparable to that of a 50-year-old. Because the risk increases with the extent of family history, there is room for clinical judgment in favor of even earlier screening, depending on the details of the family history. Some experts suggest shortening the frequency of the screening interval to every 5 years, rather than every 10 years.[147]
A common but unproven clinical practice is to initiate CRC screening 10 years before the age of the youngest CRC case in the family. There is neither direct evidence nor a strong rational argument for using aggressive screening methods simply because of a modest family history of CRC.
These issues were weighed by a panel of experts convened by the American Gastroenterological Association before publishing clinical guidelines for CRC screening, including those for persons with a positive family history of CRC.[556] These guidelines have been endorsed by a number of other organizations.
The American Cancer Society and the United States Multi-Society Task Force on Colorectal Cancer have published guidelines for average-risk individuals.[147,557-560] These guidelines address screening issues related to modest family history of CRC or adenomas. Given the heterogeneity of this group, it is beyond the scope of this more targeted discussion of major gene conditions.
Rare Colon Cancer Syndromes
PTEN hamartoma tumor syndromes (including Cowden syndrome)
Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome (BRRS) are part of a spectrum of conditions known collectively as PTEN hamartoma tumor syndromes. Approximately 85% of patients diagnosed with Cowden syndrome, and approximately 60% of patients with BRRS have an identifiable PTEN pathogenic variant.[561] In addition, PTEN pathogenic variants have been identified in patients with very diverse clinical phenotypes.[562] The term PTEN hamartoma tumor syndromes refers to any patient with a PTEN pathogenic variant, irrespective of clinical presentation.
PTEN functions as a dual-specificity phosphatase that removes phosphate groups from tyrosine, serine, and threonine. Pathogenic variants of PTEN are diverse, including nonsense, missense, frameshift, and splice-site variants. Approximately 40% of variants are found in exon 5, which encodes the phosphatase core motif, and several recurrent pathogenic variants have been observed.[563] Individuals with variants in the 5’ end or within the phosphatase core of PTEN tend to have more organ systems involved.[564]
Operational criteria for the diagnosis of Cowden syndrome have been published and subsequently updated.[565,566] These included major, minor, and pathognomonic criteria consisting of certain mucocutaneous manifestations and adult-onset dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease). An updated set of criteria based on a systematic literature review has been suggested [567] and is currently utilized in the National Comprehensive Cancer Network (NCCN) guidelines.[444] Contrary to previous criteria, the authors concluded that there was insufficient evidence for any features to be classified as pathognomonic. With increased utilization of genetic testing, especially the use of multigene panels, clinical criteria for Cowden syndrome will need to be reconciled with the phenotype of individuals with documented germline PTENpathogenic variants who do not meet these criteria. Until then, whether Cowden syndrome and the other PTEN hamartoma tumor syndromes will be defined clinically or based on the results of genetic testing remains ambiguous. The American College of Medical Genetics and Genomics (ACMG) suggests that referral for genetics consultation be considered for individuals with a personal history of or a first-degree relative with 1) adult-onset Lhermitte-Duclos disease or 2) any three of the major or minor criteria that have been established for the diagnosis of Cowden syndrome.[568] Detailed recommendations, including diagnostic criteria for Cowden syndrome, can be found in the NCCN and ACMG guidelines.[444,568] Additionally, a predictive model that uses clinical criteria to estimate the probability of a PTEN pathogenic variant is available; a cost-effectiveness analysis suggests that germline PTEN testing is cost effective if the probability of a variant is greater than 10%.[569]
Over a 10-year period, the International Cowden Consortium (ICC) prospectively recruited a consecutive series of adult and pediatric patients meeting relaxed ICC criteria for PTENtesting in the United States, Europe, and Asia.[570] Most individuals did not meet the clinical criteria for a diagnosis of Cowden syndrome or BRRS. Of the 3,399 individuals recruited and tested, 295 probands (8.8%) and an additional 73 family members were found to harbor germline PTEN pathogenic variants. In addition to breast, thyroid, and endometrial cancers, the authors concluded that on the basis of cancer risk, melanoma, kidney cancer, and colorectal cancers should be considered part of the cancer spectra arising from germline PTEN pathogenic variants. A second study of approximately 100 patients with a germline PTEN pathogenic variant confirmed these findings and suggested a cumulative cancer risk of 85% by age 70 years.[571]
The age-adjusted risk of CRC was increased in carriers of pathogenic variants in both studies (SIR, 5.7–10.3).[570,571] In addition, one study found that 93% of individuals with PTEN pathogenic variants who had undergone at least one colonoscopy had polyps. The most common histology was hyperplastic, although adenomas and sessile serrated polyps were also observed. The increased risk of CRC among carriers of PTEN pathogenic variants has led to the recommendation of surveillance colonoscopy in these patients.[571,572] However, both the age at which to begin (30–40 y) and the subsequent frequency of colonoscopies (biennial to every 3–5 y) vary considerably and are based on expert opinion.
Peutz-Jeghers syndrome (PJS)
PJS is an early-onset autosomal dominant disorder characterized by melanocytic macules on the lips, the perioral region, and buccal region; and multiple gastrointestinal polyps, both hamartomatous and adenomatous.[573-575] Germline pathogenic variants in the STK11 gene at chromosome 19p13.3 have been identified in the vast majority of PJS families.[576-580] The most common cancers in PJS are gastrointestinal. However, other organs are at increased risk of developing malignancies. For example, the cumulative risks have been estimated to be 32% to 54% for breast cancer [8,581,582] and 21% for ovarian cancer.[581] A systematic review found a lifetime cumulative cancer risk, all sites combined, of up to 93% in patients with PJS.[583] Table 16 shows the cumulative risk of these tumors.
Females with PJS are also predisposed to the development of cervical adenoma malignum, a rare and very aggressive adenocarcinoma of the cervix.[584] In addition, females with PJS commonly develop benign ovarian sex-cord tumors with annular tubules, whereas males with PJS are predisposed to development of Sertoli-cell testicular tumors;[585] although neither of these two tumor types is malignant, they can cause symptoms related to increased estrogen production.
Although the risk of malignancy appears to be exceedingly high in individuals with PJS based on the published literature, the possibility that selection and referral biases have resulted in overestimates of these risks should be considered.
Peutz-Jeghers gene(s)
PJS is caused by pathogenic variants in the STK11 (also called LKB1) tumor suppressor gene located on chromosome 19p13.[577,578] Unlike the adenomas seen in familial adenomatous polyposis, the polyps arising in PJS are hamartomas. Studies of the hamartomatous polyps and cancers of PJS show allelic imbalance (LOH) consistent with the two-hit hypothesis, demonstrating that STK11 is a tumor suppressor gene.[588,589] However, heterozygous STK11 knockout mice develop hamartomas without inactivation of the remaining wild-type allele, suggesting that haploinsufficiency is sufficient for initial tumor development in PJS.[590] Subsequently, the cancers that develop in STK11 +/- mice do show LOH;[591] indeed, compound mutant mice heterozygous for pathogenic variants in STK11 +/- and homozygous for pathogenic variants in TP53 -/- have accelerated development of both hamartomas and cancers.[592]
Germline variants of the STK11 gene represent a spectrum of nonsense, frameshift, and missense variants, and splice-site variants and large deletions.[8,576] Approximately 85% of variants are localized to regions of the kinase domain of the expressed protein, and no germline variants have been reported in exon 9. No strong genotype-phenotype correlations have been identified.[8]
STK11 has been unequivocally demonstrated to cause PJS. Although earlier estimates using direct DNA sequencing showed a 50% pathogenic variant detection rate in STK11, studies adding techniques to detect large deletions have found pathogenic variants in up to 94% of individuals meeting clinical criteria for PJS.[576,583,593] Given the results of these studies, it is unlikely that other major genes cause PJS.
Clinical management
The high cumulative risk of cancers in PJS has led to the various screening recommendations summarized in the table of Published Recommendations for Diagnosis and Surveillance of Peutz-Jeghers Syndrome (PJS) in the PDQ summary on Genetics of Colorectal Cancer.
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