Genetics of Colorectal Cancer (PDQ®)–Health Professional Version
Attenuated Familial Adenomatous Polyposis (AFAP)
AFAP is a heterogeneous clinical entity characterized by fewer adenomatous polyps in the colon and rectum than in classic FAP. It was first described clinically in 1990 in a large kindred with a variable number of adenomas. The average number of adenomas in this kindred was 30, though they ranged in number from a few to hundreds.[192] Adenomas in AFAP are believed to form in the mid-twenties to late twenties.[68] Similar to classic FAP, the risk of CRC is higher in individuals with AFAP; the average age at diagnosis, however, is older than classic FAP at 56 years.[30,31,193] Extracolonic manifestations similar to those in classic FAP also occur in AFAP. These manifestations include upper GI polyps (FGPs, duodenal adenomas, and duodenal adenocarcinoma), osteomas, epidermoid cysts, and desmoid tumors.[68]
AFAP is associated with particular subsets of APC pathogenic variants, including missense changes. Three groups of site-specific APC pathogenic variants causing AFAP have been characterized:[30-33,194,195]
- Pathogenic variants associated with the 5’ end of APC and exon 4 in which patients can manifest 2 to more than 500 adenomas, including the classic FAP phenotype and upper GI polyps.
- Exon 9–associated phenotypes in which patients may have 1 to 150 adenomas but no upper GI manifestations.
- 3’ region pathogenic variants in which patients have very few adenomas (<50).
APC gene testing is an important component of the evaluation of patients suspected of having AFAP.[196] It has been recommended that the management of AFAP patients include colonoscopy rather than flexible sigmoidoscopy because the adenomas can be predominantly right-sided.[196] The role for and timing of risk-reducing colectomy in AFAP is controversial.[197] If germline APC pathogenic variant testing is negative in suspected AFAP individuals, genetic testing for MUTYH pathogenic variants may be warranted.[137]
Patients found to have an unusually or unacceptably high adenoma count at an age-appropriate colonoscopy pose a differential diagnostic challenge.[198,199] In the absence of family history of similarly affected relatives, the differential diagnosis may include AFAP (including MAP), Lynch syndrome, or an otherwise unclassified sporadic or genetic problem. A careful family history may implicate AFAP or Lynch syndrome.
Table 8 summarizes the clinical practice guidelines from different professional societies regarding surveillance of AFAP.
MUTYH-Associated Polyposis (MAP)
MAP is an autosomal recessively inherited polyposis syndrome caused by pathogenic variants in the Mut Y homolog gene. The Mut Y homolog gene, which is known as MUTYH, was initially called MYH, but was subsequently corrected because the myosin heavy chain gene already had that designation. MUTYH is located on chromosome 1p34.3-32.1.[201] The protein encoded by MUTYH is a base excision repair glycosylase, which repairs one of the most common forms of oxidative damage. Over one hundred unique sequence variants of MUTYH have been reported (Leiden Open Variation Database). A founder pathogenic variant with ethnic differentiation is assumed for MUTYH pathogenic variants. In white populations of northern European descent, two major variants, Y179C and G396D (formerly known as Y165C and G382D), account for 70% of biallelic pathogenic variants in MAP patients; 90% of these patients carry at least one of these pathogenic variants.[202] Other causative variants that have been found include P405L (formerly known as P391L) (Netherlands),[203,204] E480X (India),[205] Y104X (Pakistan),[206] 1395delGGA (Italy),[207,208] 1186-1187insGG (Portugal),[209] and p.A359V (Japan and Korea).[210-212]
The MUTYH gene was first linked to polyposis in 2002 in three siblings with multiple colonic adenomas and CRC but no APC pathogenic variant.[142] MAP has a broad clinical spectrum. Most often it resembles the clinical picture of AFAP, but it has been reported in individuals with phenotypic resemblance to classical FAP and Lynch syndrome.[213] MAP patients tend to develop fewer adenomas at a later age than patients with APC pathogenic variants [140,214] but still carry a high risk of CRC (35%–75%).[7,215,216] A 2012 study of colorectal adenoma burden in 7,225 individuals reported a prevalence of biallelic MUTYH pathogenic variants of 4% (95% CI, 3%–5%) among those with 10 to 19 adenomas, 7% (95% CI, 6%–8%) among those with 20 to 99 adenomas, and 7% (95% CI, 6%–8%) among those with 100 to 999 adenomas.[217] This broad clinical presentation results from the MUTYH gene's ability to cause disease in its homozygous or compound heterozygous forms. Based on studies from multiple FAP registries, approximately 7% to 19% of patients with a FAP phenotype and without a detectable APC germline pathogenic variant carry biallelic variants in the MUTYH gene.[7,140,205,218]
Adenomas, serrated adenomas, and hyperplastic polyps can be seen in MAP patients.[219] The CRCs tend to be right-sided and synchronous at presentation and seem to carry a better prognosis than sporadic CRC.[201] Clinical management guidelines for MAP range between once a year to every 3 years for colonoscopic surveillance beginning at age 18 to 30 years,[95,200,215] with upper endoscopic surveillance beginning at age 25 to 30 years.[200] (Refer to Table 9 for more information about available clinical practice guidelines for colon surveillance in MAP patients.) The recommended upper endoscopic surveillance interval can be based on the burden of involvement according to Spigelman criteria.[200] Total colectomy with ileorectal anastomosis or subtotal colectomy may be necessary for patients with MUTYH-associated polyposis depending on overall polyp burden.[215,220]
Although MAP is the only known biallelic (recessive) adenoma cancer predisposition syndrome described to date, there are examples of biallelic cases presenting with childhood tumors in which MMR genes are involved. (Refer to the Biallelic mismatch repair deficiency section in the Lynch syndrome section of this summary for more information.)
Table 9 summarizes the clinical practice guidelines from different professional societies regarding colon surveillance of biallelic MAP.
Many extracolonic cancers have been reported in patients with MAP including gastric, small intestinal, endometrial, liver, ovarian, bladder, thyroid, and skin cancers (melanoma, squamous epithelial, and basal cell carcinomas).[221,222] Additionally, noncancerous extracolonic manifestations have been reported in a few MAP patients including lipomas, congenital hypertrophy of the retinal pigment epithelium, osteomas, and desmoid tumors.[140,207,222,223] Female MAP patients have an increased risk of breast cancer.[224] These extracolonic manifestations seem to occur less frequently in MAP than in FAP, AFAP, or Lynch syndrome.[225,226]
Duodenal polyps in MAP
Similar to FAP, individuals with MAP often develop duodenal adenomas, and are at risk of developing duodenal cancer. Given the relatively recent identification of MAP compared with FAP, the incidence of duodenal polyps and risk of duodenal cancer in MAP is less well defined. Small case series have suggested the incidence of duodenal polyps in MAP to be approximately 30%, considerably lower than that of FAP. In a registry-based study the prevalence of duodenal polyps was 17%; however, only 50% of individuals in this study had undergone an upper GI endoscopy, suggesting the incidence of duodenal polyps was likely underestimated. The lifetime risk of duodenal cancer was estimated to be 4%.[222]
A registry study from the United Kingdom and the Netherlands explored incidence of duodenal polyps and duodenal cancer in a group of patients with MAP who were undergoing regular duodenal surveillance.[227] Of 92 patients, 31 (34%) had evidence of duodenal polyps. The median age at duodenal adenoma detection was 50 years, and in 65% of patients duodenal adenomas were diagnosed at baseline endoscopy. Eighty-four percent of patients had Spiegelman stage I or stage II polyposis at first detection of polyps, with no patients with stage IV polyposis and no high-grade dysplasia detected. In subsequent surveillance only two patients progressed to Spiegelman stage IV polyposis, after 3.6 and 7.0 years, respectively. There additionally appeared to be sparing of the ampulla, with only two individuals having diminutive polyps without dysplasia in the ampulla. No cancers were detected in patients enrolled in upper GI surveillance programs within these registries. Two individuals with MAP were diagnosed with ampullary and duodenal cancer respectively at ages 83 and 63 years at the time of first-ever upper GI endoscopies. Therefore, duodenal polyps appear less prevalent in MAP compared with FAP, and appear at a later age. On the basis of these results, the authors suggest upper GI endoscopic screening in MAP be initiated at age 35 years.
Because MAP has an autosomal recessive inheritance pattern, siblings of an affected patient have a 25% chance of also carrying biallelic MUTYH pathogenic variants and should be offered genetic testing. Similarly, testing can be offered to the partner of an affected patient so that the risk in their children can be assessed.
The clinical phenotype of monoallelic MUTYH pathogenic variants is less well characterized with respect to incidence and associated clinical phenotypes, and its role in susceptibility to polyposis and colorectal carcinoma remains unclear. Approximately 1% to 2% of the general population carry a pathogenic variant in MUTYH.[7,140,142] A 2011 meta-analysis found that carriers of monoallelic MUTYH pathogenic variants are at modestly increased risk of CRC (odds ratio [OR], 1.15; 95% CI, 0.98–1.36); however, given the rarity of carriers of monoallelic pathogenic variants, they account for only a trivial proportion of all CRC cases.[228] A large study of 2,332 heterozygotes among 9,504 relatives of 264 CRC cases with a MUTYH pathogenic variant found that the risk of CRC at age 70 years was 7.2% for men and 5.6% for women, irrespective of family history. Among those with an FDR with a CRC diagnosis before age 50 years, the risk at age 70 years was 12.5% for men and 10% for women.[216] Caution should be exercised in the interpretation of this study as the vast majority of carrier status from this study was imputed and not based on genotype. The authors felt the risk for MUTYH heterozygotes with an FDR with CRC was sufficiently high to warrant more intensive surveillance than the general population (but the same as for anyone with an FDR with CRC diagnosed before age 50 y).[214,216]
MMR genes may interact with MUTYH and increase the risk of CRC. An association between MUTYH and MSH6 has been reported. Both proteins interact together in base excision repair processes. A study reported a significant increase of MSH6 pathogenic variants in carriers of monoallelic MUTYH pathogenic variants with CRC compared with noncarriers with CRC (11.5% vs. 0%; P = .037).[229] However, a German study failed to duplicate these findings.[230] Additionally, a larger study found no increased cancer risk for carriers of MMR pathogenic variants with a MUTYH variant compared with those with a MMR pathogenic variant alone.[231]
NTHL1
A study utilizing whole-exome sequencing in 51 individuals with multiple colonic adenomas from 48 families identified a homozygous germline nonsense pathogenic variant in seven affected individuals from three unrelated families in the base-excision repair gene NTHL1.[232] These individuals had CRC, multiple adenomas (8–50), none of which were either hyperplastic or serrated, and in three affected females, there was either endometrial cancer or endometrial complex hyperplasia. There were two other individuals who developed duodenal adenomas and duodenal cancer. All pedigrees were consistent with autosomal recessive inheritance. Upon examining three cancers and five adenomas from different affected individuals, none showed microsatellite instability (MSI). These neoplasms did show enrichment of cytosine to thymine transitions. Additional studies are needed to further define the phenotype. A subsequent study of 863 families with CRC and 1,600 families without CRC confirmed an association between NTHL1 pathogenic variants and inherited CRC risk.[233]
Oligopolyposis
Oligopolyposis is a popular term used to describe the clinical presentation of a polyp count or burden that is greater than anticipated in the course of screening in average-risk patients but that falls short of the requirement for a diagnosis of FAP. Thus, oligo-, Greek for few, can mean different things to different observers. While conceding a lack of consensus on the matter, the National Comprehensive Cancer Network (NCCN) committee on CRC screening suggests an AFAP diagnosis is worth considering when 10 to less than 100 adenomas are present.[95] It will be used here to describe the circumstance in which the polyp count (generally adenoma) is large enough, with or without any attendant family history, to raise in the mind of the endoscopist the possibility of an inherited susceptibility.
In the setting of known or suspected Lynch syndrome, the detection of one to ten adenomas is still in keeping with the diagnosis. A similar adenoma count in a young patient undergoing colonoscopy for symptoms or in a screening patient over age 50 years could raise the question of Lynch syndrome. In the appropriate clinical setting—early onset and positive family history—the detection of any number of adenomas may support the testing and diagnosis of a patient for underlying Lynch syndrome pathogenic variants, consistent with guidelines such as those offered by the NCCN. Some controversy exists over the utility of testing adenoma tissue for MSI, as the yield is lower than in invasive cancer.[234] In general, and subject to the above caveats, Lynch syndrome is not routinely considered in a discussion of oligopolyposis.
One study considered a series of polyps (37 adenomas) from 21 patients with known MMR pathogenic variants, performing MSI and immunohistochemistry (IHC) for MMR protein expression.[235] Overall, MSI-high (MSI-H) was seen in 41% and in 100% of adenomas larger than 1 cm. Adenomas measuring smaller than 1 cm yielded MSI about 30% of the time. Correlation between MSI and loss of staining on IHC was fairly high, although the discordance rate (17%) was higher than in other series that evaluated invasive cancers from known carriers of MMR pathogenic variants. A higher MSI likelihood was observed in subjects older than 50 years. IHC staining in relation to gene showed 8 of 12 MLH1adenomas to have lost protein expression, with 10 of 20 adenomas from MSH2 patients to have loss of expression. In contrast, none (0 of 6) of the adenomas from carriers of MSH6pathogenic variants had loss of associated protein expression. The authors concluded that while normal MSI/IHC was simply not informative, abnormal MSI/IHC was as likely in larger (>8 mm) polyps as in cancers and thus a reasonable test to consider.
AFAP is found at the other end of the oligopolyposis spectrum. Most cases will have more than 100 adenomas, albeit at a later age and often with a predominance of microadenomas of the right colon and with fewer, larger polyps in the left colon. Cases with a positive family history and an APC pathogenic variant are clearly variant cases of FAP, as the term AFAP implies.[236] However, patients with no immediate family history and a lesser adenoma burden may not be found to have an APC pathogenic variant. The lower the polyp count the lower the probability of having an APC pathogenic variant. Some of these cases are now known to carry biallelic MUTYH pathogenic variants, although even here, the lower the adenoma count the lower the variant likelihood.[237]
Another study evaluated 152 patients with 3 to 100 adenomas and another 107 APCpathogenic variant–negative patients with a “classic” FAP polyp burden for evidence of MUTYH pathogenic variants.[140] Six patients with multiple adenomas and eight with a classic FAP burden had biallelic MUTYH pathogenic variants. The authors concluded that a cut-point of about 15 adenomas was a threshold above which MUTYH testing was reasonable, and many insurance companies in the United States have adopted a policy based on this cumulative adenoma count. Similar rates for MUTYH biallelic pathogenic variants were found by others using 20 adenomas as the threshold for considering testing.[237]
Pathogenic variants in related DNA polymerase genes POLE and POLD1 have been described in families with oligopolyposis and endometrial cancer.[238,239] An elegant approach was employed using whole-genome sequencing in 15 selected patients with more than ten adenomas before age 60 years. Several had a close relative with at least five adenomas who could also have whole-genome sequencing performed. All tested patients had CRC or a first-degree relative (FDR) with CRC. All had negative APC, MUTYH, and MMR gene pathogenic variant test results. No variants were found to be in common among the evaluated families. In one family, however, linkage had established shared regions, in which one shared variant was found (POLE p.Leu424Val; c.1270C>G), with a predicted major derangement in protein structure and function. In a validation phase, nearly 4,000 affected cases enriched for the presence of multiple adenomas were tested for this variant and compared with nearly 7,000 controls. In this exercise, 12 additional unrelated cases were found to have the L424V variant, with none of the controls having the variant. In the affected families, inheritance of multiple-adenoma risk appeared to be autosomal dominant. Somatic variants in tumors were generally consistent with the otherwise typical chromosome instability pathway, as opposed to MSI or CpG island methylator phenotype (CIMP). No extracolonic manifestations were seen.
A similar approach, whole-genome testing for shared variants, with further “filtering” by linkage analysis identified a variant in the POLD1 gene (p.Ser478Asn; c.1433G>A). This S478N variant was identified in two of the originally evaluated families, suggesting evidence of common ancestry. The validation exercise showed one patient with polyps with the variant but no controls with the variant. Somatic variant patterns were similar to the POLE variant. Several cases of early-onset endometrial cancer were seen. The mechanism underlying adenoma and carcinoma formation resulting from the POLE L424V variant appeared to be a decrease in the fidelity of replication-associated polymerase proofreading. This in turn appeared to lead to variants related to base substitution. A subsequent study confirmed that POLE pathogenic variants are a rare cause of oligopolyposis and early-onset CRC.[240] All individuals in this study were negative for germline pathogenic variants in APC, MUTYH, and the MMR genes. The POLE variant L424V was found in 3 of 485 index cases with colorectal polyposis and early-onset CRC. Tumors were MSI and deficient of one or more MMR proteins in two of three index cases. Somatic variants in MMR genes, possibly the result of hypermutability secondary to POLE deficiency, were detected in these two cases.
The study authors recommend consideration of POLE and POLD1 testing in patients with multiple or large adenomas in whom alternative pathogenic variant testing is uninformative and surveillance akin to that afforded patients with Lynch syndrome or MAP.[238,239] POLE and POLD1 pathogenic variant testing is being incorporated into the new multiple-gene (panel) tests for CRC susceptibility offered commercially.
A majority of patients with oligopolyposis involving adenomas are currently not found to have an underlying predisposition when evaluated for pathogenic variants in known predisposition genes. Such cases are generally managed as if they are at an increased risk of recurrent adenomas even when the colon can be “cleared” of polyps endoscopically.
Oligopolyposis caused by juvenile polyposis syndrome (JPS) or PJS can be distinguished from adenomatous polyposis on simple endoscopic and histologic grounds. Serrated polyposis can present in highly variable fashion. The World Health Organization (WHO) criteria for serrated polyposis (=5 serrated polyps proximal to sigmoid with 2 =1 cm, or any number of polyps proximal to sigmoid if there is a relative with serrated polyposis, or >20 serrated polyps anywhere in the colon) have never been validated. Furthermore, no genetic basis has been established, even in the uncommon familial cases. But cases of oligopolyposis of the serrated variety can initially be challenging to distinguish from oligoadenomatosis, particularly when there is an admixture of adenomas. Consequently, such patients are increasingly being referred for genetic counseling and for consideration of genetic testing. Occasional cases of MUTYH biallelic pathogenic variants have been found in patients with at least some features of serrated polyposis and serrated polyps can be seen in Lynch syndrome. Generally though, the genetic workup of serrated polyposis is unrewarding.[241-245]
Hereditary mixed polyposis, characterized by histology that often includes adenomatous and hyperplastic polyps, has been associated with GREM1 pathogenic variants in a small number of Ashkenazi Jewish families. Polyp number in this syndrome is highly variable but is often in the spectrum consistent with oligopolyposis. (Refer to the Hereditary mixed polyposis syndrome section of this summary for more information.)
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