Genetics of Colorectal Cancer (PDQ®) 6/6 —Health Professional Version - National Cancer Institute

Genetics of Colorectal Cancer (PDQ®)—Health Professional Version - National Cancer Institute

Genetics of Colorectal Cancer (PDQ®)–Health Professional Version

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 criteriaExit Disclaimer for Cowden syndrome, can be found in the NCCN and ACMG guidelines.[444,568] Additionally, a predictive modelExit Disclaimer 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.

Table 15. Cancer Risk in Individuals with Germline PTEN Pathogenic Variantsa

Cancer	Age-Adjusted SIR (95% CI)	Age-Related Penetrance Estimates
CI = confidence interval; SIR = standardized incidence ratio.
aAdapted from Tan et al.[570]
bOther historical studies have suggested a lower lifetime risk of breast cancer, in the range of 25%–50%.[567] (Refer to the PTEN hamartoma tumor syndromes [including Cowden syndrome] section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information.)
Breast	25.4 (19.8–32.0)	85% starting around age 30 yb
Colorectal	10.3 (5.6–17.4)	9% starting around age 40 y
Endometrial	42.9 (28.1–62.8)	28% starting around age 25 y
Kidney	30.6 (17.8–49.4)	34% starting around age 40 y
Melanoma	8.5 (4.1–15.6)	6% with earliest age of onset at 3 y
Thyroid	51.1 (38.1–67.1)	35% at birth and throughout life

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.

Table 16. Cumulative Cancer Risks in Peutz-Jeghers Syndrome Up To Specified Agea

Site	Age (y)	Cumulative Risk (%)b	Reference(s)
GI = gastrointestinal.
aReprinted with permission from Macmillan Publishers Ltd: Gastroenterology [583], copyright 2010.
bAll cumulative risks were increased compared with the general population (P < .05), with the exception of cervix and testes.
cGI cancers include colorectal, small intestinal, gastric, esophageal, and pancreatic.
dWesterman et al.: GI cancer does not include pancreatic cancer.[586]
eDid not include adenoma malignum of the cervix or Sertoli cell tumors of the testes.
Any cancer	60–70	37–93	[8,580-582,586,587]
GI cancerc,d	60–70	38–66	[8,582,586,587]
Gynecological cancer	60–70	13–18	[8,582]
Per origin
Stomach	65	29	[581]
Small bowel	65	13	[581]
Colorectum	65	39	[8,581]
Pancreas	65–70	11–36	[8,581]
Lung	65–70	7–17	[8,581,582]
Breast	60–70	32–54	[8,581,582]
Uterus	65	9	[581]
Ovary	65	21	[581]
Cervixe	65	10	[581]
Testese	65	9	[581]

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.

Juvenile polyposis syndrome (JPS)

JPS is a genetically heterogeneous, rare, childhood- to early adult-onset, autosomal dominant disease that presents characteristically as hamartomatous polyposis throughout the GI tract, although colorectal polyps predominate.[594] JPS can present with diarrhea, GI tract hemorrhage, protein-losing enteropathy, and prolapsing polyps.[594-596] JPS is defined by the presence of a specific type of hamartomatous polyp called a juvenile polyp, often in the setting of a family history of JPS. The diagnosis of a juvenile polyp is based on its histologic appearance, rather than age at onset. Solitary juvenile polyps of the colon or rectum are seen sporadically in infants and young children and do not imply a diagnosis of JPS. A clinical diagnosis of JPS is met by individuals fulfilling one or more of the following criteria:[597]

1. More than five juvenile polyps of the colon or rectum.
2. Juvenile polyps in other parts of the GI tract.
3. Any number of juvenile polyps and a positive family history of JPS.

JPS is caused by germline pathogenic variants in the SMAD4 gene, also known as MADH4/DPC4, at chromosome 18q21 [598] in approximately 15% to 60% of cases,[594] and by pathogenic variants in the gene encoding the bone morphogenic protein receptor 1A(BMPR1A) residing on chromosome band 10q22 in approximately 25% to 40% of cases.[599,600] Because pathogenic variants in SMAD4 and BMPR1A are known to account for juvenile polyposis, clinicians have referred young patients with fewer than five polyps for genetic testing. A study conducted on 77 patients with a total of 84 polyps found that the yield of genetic testing in patients with a limited number of polyps is minimal; of the germline variants detected, none were classified as definitely pathogenic or likely pathogenic.[601]

Genotype/phenotype correlations suggest SMAD4 variants may be associated with a greater risk of severe gastric polyposis [602] and features of hereditary hemorrhagic telangiectasia (HHT) (refer to the features of HHT below).[594] The lifetime risk of CRC in JPS has been reported to be 39%.[603] There appears to be an increased risk of gastric cancer, albeit much lower than the risk of CRC.[594] Cardiac valvular abnormalities were present in 12% of individuals with JPS who were followed through a single-institution–based polyposis registry,[594] and all those with identifiable pathogenic variants had SMAD4 variants.

JPS patients may also have signs and symptoms of HHT, such as arteriovenous malformations, mucocutaneous telangiectasias, digital clubbing, osteoarthropathy, hepatic arteriovenous malformations, and cerebellar cavernous hemangioma, suggesting that the two syndromes overlap.[604] Most HHT patients will have a pathogenic variant in the activin receptor-like kinase 1 (ALK1) gene or in the endoglin (ENG) gene, but SMAD4pathogenic variants have also been reported, although they are quite rare (approximately 1%–2% of patients with HHT).[605] In one series, 3 of 30 patients (10%) with HHT without a clinical diagnosis of JPS were found to have germline variants in SMAD4.[606] Conversely, features of HHT were noted in 21% to 22% of carriers of SMAD4 pathogenic variants in two studies of individuals with a clinical diagnosis of JPS.[594,607] In a study of 21 carriers of SMAD4 pathogenic variants from nine JPS families, 81% (17 of 21) of patients had HHT manifestations.[608] The high prevalence in this study may have been a result of the inclusion of several relatives from a single family and the inclusion of several families with the same pathogenic variant.[608]

Surveillance for HHT has been suggested in JPS patients with germline SMAD4 pathogenic variants.[594,608] On the other hand, patients with HHT without germline variants in ALK1or ENG may be considered for SMAD4 germline genetic testing; the GI tract should be evaluated if a SMAD4 germline pathogenic variant is confirmed.[609] (Refer to Table 18, Published Recommendations for Diagnosis and Surveillance of JPS, for more information.)

A severe form of JPS, in which polyposis develops in the first few years of life, is referred to as JPS of infancy. JPS of infancy is often caused by microdeletions of chromosome 10q22-23, a region that includes BMPR1A and PTEN. (Refer to the PTEN hamartoma tumor syndromes [including Cowden syndrome] section of this summary for more information about PTEN.) The phenotype often includes features such as macrocephaly and developmental delay, possibly as a result of loss of PTEN function.[610] Recurrent GI bleeding, diarrhea, exudative enteropathy, in addition to associated developmental delay, are associated with a very high rate of morbidity and mortality in these infants, thereby limiting the heritability of such cases.[610]

Juvenile polyposis gene(s)

JPS is caused by germline pathogenic variants in the SMAD4 gene in approximately 15% to 60% of cases, and to pathogenic variants in BMPR1A in approximately 25% to 40% of cases.[594,599,600] The large variability in variant frequency likely reflects the relatively small number of patients reported in individual studies. A subset of individuals meeting clinical criteria for JPS will not have an identified pathogenic variant in either SMAD4 or BMPR1A.

SMAD4 encodes a protein that is a mediator of the transforming growth factor (TGF)-beta signaling pathway, which mediates growth inhibitory signals from the cell surface to the nucleus. Germline pathogenic variants in SMAD4 predispose individuals to forming juvenile polyps and cancer,[598] and germline variants have been found in 6 of 11 exons. Most variants are unique, but several recurrent pathogenic variants have been identified in multiple independent families.[607,611]

BMPR1A is a serine-threonine kinase type I receptor of the TGF-beta superfamily that, when activated, leads to phosphorylation of SMAD4. The BMPR1A gene was first identified by linkage analysis in families with JPS who did not have identifiable pathogenic variants in SMAD4. Variants in BMPR1A include nonsense, frameshift, missense, and splice-site variants.[599] Large genomic deletions detected by MLPA have been reported in both BMPR1A and SMAD4 in patients with JPS.[607,611] Rare JPS families have demonstrated variants in the ENG and PTEN genes, but these have not been confirmed in other studies.[612,613]

CHEK2

Several studies initially suggested that a subset of families with hereditary breast and colon cancers may have a cancer family syndrome caused by a pathogenic variant in the CHEK2 gene.[614-616] However, subsequent studies have suggested that CHEK2 variants are associated with only a modest increase in CRC risk (i.e., low penetrance). One large study showed that truncating variants in CHEK2 were not significantly associated with CRC; however, a specific missense pathogenic variant (I157T) was associated with modest increased risk (OR, 1.5; 95% CI, 1.2–3.0) of CRC.[617]

Similar results were obtained in another study conducted in Poland.[618] In this study, 463 probands from Lynch syndrome and Lynch syndrome–related families and 5,496 controls were genotyped for four CHEK2 pathogenic variants, including I157T. The missense I157T allele was associated with Lynch syndrome–related cancer only for MMR variant-negative cases (OR, 2.1; 95% CI, 1.4–3.1). There was no association found with the truncating variants. Further studies are needed to confirm this finding and to determine whether they are related to FCCX.

(Refer to the CHEK2 section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information.)

Hereditary mixed polyposis syndrome (HMPS)

HMPS is a rare cancer family syndrome characterized by the development of a variety of colon polyp types, including serrated adenomas, atypical juvenile polyps and adenomas, and colon adenocarcinoma. Although initially mapped to a locus between 6q16-q21, the HMPS locus is now believed to map to 15q13-q14.[619,620] While there is considerable phenotypic overlap between JPS and HMPS, one large family has been linked to a locus on chromosome 15, raising the possibility that this may be a distinct disorder. Linkage analysis of Ashkenazi Jewish families with HMPS revealed shared haplotypes on chromosome 15q13.3.[621] An unusual heterozygous 40kb single-copy duplication was discovered upstream of gremlin 1 (GREM1) that segregated perfectly with individuals and family members with HMPS and not with unaffected controls.[621] The presence of this duplication in HMPS individuals was associated with increased expression of GREM1transcript levels in the normal intestinal epithelium.[621] GREM1 is a bone morphogenetic protein (BMP) antagonist and thus theoretically would promote the stem cell phenotype in the intestine. Germline variants leading to defective BMP signaling also underlie JPS, thus drawing a potential link between HMPS and JPS.

Although exceedingly rare, GREM1 pathogenic variants have been described in several additional families of Ashkenazi Jewish ancestry, with varying clinical presentations. Although polyposis appears to be a unifying feature in most families, there is a high degree of variability with respect to polyp number, histology, and age of onset. In addition, extracolonic malignancies have been described in several pathogenic variant carriers, although the small number of affected individuals limits the ability to definitively demonstrate a causal link to the GREM1 pathogenic variant. On the basis of relatively limited data, it is reasonable to consider GREM1-variant analysis in Ashkenazi Jewish families presenting with unexplained polyposis and/or familial CRC.[622] In such families, comprehensive variant analysis that includes testing for duplications in noncoding regions of GREM1 is necessary.

Serrated polyposis syndrome (SPS)/Hyperplastic polyposis syndrome (HPS)

Isolated and multiple hyperplastic polyps (HPs) (typically white, flat, and small) are common in the general population, and their presence does not suggest an underlying genetic disorder. Historically, the clinical diagnosis of SPS, as defined by WHO, must satisfy one of the following criteria:

• At least five histologically diagnosed HP occurring proximal to the sigmoid colon (of which at least two are >10 mm in diameter).
• One HP occurring proximal to the sigmoid colon in an individual who has at least one FDR with hyperplastic polyposis.
• More than 30 HPs distributed throughout the colon.[623]

[Note: Other groups have included serrated adenomas as part of the revised clinical criteria for SPS.[624]]

Although the vast majority of cases of SPS lack a family history of HPs, approximately half of the SPS cases have a positive family history of CRC.[625,626] Several studies show that the prevalence of colorectal adenocarcinoma in patients with formally defined criteria for SPS is 50% or more.[627-634] One study, using a variation of the WHO criteria for SPS (SPS was defined as at least five histologically diagnosed HPs and/or sessile serrated adenomas (SSAs) proximal to the sigmoid colon, of which two are greater than 10 mm in diameter, or more than 20 HPs and/or SSAs distributed throughout the colon), found an RR for CRC in 347 FDRs (41% male) from 57 pedigrees of 5.4 (95% CI, 3.7–7.8).[624]

The WHO criteria are based on expert opinion; and, there is no known susceptibility gene or genomic region that has been reproducibly linked to this disorder, so genetic diagnosis is not possible. Two studies have reported potentially causative germline variants in SPS individuals.[625,635]

In a study of 38 patients with more than 20 HPs, a large (>1 cm) HP, or HPs in the proximal colon, molecular alterations were sought in the base-excision repair genes MBD4 and MUTYH.[625] One patient was found to have biallelic MUTYH pathogenic variants, and thus was diagnosed with MUTYH-associated polyposis. No pathogenic variants were detected in MBD4 among 27 patients tested. However, six patients had single nucleotide polymorphisms of uncertain significance. Only two patients had a known family history of SPS, and ten of the 38 patients developed CRC. This series presumably included patients with sporadic HPs mixed in with other patients who may have SPS.

In a cohort of 40 SPS patients, defined as having more than five HPs or more than three HPs, two of which were larger than 1 cm in diameter, one patient was found to have a germline variant in the EPHB2 gene (D861N).[635] The patient had serrated adenomas and more than 100 HPs in her colon at age 58 years, and her mother died of colon cancer at age 36 years. EPHB2 germline variants were not found in 100 additional patients with a personal history of CRC or in 200 population-matched healthy control patients.

Far more is known about the somatic molecular genetic alterations found in the colonic tumors occurring in SPS patients. In a study of patients with either more than 20 HPs per colon, more than four HPs larger than 1 cm in diameter, or multiple (5–10) HPs per colon, a specific somatic BRAF variant (V600E) was found in polyp tissue.[636] Fifty percent of HPs (20 of 40) from these patients demonstrated the V600E BRAF pathogenic variant. The HPs from these patients also demonstrated significantly higher CpG island methylation phenotypes (CIMP-high), and fewer KRAS variants than left-sided sporadic HPs. In a previous study from this group, HPs from patients with SPS showed a loss of chromosome 1p in 21% (16 of 76) versus 0% in HPs from patients with large HPs (>1 cm), or only five to ten HPs.[628]

Many of the genetic and histological alterations found in HPs of patients with SPS are common with the CIMP pathway of colorectal adenocarcinoma. (Refer to the CIMP and the serrated polyposis pathway section in the Introduction section of this summary for more information.)

Interventions for rare colon cancer syndromes

Individuals with PJS and JPS are at increased risk of CRC and extracolonic cancers. Because these syndromes are rare, there have been no evidence-based surveillance recommendations. Because of the markedly increased risk of colorectal and other cancers in these syndromes, a number of guidelines have been published based on retrospective and case series (i.e., based exclusively on expert opinion).[148,637-640] Clinical judgment must be used in making screening recommendations based on published guidelines.

Table 17. Published Recommendations for Diagnosis and Surveillance of Peutz-Jeghers Syndrome (PJS)

ENLARGE

Organization	STK11 Gene Testing Recommendeda	Age Colon Screening Initiated	Frequency	Method	Extracolonic Screening Recommendations	Comment
ACPGBI = Association of Coloproctology of Great Britain and Ireland; BE = barium enema; C = colonoscopy; FS = flexible sigmoidoscopy; NCCN = National Comprehensive Cancer Network.
a STK11 testing includes sequencing followed by analysis for deletions (e.g., multiplex ligation-dependent probe amplification), if no variant found by sequencing.
bLung cancer risk is increased, but there are no recommendations beyond smoking cessation and heightened awareness of symptoms.
(Refer to the Other High-Penetrance Syndromes Associated With Breast and/or Gynecologic Cancer section in the PDQ summary on the Genetics of Breast and Gynecologic Cancers for more information about PJS and the risk of breast and ovarian cancer.)
Johns Hopkins (2006) [639]	Yes, at age 8 y	18 y	2–3 y	C	Breast, gynecologic (cervix, ovaries, uterus), pancreas, small intestine, stomach, testes
Johns Hopkins (2007) [640]	Yes, age not specified	Late teens or at onset of symptoms	3 y	C	Breast, gynecologic (cervix, ovaries, uterus), pancreas, small intestine, stomach, testes	Genetic testing in the late teens or at onset of symptoms.
ACPGBIExit Disclaimer(2007)		18 y	3 y	C or FS + BE	No mention of extracolonic screening	No recommendation for genetic testing; need to consider STK11/LKB1testing.
Cleveland Clinic (2007) [641]		18 y	3 y	C	Breast, gynecologic (cervix, ovaries), pancreas, small intestine, stomach, testes
Erasmus University Medical Center (2010) [583]		25–30 y		C	Breast, gynecologic (cervix, ovaries, uterus), pancreas, small intestine, stomach
NCCN (2018) [95]	No specific recommendation	Late teens	2–3 y	C	Breast, gynecologic (cervix, ovaries, uterus), lungb, pancreas, small intestine, stomach, testes	Refer to specialized team.

Level of evidence: 5

Table 18. Published Recommendations for Diagnosis and Surveillance of Juvenile Polyposis Syndrome (JPS)

ENLARGE

Organization/ Author	SMAD4 / BMPR1A Testing Recommendeda	Age Screening Initiated	Frequency	Method	Comment
ACPGBI = Association of Coloproctology of Great Britain and Ireland; BE = barium enema; C = colonoscopy; CRC = colorectal cancer; EGD = esophagogastroduodenoscopy; FS = flexible sigmoidoscopy; GI = gastrointestinal; HHT = hereditary hemorrhagic telangiectasia; NCCN = National Comprehensive Cancer Network.
a SMAD4/BMPR1A testing includes sequencing followed by analysis for deletions (e.g., multiplex ligation-dependent probe amplification), if no variant found by sequencing.[611]
bYounger, if patient has presented with symptoms.
ACPGBIExit Disclaimer(2007)		15–18 yb	1–2 y	C or FS + BE	Surveillance for gene carriers and affected until age 70 y and discussion of prophylactic surgery.
Cleveland Clinic (2007) [641]		15 y	3 y	C, EGD	Some families with SMAD4pathogenic variant also have HHT; these individuals may need to be screened for HHT.
Johns Hopkins (2007) [640]	Yes, genetic testing preferred over C	15 y or at onset of symptoms	Yearly until polyp free then every 2–3 y	C	Prophylactic surgery if >50–100 polyps, unable to manage endoscopically, severe GI bleeding, JPS with adenomatous changes, strong family history of CRC.
St. Mark's (2012) [594]	Yes, genetic testing at age 4 y	12 y	1–3 y based on severity	C, EGD	Consider HHT workup.
NCCN (2018) [95]	Yes	~15 y	2–3 y or 1 y if polyps are found	C	Refer to specialized team. In families without an identified pathogenic variant, consider substituting endoscopy every 5 y beginning at age 20 y and every 10 y beginning at age 40 y in patients in whom no polyps are found.

Level of evidence: 5

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599. Howe JR, Bair JL, Sayed MG, et al.: Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet 28 (2): 184-7, 2001. [PUBMED Abstract]
600. Zhou XP, Woodford-Richens K, Lehtonen R, et al.: Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes. Am J Hum Genet 69 (4): 704-11, 2001. [PUBMED Abstract]
601. Jelsig AM, Brusgaard K, Hansen TP, et al.: Germline variants in Hamartomatous Polyposis Syndrome-associated genes from patients with one or few hamartomatous polyps. Scand J Gastroenterol 51 (9): 1118-25, 2016. [PUBMED Abstract]
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603. Brosens LA, van Hattem A, Hylind LM, et al.: Risk of colorectal cancer in juvenile polyposis. Gut 56 (7): 965-7, 2007. [PUBMED Abstract]
604. Gallione CJ, Repetto GM, Legius E, et al.: A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 363 (9412): 852-9, 2004. [PUBMED Abstract]
605. Lesca G, Burnichon N, Raux G, et al.: Distribution of ENG and ACVRL1 (ALK1) mutations in French HHT patients. Hum Mutat 27 (6): 598, 2006. [PUBMED Abstract]
606. Gallione CJ, Richards JA, Letteboer TG, et al.: SMAD4 mutations found in unselected HHT patients. J Med Genet 43 (10): 793-7, 2006. [PUBMED Abstract]
607. Aretz S, Stienen D, Uhlhaas S, et al.: High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome. J Med Genet 44 (11): 702-9, 2007. [PUBMED Abstract]
608. O'Malley M, LaGuardia L, Kalady MF, et al.: The prevalence of hereditary hemorrhagic telangiectasia in juvenile polyposis syndrome. Dis Colon Rectum 55 (8): 886-92, 2012. [PUBMED Abstract]
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610. Dahdaleh FS, Carr JC, Calva D, et al.: Juvenile polyposis and other intestinal polyposis syndromes with microdeletions of chromosome 10q22-23. Clin Genet 81 (2): 110-6, 2012. [PUBMED Abstract]
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612. van Hattem WA, Brosens LA, de Leng WW, et al.: Large genomic deletions of SMAD4, BMPR1A and PTEN in juvenile polyposis. Gut 57 (5): 623-7, 2008. [PUBMED Abstract]
613. Sweet K, Willis J, Zhou XP, et al.: Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. JAMA 294 (19): 2465-73, 2005. [PUBMED Abstract]
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615. Cybulski C, Górski B, Huzarski T, et al.: CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet 75 (6): 1131-5, 2004. [PUBMED Abstract]
616. de Jong MM, Nolte IM, Te Meerman GJ, et al.: Colorectal cancer and the CHEK2 1100delC mutation. Genes Chromosomes Cancer 43 (4): 377-82, 2005. [PUBMED Abstract]
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620. Thomas HJ, Whitelaw SC, Cottrell SE, et al.: Genetic mapping of hereditary mixed polyposis syndrome to chromosome 6q. Am J Hum Genet 58 (4): 770-6, 1996. [PUBMED Abstract]
621. Jaeger E, Leedham S, Lewis A, et al.: Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1. Nat Genet 44 (6): 699-703, 2012. [PUBMED Abstract]
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Psychosocial Issues in Hereditary Colon Cancer Syndromes

In This Section

• Introduction
• Psychosocial Issues in Lynch Syndrome
  • Participation in genetic counseling and testing for Lynch syndrome
  • Psychological impact of participating in genetic counseling and testing for Lynch syndrome
  • Psychosocial aspects of screening and risk reduction interventions for Lynch syndrome
• Psychosocial Issues in Familial Adenomatous Polyposis (FAP)
  • Participation in genetic counseling and testing for FAP
  • Psychological impact of participating in genetic counseling and testing for FAP
  • Psychosocial aspects of screening and risk reduction interventions for FAP
• Reproductive Considerations in Individuals With Lynch Syndrome or FAP
  • Assisted reproductive technology (ART)

Introduction

Psychosocial research in cancer genetic counseling and testing focuses on the interest in testing among populations at varying levels of disease risk, psychological outcomes, interpersonal and familial effects, and cultural and community reactions. The research also identifies behavioral factors that encourage or impede surveillance and other health behaviors. Data resulting from psychosocial research can guide clinician interactions with patients and may include the following:

• Decision-making about risk-reduction interventions, risk assessment, and genetic testing.
• Evaluation of psychosocial interventions to reduce distress and/or other negative sequelae related to risk notification of genetic testing.
• Resolution of ethical concerns.

This section of the summary will focus on psychosocial aspects of genetic counseling and testing for Lynch syndrome, familial adenomatous polyposis (FAP), and Peutz-Jeghers syndrome (PJS), including issues surrounding medical screening, risk-reducing surgery, and chemoprevention for these syndromes.

Psychosocial Issues in Lynch Syndrome

Participation in genetic counseling and testing for Lynch syndrome

Early research on genetic counseling/testing uptake

Early studies that evaluated the uptake of genetic counseling and testing focused on selected, high-risk research populations, including colorectal cancer (CRC) patients and unaffected family members identified at high risk of CRC largely based on family history. The participants were recruited mainly from clinical settings and familial colon cancer registries. Most studies recruited index cancer cases, typically CRCs, specifically to offer genetic counseling and germline testing for mismatch repair (MMR) variants; these were frequently offered as free services.[1-9] Counseling and testing were similarly offered to relatives of index cases with pathogenic variants. A review that summarized these early studies reported a wide range of testing uptake rates, from 14% to 75%, and included uptake among both index cases and at-risk relatives who were offered testing.[10] The review indicated that the primary reasons for undergoing genetic testing included a desire to learn about children’s risk and to learn about early detection and screening needs, as well as a reduction in uncertainty. Reasons for declining testing included cost, insurance discrimination concerns, potential adverse emotional effects for oneself or one’s family, low anticipated benefit, and lack of time.

Uptake of genetic counseling and germline testing following universal tumor screening for microsatellite instability (MSI) and/or immunohistochemistry (IHC)

While these early studies of genetic testing uptake offered preliminary insight regarding why individuals may or may not be motivated to have testing, the process for offering genetic counseling and testing differed from what has evolved into current clinical practice. Clinical practice relies less solely on family history to identify individuals who may benefit from testing, and instead utilizes universal molecular diagnostic testing of CRC and endometrial cancer tumors in newly diagnosed patients using MSI and/or IHC as an initial screen for Lynch syndrome. (Refer to the Universal tumor testing to screen for Lynch syndrome section of this summary for more information.)

While universal MSI/IHC screening is increasingly being adopted to identify newly diagnosed patients who may have a germline variant, an important implication is that not all individuals who may be appropriate for germline testing follow through with recommended genetic counseling and testing services. Two reports from a single institution found that 20% and 13% of CRC and endometrial cancer index cases, respectively, with abnormal IHC results followed through with germline variant testing for Lynch syndrome.[11,12] These studies did not solicit reasons for follow through with genetic counseling and testing. However, it has been suggested that higher levels of patient completion of genetic testing after abnormal MSI/IHC results may be associated with having genetic counselors involved in this process to disclose screen-positive results, provide counseling after MSI/IHC testing, or facilitate referrals.[13]

In a study of 145 patients with CRC in the Kaiser Permanente Northwest health care system who were surveyed before receiving their MSI results, most patients had a positive attitude toward MSI/IHC screening.[14] The majority (84.8%) endorsed six or more benefits of MSI/IHC screening; however, 89.4% also endorsed fewer than four potential barriers, primarily the cost of additional testing and surveillance. Patients with stronger family histories of cancer were more likely to cite fewer barriers of MSI/IHC screening. Patients also experienced minimal distress associated with the screening, with 77.2% of participants having a score of zero (indicating no distress).

Education regarding family history and cancer risk and encouragement to have testing from health care providers may facilitate uptake of genetic counseling and testing. A small (n = 19) qualitative study of newly diagnosed patients with CRC who met high-risk criteria for referral to cancer genetics risk assessment and counseling identified potential reasons why patients may not seek counseling as recommended. These reasons included incomplete knowledge of family cancer history and not realizing the relevance of family history to their personal cancer diagnosis; lack of a specific, direct physician’s recommendation for counseling; and viewing counseling as a lower priority than coping with the immediate demands of a new cancer diagnosis.[15] In a follow-up survey of 91 individuals in a randomized trial to promote colonoscopy screening in those at risk for Lynch syndrome, only 24% reported ever having discussed genetic testing with their physicians, and the most common barrier to undergoing testing was lack of advice to do so by a health care provider.[16]

Uptake of cascade screening by at-risk relatives

There is increasing adoption of universal screening of newly diagnosed tumors for Lynch syndrome in clinical practice. However, the clinical benefit and cost-effectiveness of this process have been attributed to uptake of cascade screening, or predictive testing among at-risk relatives of index cancer cases who are found to have a pathogenic germline variant. A systematic review evaluated the frequency and predictors of genetic testing uptake by first-degree relatives (FDRs) of index cases with Lynch syndrome.[17] Among four studies that were included in the review and reported uptake rates among FDRs, results showed that 34% to 52% of FDRs had undergone testing. Factors associated with testing uptake in relatives included age (<50 y), female sex, parenthood, employment status, level of education, participation in medical research, psychological factors (lack of depressive symptoms), and the number of relatives affected with cancer.

A large retrospective study of genetic testing uptake across three generations of Finnish families enrolled in a Lynch syndrome registry also found an incomplete uptake of predictive testing among at-risk relatives of individuals with pathogenic variants, and a decreasing uptake rate by generation.[18] Among 1,184 probands with a Lynch syndrome variant, 67%, 43%, and 24% of at-risk adult first-, second-, and third-generation relatives, respectively, had predictive testing. Among 539 first-generation Lynch syndrome variant carriers, 62% of their at-risk adult children underwent testing. In multivariate analysis, older age, family-specific variant (MLH1 and MSH2 vs. MSH6), being an only child or having a sibling with a pathogenic variant, and having a parent who adhered to colonoscopy surveillance were associated with predictive testing uptake. This study suggested that family-level factors such as predictive testing and screening behavior may influence predictive testing among at-risk relatives of individuals with Lynch syndrome–associated variants.

Published reports of interventions to increase uptake of cascade screening in Lynch syndrome families are limited. An Australian paper compared two approaches for informing at-risk relatives about pathogenic variants for hereditary cancers, including Lynch syndrome.[19] In this study, index cases from 33 kindreds who had undergone genetic testing provided consent for their clinicians to send detailed letters to at-risk relatives advising them about the identification of an inherited cancer predisposition in the family. Letters also included a recommendation to discuss the information with a physician or genetics specialist, and provided information about what a genetics evaluation comprised. Within the first 2 years of follow-up, 40% of first- and second-degree relativeshad had predictive genetic testing, were determined to be presumed noncarriers, or had undergone evaluation but declined genetic testing. The authors compared these findings with a cohort of 41 kindreds seen prior to the initiation of the clinician-generated letters, of whom variant-positive index cases had only been asked to advise relatives that genetic testing was available. In the earlier cohort, 23% of at-risk relatives had sought services to clarify their genetic risk status, which was significantly fewer compared with the group receiving clinician-generated letters (P = .001). Receipt of the letters did not generate concerns about a breach of privacy or autonomy.

Refer to the Ethical, Legal, and Social Implications section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for information about ethical concerns, including duty to warn.

Psychological impact of participating in genetic counseling and testing for Lynch syndrome

Studies have examined the psychological status of individuals before, during, and after genetic counseling and testing for Lynch syndrome. Some studies have included only persons with no personal history of any Lynch syndrome–associated cancers,[20-23] and others have included both CRC patients and cancer-unaffected persons who are at risk of having a Lynch syndrome pathogenic variant.[24-28] Cross-sectional evaluations of the psychosocial characteristics of individuals undergoing Lynch syndrome genetic counseling and testing have indicated that mean pretest scores of psychological functioning for most participants are within normal limits,[24-26] although one study comparing affected and unaffected individuals showed that affected individuals had greater distress and worry associated with Lynch syndrome.[29]

Several longitudinal studies have evaluated psychological outcomes before genetic counseling and testing for Lynch syndrome and at multiple time periods in the year after disclosure of test results. One study examined changes in anxiety based on personal cancer history, gender, and age (younger than 50 y vs. older than 50 y) before and 2 weeks after a pretest genetic-counseling session. Affected and unaffected female participants in both age groups and affected men older than 50 years showed significant decreases in anxiety over time. Unaffected men younger than 50 years maintained low levels of anxiety; however, affected men younger than 50 years showed no reductions in the anxiety levels reported at the time of pretest counseling.[30] A study that evaluated psychological distress 8 weeks postcounseling (before disclosure of test results) among both affected and unaffected individuals found a significant reduction in general anxiety, cancer worry, and distress.[29] In general, findings from studies within the time period immediately after disclosure of pathogenic variant status (e.g., 2 weeks to 1 month) suggested that carriers of mismatch repair (MMR) pathogenic variants may experience increased general distress,[22,27] cancer-specific distress,[20,21] or cancer worries [27] relative to their pretest measurements. Carriers often experienced significantly higher distress after disclosure of test results than do individuals who do not carry a pathogenic variant previously identified in the family (noncarrier).[20-22,27] However, in most cases, carriers’ distress levels subsided during the course of the year after disclosure [22,27] and did not differ from pretest distress levels at 1 year postdisclosure.[20,21] Findings from these studies also indicated that noncarriers experienced a reduction or no change in distress up to 1 year after results disclosure.[20-22,27] A study that included unaffected individuals and CRC patients found that distress levels among patients did not differ between carriers and individuals who received results that were uninformative or showed a variant of unknown significance at any point up to 1 year posttest and were similar compared with pretest distress levels.[28]

A limited number of studies have examined longer-term psychosocial outcomes after Lynch syndrome genetic counseling and testing.[20,31,32] Longitudinal studies that evaluated psychological distress before and after genetic testing found that long-term distress levels (measured at 3 or 7 years posttesting) among carriers and noncarriers of pathogenic variants were similar to distress levels at baseline.[20,32] with one exception: noncarriers’ cancer-specific distress scores in one study [20] showed a sustained decrease posttesting and were significantly lower than their baseline scores and with carriers’ scores at 1 year posttesting, with a similar trend observed at 3 years posttesting. In one study, carriers were more likely to be worried about CRC risk at 7 years posttesting; however, noncarriers who reported worry about CRC (i.e., “worried to some extent” or “very worried”) were more likely to doubt the validity of their test result than were noncarriers who reported no worry.[32] When asked about their satisfaction with the decision to have testing, the majority of carriers and noncarriers were extremely satisfied up to 7 years posttesting and indicated they would be willing to undergo testing again.[32]

Findings from some studies suggested that there may be subgroups of individuals at higher risk of psychological distress after disclosure of test results, including those who present with relatively higher scores on measures of general or cancer-specific distress before undergoing testing.[24-28,33] A study of CRC patients who had donated blood for Lynch syndrome testing found that higher levels of depressive symptoms and/or anxiety were found among women, younger persons, nonwhites, and those with less formal education and fewer and less satisfactory sources of social support.[24] A subgroup of individuals who showed higher levels of psychological distress and lower quality of life and social support were identified from the same population; in addition, this subgroup was more likely to worry about finding out that they were carriers of Lynch syndrome pathogenic variants and being able to cope with learning their test results.[25] In a follow-up report that evaluated psychological outcomes after the disclosure of test results among CRC patients and relatives at risk of having a Lynch syndrome pathogenic variant, a subgroup with the same psychosocial characteristics experienced higher levels of general distress and distress specific to the experience of having genetic testing within the year after disclosure, regardless of variant status. Nonwhites and those with lower education had higher levels of depression and anxiety scores at all times compared with whites and those with higher education, respectively.[27] Other studies have also found that a prior history of major or minor depression, higher pretest levels of cancer-specific distress, having a greater number of cancer-affected first-degree relatives, greater grief reactions, and greater emotional illness–related representations predicted higher levels of distress from 1 to 6 months after disclosure of test results.[28,33] While further research is needed in this area, case studies indicate that it is important to identify persons who may be at risk of experiencing psychiatric distress and to provide psychological support and follow-up throughout the genetic counseling and genetic testing process.[34]

Studies also have examined the effect of Lynch syndrome genetic counseling and testing on cancer risk comprehension. One study reported that nearly all carriers and noncarriers of pathogenic variants could accurately recall the test result 1 year after disclosure. More noncarriers than carriers correctly identified their risk of developing CRC at both 1 month and 1 year after result disclosure. Carriers of pathogenic variants who incorrectly identified their CRC risk were more likely to have had lower levels of pretest subjective risk perception compared with those who correctly identified their level of risk.[22] Another study reported that accuracy of estimating colorectal and endometrial cancer risk improved after disclosure of variant status in carriers and noncarriers.[23]