Although almost all gastrointestinal cancers develop from sporadic genomic events, approximately 5% arise from germline mutations in genes associated with cancer predisposition. The number of these genes continues to increase. Tumor phenotypes and family history provide the framework for identifying at-risk individuals. The diagnosis of a hereditary cancer syndrome has implications for management of patients and their families. Systematic approaches that integrate family history and molecular characterization of tumors and polyps facilitate identification of individuals with this genetic predisposition. This article summarizes diagnosis and management of hereditary cancer syndromes associated with gastrointestinal cancers.
Key points
- •
Although almost all gastrointestinal cancers develop as a consequence of sporadic genomic events, approximately 5% arise in the setting of germline mutations in genes known to be associated with cancer predisposition.
- •
The number of genes associated with heritable cancer syndromes continues to increase, and tumor phenotypes, along with family history, provide the framework for identifying individuals at risk.
- •
Making the diagnosis of a hereditary cancer syndrome has implications for management of patients with gastrointestinal neoplasia and for their family members.
- •
Systematic approaches that integrate family history and molecular characterization of tumors and polyps can facilitate identification of individuals with genetic predisposition to gastrointestinal cancer.
Genes and cancer
Like most other cancers, gastrointestinal neoplasms arise as a consequence of the deregulation of signaling pathways controlling cell survival and genome maintenance. In almost all tumors, genetic mutations that affect the function of genes involved in key cell regulatory functions (eg, tumor suppression and DNA repair) occur sporadically in individual cells as so-called somatic events. However, a small proportion of individuals harbor mutations in their germline DNA that predispose to the development of gastrointestinal neoplasms. Because epithelial cells of the digestive tract are among the most rapidly dividing cells in the human body, germline mutations in a variety of cancer genes can be associated with dramatic increases in risk for gastrointestinal tumors.
Identification of the various heritable syndromes associated with risk for gastrointestinal neoplasia has come about through meticulous study of hundreds of individuals belonging to cancer families. Categorization of clinical histories and tumor phenotypes has led to the identification of specific hereditary cancer syndromes and the germline DNA alterations corresponding to each ( Table 1 ). Personal and family history remains the primary components of clinical algorithms used for cancer risk stratification. However, variability in penetrance and expressivity associated with heritable gene mutations can make family history imprecise and approaches that integrate tumor histopathology and molecular phenotype with family history offer the opportunity to most effectively identify individuals with genetic predisposition to cancer. Because advances in genomic technologies promise to make tumor profiling routine as a strategy for selecting treatments, this information can also be used to identify individuals whose cancers arise as a consequence of germline mutations associated with cancer predisposition. The implementation of universal screening of colorectal cancer (CRC) for DNA mismatch repair (MMR) deficiency is effective not only in guiding oncologic therapies but also in identifying CRC patients affected with Lynch syndrome. Furthermore, there are additional histopathologic subtypes of gastrointestinal cancers (eg, signet ring cell gastric cancers, pancreatic cancers with somatic BRCA1 or BRCA2 mutations) for which genetic evaluation should be considered.
| Syndrome | Genes | Estimated Carrier Frequency (General Population) | Lifetime Cancer Risks | ||||||
|---|---|---|---|---|---|---|---|---|---|
| CRC | Gastric | Small Bowel | Pancreatic | Breast | Ovarian | Endometrial | |||
| Lynch Syndrome | MLH1 , MSH2 , MSH6 , PMS2 , EPCAM | 1 in 280–350 | e | b | — | a | a | b | d |
| Familial Adenomatous Polyposis | APC | 1 in 1000 | e | a | b | — | — | — | — |
| MUTYH -Associated Polyposis | MUTYH | 1 in 100 | c | — | — | — | — | — | — |
| Li Fraumeni Syndrome | P53 | — | b | b | a | c | — | — | |
| Juvenile Polyposis | SMAD4 BMPR1A | — | c | b | a | — | — | — | |
| Peutz-Jeghers Syndrome | STK11 | — | c | b | a | c | d | — | — |
| Cowden or PTEN Hamartoma Tumor Syndrome | PTEN | — | b | — | — | — | c | — | c |
| Hereditary Diffuse Gastric Cancer | CDH1 | — | a , b | e | — | — | d | — | — |
| Hereditary Breast Ovarian Cancer Syndrome | BRCA1 BRCA2 | — | — | — | — | a | e | c | — |
| PALB2 | TBD | c | a | ||||||
| Familial Atypical Multiple Mole Melanoma | CDKN2A | — | — | — | — | b | — | — | — |
This article presents an overview of heritable cancer syndromes associated with risk for gastrointestinal cancers, and outlines strategies for diagnosis and management of at-risk individuals.
Genes and cancer
Like most other cancers, gastrointestinal neoplasms arise as a consequence of the deregulation of signaling pathways controlling cell survival and genome maintenance. In almost all tumors, genetic mutations that affect the function of genes involved in key cell regulatory functions (eg, tumor suppression and DNA repair) occur sporadically in individual cells as so-called somatic events. However, a small proportion of individuals harbor mutations in their germline DNA that predispose to the development of gastrointestinal neoplasms. Because epithelial cells of the digestive tract are among the most rapidly dividing cells in the human body, germline mutations in a variety of cancer genes can be associated with dramatic increases in risk for gastrointestinal tumors.
Identification of the various heritable syndromes associated with risk for gastrointestinal neoplasia has come about through meticulous study of hundreds of individuals belonging to cancer families. Categorization of clinical histories and tumor phenotypes has led to the identification of specific hereditary cancer syndromes and the germline DNA alterations corresponding to each ( Table 1 ). Personal and family history remains the primary components of clinical algorithms used for cancer risk stratification. However, variability in penetrance and expressivity associated with heritable gene mutations can make family history imprecise and approaches that integrate tumor histopathology and molecular phenotype with family history offer the opportunity to most effectively identify individuals with genetic predisposition to cancer. Because advances in genomic technologies promise to make tumor profiling routine as a strategy for selecting treatments, this information can also be used to identify individuals whose cancers arise as a consequence of germline mutations associated with cancer predisposition. The implementation of universal screening of colorectal cancer (CRC) for DNA mismatch repair (MMR) deficiency is effective not only in guiding oncologic therapies but also in identifying CRC patients affected with Lynch syndrome. Furthermore, there are additional histopathologic subtypes of gastrointestinal cancers (eg, signet ring cell gastric cancers, pancreatic cancers with somatic BRCA1 or BRCA2 mutations) for which genetic evaluation should be considered.
| Syndrome | Genes | Estimated Carrier Frequency (General Population) | Lifetime Cancer Risks | ||||||
|---|---|---|---|---|---|---|---|---|---|
| CRC | Gastric | Small Bowel | Pancreatic | Breast | Ovarian | Endometrial | |||
| Lynch Syndrome | MLH1 , MSH2 , MSH6 , PMS2 , EPCAM | 1 in 280–350 | e | b | — | a | a | b | d |
| Familial Adenomatous Polyposis | APC | 1 in 1000 | e | a | b | — | — | — | — |
| MUTYH -Associated Polyposis | MUTYH | 1 in 100 | c | — | — | — | — | — | — |
| Li Fraumeni Syndrome | P53 | — | b | b | a | c | — | — | |
| Juvenile Polyposis | SMAD4 BMPR1A | — | c | b | a | — | — | — | |
| Peutz-Jeghers Syndrome | STK11 | — | c | b | a | c | d | — | — |
| Cowden or PTEN Hamartoma Tumor Syndrome | PTEN | — | b | — | — | — | c | — | c |
| Hereditary Diffuse Gastric Cancer | CDH1 | — | a , b | e | — | — | d | — | — |
| Hereditary Breast Ovarian Cancer Syndrome | BRCA1 BRCA2 | — | — | — | — | a | e | c | — |
| PALB2 | TBD | c | a | ||||||
| Familial Atypical Multiple Mole Melanoma | CDKN2A | — | — | — | — | b | — | — | — |
This article presents an overview of heritable cancer syndromes associated with risk for gastrointestinal cancers, and outlines strategies for diagnosis and management of at-risk individuals.
Colorectal cancer
CRC is the third most common cancer affecting men and women in the United States, with the average individual having a lifetime risk of 5%. Family history is among the strongest predictors of risk for CRC; consequently, current algorithms for CRC screening and surveillance rely heavily on family history of CRC to determine age to begin screening and surveillance intervals. Approximately 1 in 3 individuals diagnosed with CRC reports a diagnosis of CRC in a close relative and, on average, 1 in 20 CRC patients carries a germline mutation associated with a heritable cancer syndrome. The National Comprehensive Cancer Network (NCCN) criteria for identifying individuals for whom genetic referral should be considered for evaluation for genetic syndromes associated with CRC risk are presented in Box 1 . Although routine implementation of CRC screening among individuals age 50 years and older has resulted in overall reductions of CRC-related incidence and mortality, incidence of CRC among individuals age less than 50 years continues to rise by 1.5% per year. The prevalence of germline mutations associated with cancer predisposition is higher among individuals diagnosed at young ages and studies suggest many of these do not meet the classic diagnostic criteria for the associated syndrome. Several hereditary cancer syndromes confer lifetime risks of CRC that exceed 50% in the absence of medical or surgical intervention, justifying the importance of presymptomatic diagnosis for these high-risk individuals.
- 1.
Individuals meeting the revised Bethesda guidelines
- 2.
Individuals meeting the Amsterdam criteria
- 3.
Individuals with greater than 20 colorectal adenomas
- 4.
Individuals with multiple gastrointestinal hamartomatous polyps or serrated polyposis
- 5.
Individuals from a family with a known hereditary syndrome associated with CRC with or without a known mutation
- 6.
Individuals with desmoid tumor, cribriform-morular variant of papillary thyroid cancer, or hepatoblastoma
Family history has long been a cornerstone for CRC risk assessment and identification of individuals at risk for hereditary CRC. The Amsterdam criteria (≥3 relatives diagnosed with CRC, in 2 or more consecutive generations, with at least 1 case diagnosed at age <50 years) were originally developed for research purposes to identify individuals with presumed autosomal dominant inherited predisposition syndromes. Although the Amsterdam criteria have proven invaluable in identifying families with germline mutations in DNA MMR genes associated with Lynch syndrome, observations that fewer than half of families with genetically confirmed Lynch syndrome meet the Amsterdam criteria and that 1 in 4 individuals with germline MMR mutations have atypical family histories illustrate the limited sensitivity of family history of cancer for identifying individuals with heritable cancer syndromes.
Tumor analysis offers another avenue for identifying individuals with genetic predisposition to cancer. CRCs develop through different molecular pathways (eg, chromosomal instability, DNA MMR deficiency, and aberrant DNA methylation) that are associated with differences in treatment responses and prognosis; consequently molecular profiling of CRCs for somatic mutations in BRAF , KRAS , and DNA MMR status has been integrated into standard algorithms used to guide therapy. Universal screening of CRC tumors for DNA MMR deficiency associated with Lynch syndrome is the starting point for clinical algorithms used to stratify CRC patients with regard to risk for heritable cancer syndromes ( Fig. 1 ).
Lynch Syndrome
Lynch syndrome, also known as hereditary nonpolyposis CRC (HNPCC), is responsible for 3% of all CRC cases, making it the most common heritable syndrome associated with risk for CRC. The molecular basis of Lynch syndrome is germline mutations in 1 of the DNA MMR genes ( MLH1 , MSH2 , MSH6 , PMS2 , or EPCAM ) that lead to accumulation of mutations and development of tumors, which exhibit high levels of DNA microsatellite instability (MSI)-H. The carrier rate of germline MMR mutations is estimated to be 1 in 280 to 440 in the general population. CRC is the most common cancer affecting MMR mutation carriers, with lifetime risk of CRC ranging from 22% to 75% and endometrial cancer risks for women ranging from 32% to 45%. Risks for additional extracolonic cancers are also increased for carriers of DNA MMR germline mutations, among these ovarian, gastric, small intestinal, urinary tract, brain, pancreatic, and sebaceous neoplasms of the skin.
Diagnosis
Identification of individuals at risk for Lynch syndrome involves assessment of personal and family history and tumor phenotypes, and the diagnosis is confirmed once a pathogenic mutation in a DNA MMR gene ( MLH1 , MSH2 , MSH6 , PMS2 , or EPCAM ) is identified through testing of germline DNA. Clinical guidelines (eg, Amsterdam criteria, Bethesda guidelines ) and risk prediction models (eg, MMRPro, PREMM1,2,6 ) have been used for identifying carriers of MMR mutations based on personal and family history; however, universal screening of all CRC tumors for MMR deficiency has been shown to be the most sensitive and cost-effective strategy for identifying individuals with Lynch syndrome.
Tumor screening
CRC tumors can be screened for MMR deficiency using polymerase chain reaction–based testing for instability at DNA MSI or through immunohistochemistry (IHC) staining for DNA MMR proteins MLH1, MSH2, MSH6, and PMS2. Absence of expression of 1 or more MMR proteins is considered diagnostic of MMR deficiency. Approximately 15% of CRCs are MMR-deficient, with most of these exhibiting loss of MLH1 or PMS2 protein expression as a result of somatic mutations in BRAF or MLH1 promoter hypermethylation. Individuals whose tumors exhibit either loss of MSH2 and/or MSH6 proteins, or loss of MLH1 and/or PMS2 in the absence of somatic BRAF mutations or MLH1 promoter hypermethylation should be tested for germline mutations in MMR genes to confirm the diagnosis of Lynch syndrome. Lynch syndrome can be implicated in approximately 3% of all CRCs, and most Lynch syndrome–associated CRCs are MMR-deficient. Although sensitivity of either MSI or IHC individually for identifying individuals with Lynch syndrome ranges from 77% to 90%, results can be discordant, and false negatives can occur, especially in CRCs associated with germline mutations in MSH6 . Although tumor screening of endometrial cancers has similar performance characteristics to CRC, testing of other neoplasms (eg, ovarian cancers, colorectal adenomas ) for MMR deficiency may be less sensitive.
Management
Making a diagnosis of Lynch syndrome has significant implications for clinical management for patients who have cancer and their at-risk relatives. Lynch syndrome–associated colorectal neoplasms develop at young ages and exhibit accelerated adenoma-carcinoma progression compared with sporadic CRC, thus specialized surveillance is required with colonoscopy every 1 to 2 years beginning at age 20 to 25 years. Given the high risk for endometrial cancer, it is recommended that women begin annual surveillance with endometrial biopsy and transvaginal ultrasound starting at age 30 to 35 years, with consideration for prophylactic hysterectomy once childbearing has been completed ( Box 2 ).
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
