Incorporating Colorectal Cancer Genetic Risk Assessment into Gastroenterology Practice

  • Benjamin SternEmail author
  • Thomas McGarrity
  • Maria Baker
Genetics in Gastroenterology Practice (B Katona, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Genetics in Gastroenterology Practice


Purpose of review

Decades have passed since the underlying molecular etiologies of the most common hereditary forms of colorectal cancer (CRC), Lynch syndrome, and familial adenomatous polyposis (FAP) were first described. With the advent of next-generation sequencing (NGS) panels, the landscape of hereditary CRC testing has changed dramatically. We review available screening strategies, novel CRC predisposition genes, and challenges and opportunities in this field.

Recent findings

Improved sensitivity and availability of NGS panel testing have greatly expanded our understanding regarding the number of CRC syndromes and their phenotypic expression. A variety of screening strategies are available to identify heritable CRC syndromes, potentially decreasing morbidity and mortality in this population. However, these screening strategies remain imperfect and present challenges regarding their implementation in clinical practice. Screening strategies include universal screening of CRC tumors for Lynch syndrome, clinical prediction algorithms, and risk assessment questionnaires. Additionally, there remains a gap in our understanding of the clinical implications of novel gene mutations of variable penetrance and unexpected NGS panel test results. Incorporation of single nucleotide polymorphisms (SNPs) may help to further refine cancer risk assessment, and the clinical introduction of RNA analysis may allow us to clarify variants of unknown significance (VUSs) and identify deep intronic mutations that would otherwise be missed.


Recognition of genetic predisposition to CRC is critical for the practicing gastroenterologist. The evolving field of cancer genetics offers great challenges and opportunities for improved CRC management.


Hereditary colorectal cancer Polyposis Cancer risk assessment Genetic counseling Cancer genetic testing Next-generation sequencing panel 



The primary author acknowledges Heather Stern for her editorial support.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Human and animal rights and informed consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Schuster SC. Next-generation sequencing transforms today’s biology. Nat Methods. 2008;5(1):16–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Kastrinos F, Stoffel EM. History, genetics, and strategies for cancer prevention in Lynch syndrome. Clin Gastroenterol Hepatol. 2014;12(5):715–27 quiz e41–3.PubMedCrossRefGoogle Scholar
  3. 3.
    Karlitz JJ, Hsieh MC, Liu Y, Blanton C, Schmidt B, Jessup JM, et al. Population-based lynch syndrome screening by microsatellite instability in patients ≤50: prevalence, testing determinants, and result availability prior to colon surgery. Am J Gastroenterol. 2015;110(7):948–55.PubMedCrossRefGoogle Scholar
  4. 4.
    Llor X. Building a cancer genetics and prevention program. Clin Gastroenterol Hepatol. 2016;14(11):1516–20.PubMedCrossRefGoogle Scholar
  5. 5.
    Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, et al. Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med. 2000;343(2):78–85.PubMedCrossRefGoogle Scholar
  6. 6.
    Giardiello FM, Brensinger JD, Petersen GM. AGA technical review on hereditary colorectal cancer and genetic testing. Gastroenterology. 2001;121(1):198–213.PubMedCrossRefGoogle Scholar
  7. 7.
    Valle L. Recent discoveries in the genetics of familial colorectal cancer and polyposis. Clin Gastroenterol Hepatol. 2017;15(6):809–19.PubMedCrossRefGoogle Scholar
  8. 8.
    Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW, et al. ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015;110(2):223–62 quiz 63.PubMedCrossRefGoogle Scholar
  9. 9.
    Giardiello FM, Allen JI, Axilbund JE, Boland CR, Burke CA, Burt RW, et al. Guidelines on genetic evaluation and management of lynch syndrome: a consensus statement by the US multi-society task force on colorectal cancer. Gastroenterology. 2014;147(2):502–26.PubMedCrossRefGoogle Scholar
  10. 10.
    Jasperson K, Burt RW. The genetics of colorectal cancer. Surg Oncol Clin N Am. 2015;24(4):683–703.PubMedCrossRefGoogle Scholar
  11. 11.
    Provenzale D, Gupta S, Ahnen DJ, Chen LM, Chung DC, Cooper G, et al. Genetic/familial high-risk assessment: colorectal version 2. NCCN Clinical Practice Guidelines in Oncology. 2019.The NCCN guidelines are the recognized standard for clinical policy in cancer care and are the most detailed and most frequently updated clinical practice guidelines available in any area of medicine. This particular guideline addresses the identification and management of patients at risk for hereditary colorectal cancer.Google Scholar
  12. 12.
    Stoffel E, Mukherjee B, Raymond VM, Tayob N, Kastrinos F, Sparr J, et al. Calculation of risk of colorectal and endometrial cancer among patients with lynch syndrome. Gastroenterology. 2009;137(5):1621–7.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Singh H, Schiesser R, Anand G, Richardson PA, El-Serag HB. Underdiagnosis of Lynch syndrome involves more than family history criteria. Clin Gastroenterol Hepatol. 2010;8(6):523–9.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Tranø G, Wasmuth HH, Sjursen W, Hofsli E, Vatten LJ. Awareness of heredity in colorectal cancer patients is insufficient among clinicians: a Norwegian population-based study. Color Dis. 2009;11(5):456–61.CrossRefGoogle Scholar
  15. 15.
    Sjursen W, Haukanes BI, Grindedal EM, Aarset H, Stormorken A, Engebretsen LF, et al. Current clinical criteria for lynch syndrome are not sensitive enough to identify MSH6 mutation carriers. J Med Genet. 2010;47(9):579–85.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, et al. Feasibility of screening for lynch syndrome among patients with colorectal cancer. J Clin Oncol. 2008;26(35):5783–8.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Stoffel EM, Yurgelun MB. Genetic predisposition to colorectal cancer: implications for treatment and prevention. Semin Oncol. 2016;43(5):536–42.PubMedCrossRefGoogle Scholar
  18. 18.
    Berera S, Koru-Sengul T, Miao F, Carrasquillo O, Nadji M, Zhang Y, et al. Colorectal tumors from different racial and ethnic minorities have similar rates of mismatch repair deficiency. Clin Gastroenterol Hepatol. 2016;14(8):1163–71.PubMedCrossRefGoogle Scholar
  19. 19.
    Barzi A, Sadeghi S, Kattan MW, Meropol NJ. Comparative effectiveness of screening strategies for Lynch syndrome. J Natl Cancer Inst. 2015;107(4).Google Scholar
  20. 20.
    Hampel H, Pearlman R, Beightol M, Zhao W, Jones D, Frankel WL, et al. Assessment of tumor sequencing as a replacement for lynch syndrome screening and current molecular tests for patients with colorectal cancer. JAMA Oncol. 2018;4(6):806–13.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Lu KH, Wood ME, Daniels M, Burke C, Ford J, Kauff ND, et al. American Society of Clinical Oncology expert statement: collection and use of a cancer family history for oncology providers. J Clin Oncol. 2014;32(8):833–40.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    • Kastrinos F, Uno H, Ukaegbu C, Alvero C, McFarland A, Yurgelun MB, et al. Development and validation of the PREMM. J Clin Oncol. 2017;35(19):2165–72.This paper incorporates all Lynch-associated genes into a new clinical prediction model, PREMM5, and discusses the use of a lower threshold of 2.5%.Google Scholar
  23. 23.
    Dinh TA, Rosner BI, Atwood JC, Boland CR, Syngal S, Vasen HF, et al. Health benefits and cost-effectiveness of primary genetic screening for Lynch syndrome in the general population. Cancer Prev Res (Phila). 2011;4(1):9–22.CrossRefGoogle Scholar
  24. 24.
    Luba DG, DiSario JA, Rock C, Saraiya D, Moyes K, Brown K, et al. Community practice implementation of a self-administered version of PREMM. Clin Gastroenterol Hepatol. 2018;16(1):49–58.Google Scholar
  25. 25.
    Kastrinos F, Allen JI, Stockwell DH, Stoffel EM, Cook EF, Mutinga ML, et al. Development and validation of a colon cancer risk assessment tool for patients undergoing colonoscopy. Am J Gastroenterol. 2009;104(6):1508–18.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    •• Guivatchian T, Koeppe ES, Baker JR, Moisa C, Demerath M, Foor-Pessin C, et al. Family history in colonoscopy patients: feasibility and performance of electronic and paper-based surveys for colorectal cancer risk assessment in the outpatient setting. Gastrointest Endosc. 2017;86(4):684–91.This study uses an expanded 5-question version of the Kastrinos questionairre for risk assessment of hereditary CRC syndromes.PubMedCrossRefGoogle Scholar
  27. 27.
    Kessels K, Eisinger JD, Letteboer TG, Offerhaus GJA, Siersema PD, Moons LMG. Sending family history questionnaires to patients before a colonoscopy improves genetic counseling for hereditary colorectal cancer. J Dig Dis. 2017;18(6):343–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Walker JG, Bickerstaffe A, Hewabandu N, Maddumarachchi S, Dowty JG, Jenkins M, et al. The CRISP colorectal cancer risk prediction tool: an exploratory study using simulated consultations in Australian primary care. BMC Med Inform Decis Mak. 2017;17(1):13.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Gunaratnam NT, Akce M, Al Natour R, Bartley AN, Fioritto AF, Hanson K, et al. Screening for cancer genetic syndromes with a simple risk-assessment tool in a community-based open-access colonoscopy practice. Am J Gastroenterol. 2016;111(5):589–93.PubMedCrossRefGoogle Scholar
  30. 30.
    McAllister B, McGarrity T, Soriano C, Cooper J, Walter V, Loloi J, et al. Comparison of colorectal cancer (CRC) screening rates obtained by electronic medical record (EMR) query versus patient-directed Ssurvey in primary care practice. American College of Gastroenterology. 2018:P0223.Google Scholar
  31. 31.
    McGarrity T, Soriano C, McAllister B, Cooper J, Zhu J, Peiffer L, et al. Results of an electronic patient survey to determine up-to-date colorectal cancer screening status and identify high-risk individuals. American College of Gastroenterology. 2018:P0230.Google Scholar
  32. 32.
    Rubinstein WS, Acheson LS, O'Neill SM, Ruffin MT, Wang C, Beaumont JL, et al. Clinical utility of family history for cancer screening and referral in primary care: a report from the family Healthware impact trial. Genet Med. 2011;13(11):956–65.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Feero WG, Facio FM, Glogowski EA, Hampel HL, Stopfer JE, Eidem H, et al. Preliminary validation of a consumer-oriented colorectal cancer risk assessment tool compatible with the US Surgeon General’s My Family Health Portrait. Genet Med. 2015;17(9):753–6.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Walker JG, Licqurish S, Chiang PP, Pirotta M, Emery JD. Cancer risk assessment tools in primary care: a systematic review of randomized controlled trials. Ann Fam Med. 2015;13(5):480–9.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Snyder C. Evolution of cancer risk assessment and counseling related to psychological, financial and legal implications. Familial Cancer. 2016;15(3):493–6.PubMedCrossRefGoogle Scholar
  36. 36.
    Hampel H. Genetic counseling and cascade genetic testing in Lynch syndrome. Familial Cancer. 2016;15(3):423–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Sharaf RN, Myer P, Stave CD, Diamond LC, Ladabaum U. Uptake of genetic testing by relatives of lynch syndrome probands: a systematic review. Clin Gastroenterol Hepatol. 2013;11(9):1093–100.PubMedCrossRefGoogle Scholar
  38. 38.
    Robson ME, Bradbury AR, Arun B, Domchek SM, Ford JM, Hampel HL, et al. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2015;33(31):3660–7.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Pearlman R, Frankel WL, Swanson B, Zhao W, Yilmaz A, Miller K, et al. Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer. JAMA Oncol. 2017;3(4):464–71.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Cragun D, Radford C, Dolinsky JS, Caldwell M, Chao E, Pal T. Panel-based testing for inherited colorectal cancer: a descriptive study of clinical testing performed by a US laboratory. Clin Genet. 2014;86(6):510–20.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Lindor NM, Rabe K, Petersen GM, Haile R, Casey G, Baron J, et al. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA. 2005;293(16):1979–85.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.•
    Broderick P, Dobbins SE, Chubb D, Kinnersley B, Dunlop MG, Tomlinson I, et al. Validation of recently proposed colorectal cancer susceptibility gene variants in an analysis of families and patients-a systematic review. Gastroenterology. 2017;152(1):75-7.e4.This study used high-throughput sequencing analysis to validate association between gene variants and development of CRC.PubMedCrossRefGoogle Scholar
  43. 43.
    Katona BW, Yurgelun MB, Garber JE, Offit K, Domchek SM, Robson ME, et al. A counseling framework for moderate-penetrance colorectal cancer susceptibility genes. Genet Med. 2018;20(11):1324–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Rayner E, van Gool IC, Palles C, Kearsey SE, Bosse T, Tomlinson I, et al. A panoply of errors: polymerase proofreading domain mutations in cancer. Nat Rev Cancer. 2016;16(2):71–81.PubMedCrossRefGoogle Scholar
  45. 45.
    McKenna DB, Van Den Akker J, Zhou AY, Ryan L, Leon A, O’Connor R, et al. Identification of a novel GREM1 duplication in a patient with multiple colon polyps. Familial Cancer. 2019;18(1):63–6.PubMedCrossRefGoogle Scholar
  46. 46.
    Weren RD, Ligtenberg MJ, Geurts van Kessel A, De Voer RM, Hoogerbrugge N, Kuiper RP. NTHL1 and MUTYH polyposis syndromes: two sides of the same coin? J Pathol. 2018;244(2):135–42.PubMedCrossRefGoogle Scholar
  47. 47.
    Quintana I, Mejías-Luque R, Terradas M, Navarro M, Piñol V, Mur P, et al. Evidence suggests that germline. Gut. 2018;67(12):2230–2.PubMedCrossRefGoogle Scholar
  48. 48.
    AlDubayan SH, Giannakis M, Moore ND, Han GC, Reardon B, Hamada T, et al. Inherited DNA-repair defects in colorectal cancer. Am J Hum Genet. 2018;102(3):401–14.Google Scholar
  49. 49.
    Oh M, McBride A, Yun S, Bhattacharjee S, Slack M, Martin JR, et al. BRCA1 and BRCA2 gene mutations and colorectal cancer risk: systematic review and meta-analysis. J Natl Cancer Inst. 2018;110(11):1178–89.PubMedCrossRefGoogle Scholar
  50. 50.
    Rivera B, Perea J, Sánchez E, Villapún M, Sánchez-Tomé E, Mercadillo F, et al. A novel AXIN2 germline variant associated with attenuated FAP without signs of oligondontia or ectodermal dysplasia. Eur J Hum Genet. 2014;22(3):423–6.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Clarke E, Green RC, Green JS, Mahoney K, Parfrey PS, Younghusband HB, et al. Inherited deleterious variants in GALNT12 are associated with CRC susceptibility. Hum Mutat. 2012;33(7):1056–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Adam R, Spier I, Zhao B, Kloth M, Marquez J, Hinrichsen I, et al. Exome sequencing identifies Biallelic MSH3 Germline mutations as a recessive subtype of colorectal adenomatous polyposis. Am J Hum Genet. 2016;99(2):337–51.PubMedCrossRefGoogle Scholar
  53. 53.
    Lorans M, Dow E, Macrae FA, Winship IM, Buchanan DD. Clin Colorectal Cancer. 2018;17(2):e293–305.PubMedCrossRefGoogle Scholar
  54. 54.
    Susswein LR, Marshall ML, Nusbaum R, Vogel Postula KJ, Weissman SM, Yackowski L, et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016;18(8):823–32.Google Scholar
  55. 55.
    Yurgelun MB, Allen B, Kaldate RR, Bowles KR, Judkins T, Kaushik P, et al. Identification of a variety of mutations in cancer predisposition genes in patients with suspected Lynch syndrome. Gastroenterology. 2015;149(3):604–13.e20.PubMedCrossRefGoogle Scholar
  56. 56.
    Eccles BK, Copson E, Maishman T, Abraham JE, Eccles DM. Understanding of BRCA VUS genetic results by breast cancer specialists. BMC Cancer. 2015;15:936.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Jenkins MA, Win AK, Dowty JG, MacInnis RJ, Makalic E, Schmidt DF, et al. Ability of known susceptibility SNPs to predict colorectal cancer risk for persons with and without a family history. Fam Cancer. 2019.Incorporation of SNPs into CRC screening strategies compared to family history.Google Scholar
  58. 58.
    Jeon J, Du M, Schoen RE, Hoffmeister M, Newcomb PA, Berndt SI, et al. Determining risk of colorectal cancer and starting age of screening based on lifestyle, environmental, and genetic factors. Gastroenterology. 2018;154(8):2152–64.e19.CrossRefGoogle Scholar
  59. 59.
    • Conner BR, Hernandez F, Souders B, Landrith T, Boland CR, Karam R. RNA analysis identifies pathogenic duplications in MSH2 in patients with lynch syndrome. Gastroenterology. 2019;156(6):1924–5.e4.Use of RNA analysis to further clarify VUSs in patients with MSH2 mutations.CrossRefGoogle Scholar
  60. 60.
    Bouvet D, Bodo S, Munier A, Guillerm E, Bertrand R, Colas C, et al. Methylation tolerance-based functional assay to assess variants of unknown significance in the MLH1 and MSH2 genes and identify patients with lynch syndrome. Gastroenterology. 2019;157(2):421–31.PubMedCrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Division of Gastroenterology and HepatologyPenn State Health Milton S. Hershey Medical CenterHersheyUSA
  2. 2.Division of Hematology OncologyPenn State Health Milton S. Hershey Medical Center, Penn State Cancer InstituteHersheyUSA

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