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Genetic testing for hereditary gastrointestinal cancer syndromes: Interpreting results in today's practice

  • Jacquelyn M. Powers
  • Jessica E. Ebrahimzadeh
  • Bryson W. KatonaEmail author
Genetics in Gastroenterology Practice (B Katona, Section Editor)
  • 10 Downloads
Part of the following topical collections:
  1. Topical Collection on Genetics in Gastroenterology Practice

Abstract

Purpose of review

Advances in genomics have led to the discovery of multiple predisposition genes linked to increased risk for gastrointestinal (GI) cancer. The goal of this review is to assist physicians and allied health care professionals in understanding the current paradigm shift in clinical genetic testing for hereditary GI cancer predisposition syndromes; with a focus on multigene panel testing (MGPT) and test results interpretation. Additionally, this review introduces direct-to-consumer and at-home genetic testing. Both delivery models are increasing in popularity and clinicians will be expected to address results from patients who utilize these approaches.

Recent findings

Technological advancement and reduced costs have transformed the genetic testing approach from single syndrome genetic testing to broad-based MGPT. MGPT has the benefit of aiding in efficient genetic diagnosis; however, clinicians should be knowledgeable of possible results including variants of uncertain significance, secondary findings, and pathogenic variants within high- and low-to-moderate risk genes, as well as genes for which risks are ill-defined.

Summary

The landscape of clinical cancer genetics continues to evolve rapidly. Timely updates are critical to ensure the medical community is familiar with current considerations and ongoing challenges regarding genetic testing for hereditary GI cancer susceptibility.

Keywords

Multigene panel testing variant interpretation gastrointestinal cancer susceptibility cancer genetics direct-to-consumer genetics 

Notes

Funding

NIH/NIDDK grants K08DK106489 and R03DK120946 (BWK), The Lustgarten Family Colon Cancer Research Fund (BWK), and The Jason and Julie Borrelli Lynch Syndrome Research Fund (BWK).

Compliance with ethical standards

Conflict of interest

Bryson Katona reports grants from NIH/NIDDK, paid travel related to a clinical trial from Janssen, and is a consultant for Exact Sciences. Jacquelyn Powers reports consulting for CareVive. Jessica Ebrahimzadeh declares that she has 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.
    Valle L, de Voer RM, Goldberg Y, Sjursen W, Forsti A, Ruiz-Ponte C, et al. Update on genetic predisposition to colorectal cancer and polyposis. Mol Asp Med. 2019;69:10–26.CrossRefGoogle Scholar
  2. 2.
    Lorans M, Dow E, Macrae FA, Winship IM, Buchanan DD. Update on hereditary colorectal cancer: improving the clinical utility of multigene panel testing. Clin Colorectal Cancer. 2018;17(2):e293–305.CrossRefGoogle Scholar
  3. 3.
    Kumar S, Long JM, Ginsberg GG, Katona BW. The role of endoscopy in the management of hereditary diffuse gastric cancer syndrome. World J Gastroenterol. 2019;25(23):2878–86.CrossRefGoogle Scholar
  4. 4.
    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.CrossRefGoogle Scholar
  5. 5.
    Møller P, Seppälä TT, Bernstein I, Holinski-Feder E, Sala P, Gareth Evans D, et al. Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database. Gut. 2018;67(7):1306–16.CrossRefGoogle Scholar
  6. 6.
    American Cancer Society. Cancer facts & figures 2019.Google Scholar
  7. 7.
    •• Katona BW, Yurgelun MB, Garber JE, Offit K, Domchek SM, Robson ME, et al. A counseling framework for moderate-penetrance colorectal cancer susceptibility genes. Gen Med. 2018;20(11):1324–7 This report introduces a counseling framework for common low-moderate penetrance CRC risk genes that can be identified on MGPT.Google Scholar
  8. 8.
    Butterworth AS, Higgins JP, Pharoah P. Relative and absolute risk of colorectal cancer for individuals with a family history: a meta-analysis. Eur J Cancer. 2006;42(2):216–27.CrossRefGoogle Scholar
  9. 9.
    Locker GY, Lynch HT. Genetic factors and colorectal cancer in Ashkenazi Jews. Familial Cancer. 2004;3(3):215–21.CrossRefGoogle Scholar
  10. 10.
    Boursi B, Sella T, Liberman E, Shapira S, David M, Kazanov D, et al. The APC p.I1307K polymorphism is a significant risk factor for CRC in average risk Ashkenazi Jews. Eur J Cancer. 2013;49(17):3680–5.CrossRefGoogle Scholar
  11. 11.
    Win AK, Hopper JL, Jenkins MA. Association between monoallelic MUTYH mutation and colorectal cancer risk: a meta-regression analysis. Familial Cancer. 2011;10(1):1–9.CrossRefGoogle Scholar
  12. 12.
    Ma X, Zhang B, Zheng W. Genetic variants associated with colorectal cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. Gut. 2014;63(2):326–36.CrossRefGoogle Scholar
  13. 13.
    NCCN. National Comprehensive Cancer Network Guidelines Version 2.2019. Genetic/Familial High Risk Assessment: Colorectal. 2019.Google Scholar
  14. 14.
    Bradbury AR, Patrick-Miller L, Domchek S. Multiplex genetic testing: reconsidering utility and informed consent in the era of next-generation sequencing. Genet Med. 2015;17(2):97–8.CrossRefGoogle Scholar
  15. 15.
    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.CrossRefGoogle Scholar
  16. 16.
    • Farmer MB, Bonadies DC, Mahon SM, Baker MJ, Ghate SM, Munro C, et al. Adverse events in genetic testing: the fourth case series. Cancer J. 2019;25(4):231–6 The most recent published case series documenting inappropriate genetic test ordering, use, and interpretation.CrossRefGoogle Scholar
  17. 17.
    NSGC. National Society of Genetic Counselors: at-home genetic testing position statement. 2019.Google Scholar
  18. 18.
    • Tandy-Connor S, Guiltinan J, Krempely K, LaDuca H, Reineke P, Gutierrez S, et al. False-positive results released by direct-to-consumer genetic tests highlight the importance of clinical confirmation testing for appropriate patient care. Genet Med. 2018;20(12):1515–21 This is the first report to examine the accuracy and concordance of DTC results obtained via raw genotyping data at a CLIA approved commercial genetic laboratory.CrossRefGoogle Scholar
  19. 19.
    Guerrini CJ, Wagner JK, Nelson SC, Javitt GH, McGuire AL. Who's on third? Regulation of third-party genetic interpretation services. Genet Med. 2019.Google Scholar
  20. 20.
    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24.CrossRefGoogle Scholar
  21. 21.
    Amendola LM, Jarvik GP, Leo MC, McLaughlin HM, Akkari Y, Amaral MD, et al. Performance of ACMG-AMP variant-interpretation guidelines among nine laboratories in the Clinical Sequencing Exploratory Research Consortium. Am J Hum Genet. 2016;98(6):1067–76.CrossRefGoogle Scholar
  22. 22.
    •• Balmaña J, Digiovanni L, Gaddam P, Walsh MF, Joseph V, Stadler ZK, et al. Conflicting interpretation of genetic variants and cancer risk by commercial laboratories as assessed by the Prospective Registry of Multiplex Testing. J Clin Oncol : official journal of the American Society of Clinical Oncology. 2016;34(34):4071–8 This report highlights the remaining discordance of variant classification among CLIA approved commercial genetic testing laboratory and outlines how differences in variant interpretation may impact medical management.CrossRefGoogle Scholar
  23. 23.
    Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, et al. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 2014;42(Database issue):D980–5.CrossRefGoogle Scholar
  24. 24.
    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.CrossRefGoogle Scholar
  25. 25.
    Roberts MC, Dotson WD, DeVore CS, Bednar EM, Bowen DJ, Ganiats TG, et al. Delivery Of cascade screening for hereditary conditions: a scoping review of the literature. Health aff (Millwood). 2018;37(5):801–8.CrossRefGoogle Scholar
  26. 26.
    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.CrossRefGoogle Scholar
  27. 27.
    Renkonen-Sinisalo L, Aarnio M, Mecklin JP, Jarvinen HJ. Surveillance improves survival of colorectal cancer in patients with hereditary nonpolyposis colorectal cancer. Cancer Detect Prev. 2000;24(2):137–42.PubMedGoogle Scholar
  28. 28.
    Domchek SM, Bradbury A, Garber JE, Offit K, Robson ME. Multiplex genetic testing for cancer susceptibility: out on the high wire without a net? J Clin Oncol. 2013;31(10):1267–70.CrossRefGoogle Scholar
  29. 29.
    Mundt E, Chen D. Lowering the rate of variants of uncertain significance on Myriad’s myRisk® hereditary cancer panel. 2016.Google Scholar
  30. 30.
    LaDuca H, Polley EC, Yussuf A, Hoang L, Gutierrez S, Hart SN, et al. A clinical guide to hereditary cancer panel testing: evaluation of gene-specific cancer associations and sensitivity of genetic testing criteria in a cohort of 165,000 high-risk patients. Gen Med. 2019.Google Scholar
  31. 31.
    Ricker C, Culver JO, Lowstuter K, Sturgeon D, Sturgeon JD, Chanock CR, et al. Increased yield of actionable mutations using multi-gene panels to assess hereditary cancer susceptibility in an ethnically diverse clinical cohort. Cancer Gene Ther. 2016;209(4):130–7.CrossRefGoogle Scholar
  32. 32.
    Mersch J, Brown N, Pirzadeh-Miller S, Mundt E, Cox HC, Brown K, et al. Prevalence of variant reclassification following hereditary cancer genetic testing. JAMA. 2018;320(12):1266–74.CrossRefGoogle Scholar
  33. 33.
    Yohe S, Thyagarajan B. Review of clinical next-generation sequencing. Arch Pathol Lab Med. 2017;141(11):1544–57.CrossRefGoogle Scholar
  34. 34.
    NSGC. National Society of Genetic Counselors: genetic testing of minors for adult-onset conditions position statement. Accepted April 12, 2018.Google Scholar
  35. 35.
    Ballester V, Cruz-Correa M. How and when to consider genetic testing for colon cancer? Gastroenterology. 2018;155(4):955–9.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Jacquelyn M. Powers
    • 1
  • Jessica E. Ebrahimzadeh
    • 1
  • Bryson W. Katona
    • 2
    Email author
  1. 1.Division of Hematology/Oncology, Department of MedicineUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaUSA
  2. 2.Division of Gastroenterology, Department of MedicineUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaUSA

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