1932

Abstract

The prevalence of genetic predisposition to cancer is greater than initially appreciated, yet most affected individuals remain undiagnosed. Deleterious germline variants in cancer predisposition genes are implicated in 1 in 10 cases of advanced cancer. Next-generation sequencing technologies have made germline and tumor DNA sequencing more accessible and less expensive. Expanded access to clinical genetic testing will improve identification of individuals with genetic predisposition to cancer and provide opportunities to effectively reduce morbidity through precision cancer therapies and surveillance. Cross-disciplinary clinical education in genomic medicine is needed to translate advances in genomic medicine into improved health outcomes.

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2020-01-27
2024-04-25
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Literature Cited

  1. 1. 
    Collins FS, Green ED, Guttmacher AE, Guyer MS, Institute USNHGR. 2003. A vision for the future of genomics research. Nature 422:835–47
    [Google Scholar]
  2. 2. 
    Pon JR, Marra MA. 2015. Driver and passenger mutations in cancer. Annu. Rev. Pathol. 10:25–50
    [Google Scholar]
  3. 3. 
    Grady WM, Carethers JM. 2008. Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology 135:1079–99
    [Google Scholar]
  4. 4. 
    Carethers JM, Jung BH. 2015. Genetics and genetic biomarkers in sporadic colorectal cancer. Gastroenterology 149:1177–90
    [Google Scholar]
  5. 5. 
    Stoffel EM, Boland CR. 2015. Genetics and genetic testing in hereditary colorectal cancer. Gastroentero-logy 149:1191–203
    [Google Scholar]
  6. 6. 
    Robinson DR, Wu YM, Lonigro RJ et al. 2017. Integrative clinical genomics of metastatic cancer. Nature 548:297–303
    [Google Scholar]
  7. 7. 
    Mody RJ, Wu YM, Lonigro RJ et al. 2015. Integrative clinical sequencing in the management of refractory or relapsed cancer in youth. JAMA 314:913–25
    [Google Scholar]
  8. 8. 
    Zhang J, Walsh MF, Wu G et al. 2015. Germline mutations in predisposition genes in pediatric cancer. N. Engl. J. Med. 373:2336–46
    [Google Scholar]
  9. 9. 
    Mandelker D, Zhang L, Kemel Y et al. 2017. Mutation detection in patients with advanced cancer by universal sequencing of cancer-related genes in tumor and normal DNA versus guideline-based germline testing. JAMA 318:825–35
    [Google Scholar]
  10. 10. 
    Yurgelun MB, Kulke MH, Fuchs CS et al. 2017. Cancer susceptibility gene mutations in individuals with colorectal cancer. J. Clin. Oncol. 35:1086–95
    [Google Scholar]
  11. 11. 
    Brand R, Borazanci E, Speare V et al. 2018. Prospective study of germline genetic testing in incident cases of pancreatic adenocarcinoma. Cancer 124:3520–27
    [Google Scholar]
  12. 12. 
    Yurgelun MB, Chittenden AB, Morales-Oyarvide V et al. 2019. Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer. Genet. Med. 21:213–23
    [Google Scholar]
  13. 13. 
    Pritchard CC, Mateo J, Walsh MF et al. 2016. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N. Engl. J. Med. 375:443–53
    [Google Scholar]
  14. 14. 
    Walsh T, Casadei S, Lee MK et al. 2011. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. PNAS 108:18032–37
    [Google Scholar]
  15. 15. 
    Norquist BM, Harrell MI, Brady MF et al. 2016. Inherited mutations in women with ovarian carcinoma. JAMA Oncol 2:482–90
    [Google Scholar]
  16. 16. 
    Easton DF, Pharoah PD, Antoniou AC et al. 2015. Gene-panel sequencing and the prediction of breast-cancer risk. N. Engl. J. Med. 372:2243–57
    [Google Scholar]
  17. 17. 
    Manchanda R, Legood R, Burnell M et al. 2015. Cost-effectiveness of population screening for BRCA mutations in Ashkenazi Jewish women compared with family history-based testing. J. Natl. Cancer Inst. 107:380
    [Google Scholar]
  18. 18. 
    Kuchenbaecker KB, Hopper JL, Barnes DR et al. 2017. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 317:2402–16
    [Google Scholar]
  19. 19. 
    Berry DA, Iversen ES Jr., Gudbjartsson DF et al. 2002. BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. J. Clin. Oncol. 20:2701–12
    [Google Scholar]
  20. 20. 
    Grant RC, Holter S, Borgida A et al. 2018. Comparison of practice guidelines, BRCAPRO, and genetic counselor estimates to identify germline BRCA1 and BRCA2 mutations in pancreatic cancer. J. Genet. Couns. 27:988–95
    [Google Scholar]
  21. 21. 
    National Comprehensive Cancer Network (NCCN) 2019. Genetic/familial high risk assessment: breast and ovarian. NCCN Clinical Practice Guidelines in Oncology. Version 3.2019. http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf
    [Google Scholar]
  22. 22. 
    American Society of Breast Surgeons 2019. Consensus guideline on genetic testing for hereditary breast cancer. https://breastsurgeons.org/docs/statements/Consensus-Guideline-on-Genetic-Testing-for-Hereditary-Breast-Cancer.pdf
  23. 23. 
    Levy-Lahad E, Lahad A, King MC 2015. Precision medicine meets public health: population screening for BRCA1 and BRCA2. J. Natl. Cancer Inst 107:420
    [Google Scholar]
  24. 24. 
    Moyer VA, US Preventive Services Task Force. 2014. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. Ann. Intern. Med. 160:271–81
    [Google Scholar]
  25. 25. 
    Fong PC, Boss DS, Yap TA et al. 2009. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361:123–34
    [Google Scholar]
  26. 26. 
    Moore K, Colombo N, Scambia G et al. 2018. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N. Engl. J. Med. 379:2495–505
    [Google Scholar]
  27. 27. 
    Golan T, Hammel P, Reni M et al. 2019. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N. Engl. J. Med. 381:317–27
    [Google Scholar]
  28. 28. 
    Mateo J, Carreira S, Sandhu S et al. 2015. DNA-repair defects and olaparib in metastatic prostate cancer. N. Engl. J. Med. 373:1697–708
    [Google Scholar]
  29. 29. 
    Domchek SM, Friebel TM, Singer CF et al. 2010. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 304:967–75
    [Google Scholar]
  30. 30. 
    Giri VN, Knudsen KE, Kelly WK et al. 2018. Role of genetic testing for inherited prostate cancer risk: Philadelphia Prostate Cancer Consensus Conference 2017. J. Clin. Oncol. 36:414–24
    [Google Scholar]
  31. 31. 
    Stoffel EM, McKernin SE, Brand R et al. 2019. Evaluating susceptibility to pancreatic cancer: ASCO provisional clinical opinion. J. Clin. Oncol. 37:153–64
    [Google Scholar]
  32. 32. 
    Hampel H, Frankel WL, Martin E et al. 2005. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N. Engl. J. Med. 352:1851–60
    [Google Scholar]
  33. 33. 
    Haraldsdottir S, Rafnar T, Frankel WL et al. 2017. Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2. Nat. Commun. 8:14755
    [Google Scholar]
  34. 34. 
    Syngal S, Brand RE, Church JM et al. 2015. ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am. J. Gastroenterol. 110:223–62
    [Google Scholar]
  35. 35. 
    Carethers JM. 2017. Microsatellite instability pathway and EMAST in colorectal cancer. Curr. Colorectal Cancer Rep. 13:73–80
    [Google Scholar]
  36. 36. 
    Carethers JM. 2016. Hereditary, sporadic and metastatic colorectal cancers are commonly driven by specific spectrums of defective DNA mismatch repair components. Trans. Am. Clin. Climatol. Assoc. 127:81–97
    [Google Scholar]
  37. 37. 
    Kastrinos F, Uno H, Ukaegbu C et al. 2017. Development and validation of the PREMM5 model for comprehensive risk assessment of Lynch syndrome. J. Clin. Oncol. 35:2165–72
    [Google Scholar]
  38. 38. 
    Dinh TA, Rosner BI, Atwood JC et al. 2011. Health benefits and cost-effectiveness of primary genetic screening for Lynch syndrome in the general population. Cancer Prev. Res. 4:9–22
    [Google Scholar]
  39. 39. 
    Evaluation of Genomic Applications in Practice and Prevention Working Group 2009. Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet. Med. 11:35–41
    [Google Scholar]
  40. 40. 
    Latham A, Srinivasan P, Kemel Y et al. 2019. Microsatellite instability is associated with the presence of Lynch syndrome pan-cancer. J. Clin. Oncol. 37:286–95
    [Google Scholar]
  41. 41. 
    Le DT, Uram JN, Wang H et al. 2015. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372:2509–20
    [Google Scholar]
  42. 42. 
    Schmeler KM, Lynch HT, Chen LM et al. 2006. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N. Engl. J. Med. 354:261–69
    [Google Scholar]
  43. 43. 
    Lu KH, Wood ME, Daniels M et al. 2014. American Society of Clinical Oncology expert statement: collection and use of a cancer family history for oncology providers. J. Clin. Oncol. 32:833–40
    [Google Scholar]
  44. 44. 
    Stoffel EM, Koeppe E, Everett J et al. 2017. Germline genetic features of young individuals with co-lorectal cancer. Gastroenterology 154:897–905
    [Google Scholar]
  45. 45. 
    Pearlman R, Frankel WL, Swanson B et al. 2017. Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer. JAMA Oncol 3:464–71
    [Google Scholar]
  46. 46. 
    National Comprehensive Cancer Network (NCCN) 2018. Genetic/familial high-risk assessment: colorectal. NCCN Clinical Practice Guidelines in Oncology. Version 1.2018. http://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf
  47. 47. 
    Ladabaum U, Wang G, Terdiman J et al. 2011. Strategies to identify the Lynch syndrome among patients with colorectal cancer: a cost-effectiveness analysis. Ann. Intern. Med. 155:69–79
    [Google Scholar]
  48. 48. 
    Khoury MJ, Feero WG, Chambers DA et al. 2018. A collaborative translational research framework for evaluating and implementing the appropriate use of human genome sequencing to improve health. PLOS Med 15:e1002631
    [Google Scholar]
  49. 49. 
    Hughes KS. 2017. Genetic testing: What problem are we trying to solve. ? J. Clin. Oncol. 35:3789–91
    [Google Scholar]
  50. 50. 
    Haddow JE, Palomaki GE. 2003. ACCE: a model process for evaluating data on emerging genetic tests. Human Genome Epidemiology: A Scientific Foundation for Using Genetic Information to Improve Health and Prevent Disease M Khoury, J Little, W Burke 217–33 New York: Oxford Univ. Press
    [Google Scholar]
  51. 51. 
    Richards S, Aziz N, Bale S et al. 2015. 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. 17:405–24
    [Google Scholar]
  52. 52. 
    Offit K. 2016. The future of clinical cancer genomics. Semin. Oncol. 43:615–22
    [Google Scholar]
  53. 53. 
    Gill J, Obley AJ, Prasad V 2018. Direct-to-consumer genetic testing: the implications of the US FDA's first marketing authorization for BRCA mutation testing. JAMA 319:2377–78
    [Google Scholar]
  54. 54. 
    Kurian AW, Hare EE, Mills MA et al. 2014. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J. Clin. Oncol. 32:2001–9
    [Google Scholar]
  55. 55. 
    Yurgelun MB, Allen B, Kaldate RR et al. 2015. Identification of a variety of mutations in cancer predisposition genes in patients with suspected Lynch syndrome. Gastroenterology 149:604–13
    [Google Scholar]
  56. 56. 
    Carethers JM, Stoffel EM. 2015. Lynch syndrome and Lynch syndrome mimics: the growing complex landscape of hereditary colon cancer. World J. Gastroenterol. 21:9253–61
    [Google Scholar]
  57. 57. 
    Katona BW, Yurgelun MB, Garber JE et al. 2018. A counseling framework for moderate-penetrance colorectal cancer susceptibility genes. Genet. Med. 20:1324–27
    [Google Scholar]
  58. 58. 
    Domchek SM, Bradbury A, Garber JE et al. 2013. Multiplex genetic testing for cancer susceptibility: out on the high wire without a net. ? J. Clin. Oncol. 31:1267–70
    [Google Scholar]
  59. 59. 
    Robson ME, Bradbury AR, Arun B et al. 2015. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J. Clin. Oncol. 33:3660–67
    [Google Scholar]
  60. 60. 
    Hampel H, Bennett RL, Buchanan A et al. 2015. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet. Med. 17:70–87
    [Google Scholar]
  61. 61. 
    Kurian AW, Li Y, Hamilton AS et al. 2017. Gaps in incorporating germline genetic testing into treatment decision-making for early-stage breast cancer. J. Clin. Oncol. 35:2232–39
    [Google Scholar]
  62. 62. 
    Fox D, Spencer E, Torkamani A 2018. Returning results to family members: professional duties in genomics research in the United States. J. Leg. Med. 38:201–19
    [Google Scholar]
  63. 63. 
    Childers CP, Childers KK, Maggard-Gibbons M, Macinko J 2017. National estimates of genetic testing in women with a history of breast or ovarian cancer. J. Clin. Oncol. 35:3800–6
    [Google Scholar]
  64. 64. 
    Roberts JS, Gornick MC, Carere DA et al. 2017. Direct-to-consumer genetic testing: user motivations, decision making, and perceived utility of results. Public Health Genom 20:36–45
    [Google Scholar]
  65. 65. 
    Plichta JK, Sebastian ML, Smith LA et al. 2019. Germline genetic testing: what the breast surgeon needs to know. Ann. Surg. Oncol. 26:2184–90
    [Google Scholar]
  66. 66. 
    Khoury MJ, Iademarco MF, Riley WT 2016. Precision public health for the era of precision medicine. Am. J. Prev. Med. 50:398–401
    [Google Scholar]
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