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  • Review Article
  • Published:

Therapeutic implications of germline genetic findings in cancer

Nature Reviews Clinical Oncology volume 16, pages 386–396 (2019)Cite this article

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An Author Correction to this article was published on 17 April 2019

This article has been updated

Abstract

Cancer is a genetic disease. To date, translational cancer genomics has focused largely on somatic alterations, driven by the desire to identify targets for personalized therapy. However, therapeutically relevant information is also latent within the germline genome. In addition to cancer susceptibility, alterations present in the germ line can determine responses to both targeted and more traditional anticancer therapies, as well as their toxicities. Despite the importance of these alterations, many algorithms designed to analyse somatic mutations conversely continue to subtract information on germline genetics during analysis. In the light of low actionable yields from somatic tumour testing, a need exists for diversification of the sources of potential therapeutic biomarkers. In this Review, we summarize the literature on the therapeutic potential of alterations in the germline genome. The therapeutic value of germline information will not only be manifest as improvements in treatment but will also drive greater levels of engagement and cooperation between traditional oncology services and familial risk management clinics.

Key points

  • Expanded application of genomic sequencing has revealed a substantial burden of germline variants across a range of tumour histologies.

  • The relevance of germline variations to therapy selection is only now being fully realized.

  • The clonal nature of germline alterations makes them ideal predictive biomarkers.

  • A growing appreciation of the therapeutic relevance of germline variations is likely to increase the demand for germline testing and its clinical interpretation.

  • An added level of complexity of the clinical interpretation of germline variants exists: variants might reach a threshold of being clinically relevant for therapy but not for risk management.

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Fig. 1: Results of the quantification analysis of germline variations with therapeutic actionability.

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Change history

  • 17 April 2019

    The originally published article contained errors in the main text and in figure 1 in the reported number of patients with pathogenic or likely pathogenic germline variants. The originally reported numbers did not take into account the presence of more than one variant in an individual patient. This has been corrected in the HTML and PDF versions of the manuscript.

References

  1. Garber, J. E. & Offit, K. Hereditary cancer predisposition syndromes. J. Clin. Oncol. 23, 276–292 (2005).

    Article  PubMed  Google Scholar 

  2. Friend, S. H. et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323, 643–646 (1986).

    Article  CAS  PubMed  Google Scholar 

  3. Lichtenstein, P. 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. 343, 78–85 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Lindor, N. M., McMaster, M. L., Lindor, C. J. & Greene, M. H. Concise handbook of familial cancer susceptibility syndromes — second edition. J. Natl Cancer Inst. Monogr. 2008, 1–93 (2008).

    Article  Google Scholar 

  5. Meric-Bernstam, F. et al. Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol. Ann. Oncol. 27, 795–800 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Schrader, K. A. et al. Germline variants in targeted tumor sequencing using matched normal DNA. JAMA Oncol. 2, 104–111 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Parsons, D. et al. Diagnostic yield of clinical tumor and germline whole-exome sequencing for children with solid tumors. JAMA Oncol. 2, 616–624 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Zhang, J., Walsh, M., Wu, G. & Edmonson, M. Germline mutations in predisposition genes in pediatric cancer. N. Engl. J. Med. 374, 1390–1391 (2016).

    Article  Google Scholar 

  9. Mandelker, D. et al. 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, 825–835 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Gröbner, S. N. et al. The landscape of genomic alterations across childhood cancers. Nature 555, 321 (2018).

    Article  PubMed  CAS  Google Scholar 

  11. Kaufman, B. et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J. Clin. Oncol. 33, 244–250 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. Shroff, R. T. et al. Rucaparib monotherapy in patients with pancreatic cancer and a known deleterious BRCA mutation. JCO Precis. Oncol. https://doi.org/10.1200/PO.17.00316 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Le Tourneau, C. et al. Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial. Lancet Oncol. 16, 1324–1334 (2015).

    Article  PubMed  CAS  Google Scholar 

  14. National Cancer Institute. Executive summary: interim analysis of the NCI-MATCH trial. Cancer.gov https://dctd.cancer.gov/majorinitiatives/NCI-MATCH_Interim_Analysis_Executive_Summary.pdf (2016).

  15. Chang, M. T. et al. Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. Nat. Biotechnol. 34, 155–163 (2016).

    Article  CAS  PubMed  Google Scholar 

  16. Ghazani, A. A. et al. Assigning clinical meaning to somatic and germ-line whole-exome sequencing data in a prospective cancer precision medicine study. Genet. Med. 19, 787–795 (2017).

    Article  CAS  PubMed  Google Scholar 

  17. Schwaederle, M. et al. Association of biomarker-based treatment strategies with response rates and progression-free survival in refractory malignant neoplasms: a meta-analysis. JAMA Oncol. 2, 1452–1459 (2016).

    Article  PubMed  Google Scholar 

  18. Huang, K.-l. & Mashl, R. J. et al. Pathogenic germline variants in 10,389 adult cancers. Cell 173, 355–370 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Li Ding’s Lab. Characterization of germline variants. GitHub https://github.com/ding-lab/CharGer (2018).

  20. Richards, S. 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. 17, 405–424 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Inamura, K. Lung cancer: understanding its molecular pathology and the 2015 WHO classification. Front. Oncol. 7, 193 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Hyman, D. M. et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N. Engl. J. Med. 373, 726–736 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lopez-Chavez, A. et al. Molecular profiling and targeted therapy for advanced thoracic malignancies: a biomarker-derived, multiarm, multihistology phase II basket trial. J. Clin. Oncol. 33, 1000–1007 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Conley, B. A. & Doroshow, J. H. Molecular analysis for therapy choice: NCI MATCH. Semin. Oncol. 41, 297–299 (2014).

    Article  PubMed  Google Scholar 

  25. Thavaneswaran, S. et al. Cancer Molecular Screening and Therapeutics (MoST): a framework for multiple, parallel signal-seeking studies of targeted therapies for rare and neglected cancers. Med. J. Aust. 209, 354–355 (2018).

    Article  PubMed  Google Scholar 

  26. Cunanan, K. M. et al. Basket trials in oncology: a trade-off between complexity and efficiency. J. Clin. Oncol. 35, 271–273 (2017).

    Article  PubMed  Google Scholar 

  27. Carr, T. H. et al. Defining actionable mutations for oncology therapeutic development. Nat. Rev. Cancer 16, 319 (2016).

    Article  CAS  PubMed  Google Scholar 

  28. Simon, R. & Roychowdhury, S. Implementing personalized cancer genomics in clinical trials. Nat. Rev. Drug Discov. 12, 358–369 (2013).

    Article  CAS  PubMed  Google Scholar 

  29. Lemery, S., Keegan, P. & Pazdur, R. First FDA approval agnostic of cancer site — when a biomarker defines the indication. N. Engl. J. Med. 377, 1409–1412 (2017).

    Article  PubMed  Google Scholar 

  30. Iyevleva, A. G. & Imyanitov, E. N. Cytotoxic and targeted therapy for hereditary cancers. Hered. Cancer Clin. Pract. 14, 17 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Petrucelli, N., Daly, M. B. & Pal, T. BRCA1- and BRCA2-associated hereditary breast and ovarian cancer. GeneReviews https://www.ncbi.nlm.nih.gov/pubmed/20301425 (updated 15 Dec 2016).

  32. Gorodnova, T. et al. High response rates to neoadjuvant platinum-based therapy in ovarian cancer patients carrying germ-line BRCA mutation. Cancer Lett. 369, 363–367 (2015).

    Article  CAS  PubMed  Google Scholar 

  33. Norquist, B. et al. Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. J. Clin. Oncol. 29, 3008–3015 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Byrski, T. et al. Pathologic complete response to neoadjuvant cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res. Treat. 147, 401–405 (2014).

    Article  CAS  PubMed  Google Scholar 

  35. Byrski, T. et al. Results of a phase II open-label, non-randomized trial of cisplatin chemotherapy in patients with BRCA1-positive metastatic breast cancer. Breast Cancer Res. 14, R110 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Tutt, A. et al. The TNT trial: a randomized phase III trial of carboplatin compared to docetaxel for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012). Cancer Res. 75, S3–01 (2015).

    Article  CAS  Google Scholar 

  37. Helwick, C. TNT trial supports platinums in BRCA-mutated breast cancer. ASCO Post http://www.ascopost.com/issues/february-25-2015/tnt-trial-supports-platinums-in-brca-mutated-breast-cancer/ (2015).

  38. Vencken, P. et al. Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients. Ann. Oncol. 22, 1346–1352 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Alsop, K. et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J. Clin. Oncol. 30, 2654–2663 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pomerantz, M. M. et al. The association between germline BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer. Cancer 123, 3532–3539 (2017).

    Article  CAS  PubMed  Google Scholar 

  41. Benafif, S. & Hall, M. An update on PARP inhibitors for the treatment of cancer. Onco Targets Ther. 8, 519–528 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Tutt, A. et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376, 235–244 (2010).

    Article  CAS  PubMed  Google Scholar 

  43. Audeh, M. et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 376, 245–251 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. Gelmon, K. et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 12, 852–861 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Sandhu, S. et al. The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol. 14, 882–892 (2013).

    Article  CAS  PubMed  Google Scholar 

  46. Mirza, M. R. et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N. Engl. J. Med. 375, 2154–2164 (2016).

    Article  CAS  PubMed  Google Scholar 

  47. US Food & Drug Administration. FDA approves olaparib tablets for maintenance treatment in ovarian cancer. FDA.gov https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm572143.htm (updated 17 Aug 2017).

  48. Robson, M. et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N. Engl. J. Med. 377, 523–533 (2017).

    Article  CAS  PubMed  Google Scholar 

  49. Litton, J. K. et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N. Engl. J. Med. 379, 753–763 (2018).

    Article  CAS  PubMed  Google Scholar 

  50. Mateo, J. et al. DNA-repair defects and olaparib in metastatic prostate cancer. N. Engl. J. Med. 373, 1697–1708 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Helleday, T. PARP inhibitor receives FDA breakthrough therapy designation in castration resistant prostate cancer: beyond germline BRCA mutations. Ann. Oncol. 27, 755–757 (2016).

    Article  CAS  PubMed  Google Scholar 

  52. Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02184195 (2018).

  54. Pennington, K. P. et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin. Cancer Res. 20, 764–775 (2014).

    Article  CAS  PubMed  Google Scholar 

  55. McCabe, N. et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 66, 8109–8115 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Villalona-Calero, M. A. et al. Veliparib alone or in combination with mitomycin C in patients with solid tumors with functional deficiency in homologous recombination repair. J. Natl Cancer Inst. 108, djv437 (2016).

    Article  PubMed Central  CAS  Google Scholar 

  57. Bowden, N. A. Nucleotide excision repair: why is it not used to predict response to platinum-based chemotherapy? Cancer Lett. 346, 163–171 (2014).

    Article  CAS  PubMed  Google Scholar 

  58. Epstein, E. H. Basal cell carcinomas: attack of the hedgehog. Nat. Rev. Cancer 8, 743–754 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rimkus, T., Carpenter, R., Qasem, S., Chan, M. & Lo, H. Targeting the Sonic Hedgehog signaling pathway: review of Smoothened and GLI inhibitors. Cancers 8, 1–23 (2016).

    Article  CAS  Google Scholar 

  60. Tang, J. et al. Inhibiting the Hedgehog pathway in patients with the basal-cell nevus syndrome. N. Engl. J. Med. 366, 2180–2188 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Basset-Seguin, N. et al. Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial. Lancet Oncol. 16, 729–736 (2015).

    Article  CAS  PubMed  Google Scholar 

  62. Kim, J. et al. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell 17, 388–399 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kim, D. J. et al. Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma. J. Clin. Oncol. 32, 745–751 (2014).

    Article  CAS  PubMed  Google Scholar 

  64. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02354261 (2018).

  65. HedgePath Pharmaceuticals, Inc. HedgePath Pharmaceuticals announces positive interim data in its phase II (b) cancer trial. PR Newswire https://www.prnewswire.com/news-releases/hedgepath-pharmaceuticals-announces-positive-interim-data-in-its-phase-iib-cancer-trial-300308347.html (2016).

  66. Smith, M. J. et al. Germline mutations in SUFU cause Gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations. J. Clin. Oncol. 32, 4155–4161 (2014).

    Article  CAS  PubMed  Google Scholar 

  67. Gajjar, A. et al. Phase I study of vismodegib in children with recurrent or refractory medulloblastoma: a Pediatric Brain Tumor Consortium study. Clin. Cancer Res. 19, 6305–6312 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Kool, M. et al. Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell 25, 393–405 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Robinson, G. et al. Vismodegib exerts targeted efficacy against recurrent Sonic Hedgehog-subgroup medulloblastoma: results from phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032. J. Clin. Oncol. 33, 2646–2654 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ponti, G. et al. PTCH1 germline mutations and the basaloid follicular hamartoma values in the tumor spectrum of basal cell carcinoma syndrome (NBCCS). Anticancer Res. 38, 471–476 (2018).

    Article  PubMed  CAS  Google Scholar 

  71. Scarpa, M. et al. Mismatch repair gene defects in sporadic colorectal cancer enhance immune surveillance. Oncotarget 6, 43472–43482 (2015).

    PubMed  PubMed Central  Google Scholar 

  72. Vasen, H. F. A. et al. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J. Med. Genet. 44, 353–362 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Banerjea, A. et al. Colorectal cancers with microsatellite instability display mRNA expression signatures characteristic of increased immunogenicity. Mol. Cancer 3, 21 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Phillips, S. et al. Tumour-infiltrating lymphocytes in colorectal cancer with microsatellite instability are activated and cytotoxic. Br. J. Surg. 91, 469–475 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Le, D. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Eng. J. Med. 372, 2509–2520 (2015).

    Article  CAS  Google Scholar 

  76. Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bouffet, E. et al. Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J. Clin. Oncol. 34, 2206–2211 (2016).

    Article  CAS  PubMed  Google Scholar 

  78. Wimmer, K. et al. Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium ‘Care for CMMRD’ (C4CMMRD). J. Med. Genet. 51, 355–365 (2014).

    Article  CAS  PubMed  Google Scholar 

  79. Mouw, K. W. DNA damage and repair biomarkers of immunotherapy response. Cancer Discov. 7, 675–693 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Esteban-Jurado, C. et al. POLE and POLD1 screening in 155 patients with multiple polyps and early-onset colorectal cancer. Oncotarget 8, 26732–26743 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Mehnert, J. M. et al. Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer. J. Clin. Invest. 126, 2334–2340 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Johanns, T. M. et al. Immunogenomics of hypermutated glioblastoma: a patient with germline POLE deficiency treated with checkpoint blockade immunotherapy. Cancer Discov. 6, 1230–1236 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Bamba, S. et al. Familial and multiple gastrointestinal stromal tumors with fair response to a half-dose of imatinib. Intern. Med. 54, 759–764 (2015).

    Article  CAS  PubMed  Google Scholar 

  84. Lasota, J. & Miettinen, M. KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs). Semin. Diagn. Pathol. 23, 91–102 (2006).

    Article  PubMed  Google Scholar 

  85. Demetri, G. D. et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368, 1329–1338 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Demetri, G. D. et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N. Engl. J. Med. 347, 472–480 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Hirota, S. et al. Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors. Gastroenterology 125, 660–667 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. Chompret, A. et al. PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor. Gastroenterology 126, 318–321 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Ricci, R. et al. PDGFRA-mutant syndrome. Mod. Pathol. 28, 954–964 (2015).

    Article  CAS  PubMed  Google Scholar 

  90. Mosse, Y. P. et al. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children’s Oncology Group phase 1 consortium study. Lancet Oncol. 14, 472–480 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Postow, M. A. & Robson, M. E. Inherited gastrointestinal stromal tumor syndromes: mutations, clinical features, and therapeutic implications. Clin. Sarcoma Res. 2, 16 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Hadoux, J. et al. SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma. Int. J. Cancer 135, 2711–2720 (2014).

    Article  CAS  PubMed  Google Scholar 

  93. Hegi, M. E. et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 352, 997–1003 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Kulke, M. H. et al. O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors. Clin. Cancer Res. 15, 338–345 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Helfferich, J. et al. Neurofibromatosis type 1 associated low grade gliomas: A comparison with sporadic low grade gliomas. Crit. Rev. Oncol. Hematol. 104, 30–41 (2016).

    Article  PubMed  Google Scholar 

  96. Dombi, E. et al. Activity of selumetinib in neurofibromatosis type 1–related plexiform neurofibromas. N. Engl. J. Med. 375, 2550–2560 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Krampitz, G. W. & Norton, J. A. RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma. Cancer 120, 1920–1931 (2014).

    Article  CAS  PubMed  Google Scholar 

  98. Wells, S. A. Jr et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J. Clin. Oncol. 30, 134–141 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Fox, E. et al. Vandetanib in children and adolescents with multiple endocrine neoplasia type 2B associated medullary thyroid carcinoma. Clin. Cancer Res. 19, 4239–4248 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Elisei, R., Shane, L., Schlumberger, M. & Muller, S. Cabozantinib in progressive medullary thyroid cancer. J. Clin. Oncol. 31, 3639–3646 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Haddad, R. I. New developments in thyroid cancer. J. Natl Compr. Canc. Netw. 11 (Suppl.), 705–707 (2013).

    Article  PubMed  Google Scholar 

  102. Bell, D. et al. Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR. Nat. Genet. 37, 1315–1316 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Camidge, D. R. et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol. 13, 1011–1019 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Chen, Y. et al. Oncogenic mutations of ALK kinase in neuroblastoma. Nature 455, 971–974 (2008).

    Article  CAS  PubMed  Google Scholar 

  105. Bresler, S. C. et al. ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. Cancer Cell 26, 682–694 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Schmidt, L. et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat. Genet. 16, 68–73 (1997).

    Article  CAS  PubMed  Google Scholar 

  107. Tovar, E. A. & Graveel, C. R. MET in human cancer: germline and somatic mutations. Ann. Transl Med. 5, 205 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Choueiri, T. K. et al. Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. J. Clin. Oncol. 31, 181–186 (2013).

    Article  CAS  PubMed  Google Scholar 

  109. Krishnaswamy, S. et al. Ethnic differences and functional analysis of MET mutations in lung cancer. Clin. Cancer Res. 15, 5714–5723 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kim, I.-J. et al. A novel germline mutation in the MET extracellular domain in a Korean patient with the diffuse type of familial gastric cancer. J. Med. Genet. 40, e97 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Neklason, D. W. et al. Activating mutation in MET oncogene in familial colorectal cancer. BMC Cancer 11, 424 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Tee, A. R. & Blenis, J. mTOR, translational control and human disease. Semin. Cell Dev. Biol. 16, 29–37 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Marsh, D. J. et al. Rapamycin treatment for a child with germline PTEN mutation. Nat. Clin. Pract. Oncol. 5, 357–361 (2008).

    Article  CAS  PubMed  Google Scholar 

  114. Lim, S. et al. Next-generation sequencing reveals somatic mutations that confer exceptional response to everolimus. Oncotarget 7, 10547–10556 (2016).

    PubMed  PubMed Central  Google Scholar 

  115. Robinson, J. et al. Oral rapamycin reduces tumour burden and vascularization in Lkb1(+/−) mice. J. Pathol. 219, 35–40 (2009).

    Article  CAS  PubMed  Google Scholar 

  116. Nordstrom-O’Brien, M. et al. Genetic analysis of von Hippel-Lindau disease. Hum. Mut. 31, 521–537 (2010).

    PubMed  Google Scholar 

  117. Yang, J. C. et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N. Engl. J. Med. 349, 427–434 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Maher, E. R., Neumann, H. P. & Richard, S. von Hippel-Lindau disease: a clinical and scientific review. Eur. J. Hum. Genet. 19, 617–623 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Escudier, B. et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 23, 65–71 (2012).

    Article  Google Scholar 

  120. Lee, A. M. et al. DPYD variants as predictors of 5-fluorouracil toxicity in adjuvant colon cancer treatment (NCCTG N0147). J. Natl Cancer Inst. 106, dju298 (2014).

    PubMed  PubMed Central  Google Scholar 

  121. Marcuello, E. et al. UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. Br. J. Cancer 91, 678–682 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Fukuda, M. et al. Relationship between UGT1A1*27 and UGT1A1*7 polymorphisms and irinotecan-related toxicities in patients with lung cancer. Thorac. Cancer 9, 51–58 (2018).

    Article  CAS  PubMed  Google Scholar 

  123. Re, M. D., Rofi, E., Citi, V., Fidilio, L. & Danesi, R. Should CYP2D6 be genotyped when treating with tamoxifen? Pharmacogenomics 17, 1967–1969 (2016).

    Article  PubMed  CAS  Google Scholar 

  124. Schroth, W. et al. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA 302, 1429–1436 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Bhatia, S. Genetic variation as a modifier of association between therapeutic exposure and subsequent malignant neoplasms in cancer survivors. Cancer 121, 648–663 (2015).

    Article  PubMed  Google Scholar 

  126. Long, G. et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J. Clin. Oncol. 29, 1239–1246 (2011).

    Article  PubMed  Google Scholar 

  127. Smalley, K. et al. Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas. Mol. Cancer Ther. 7, 2876–2883 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Governa, M. et al. Association of CDK4 germline and BRAF somatic mutations in a patient with multiple primary melanomas and BRAF inhibitor resistance. Melanoma Res. 25, 443–446 (2015).

    Article  PubMed  Google Scholar 

  129. de Vos tot Nederveen Cappel, W. H. et al. Survival after adjuvant 5-FU treatment for stage III colon cancer in hereditary nonpolyposis colorectal cancer. Int. J. Cancer 109, 468–471 (2004).

    Article  PubMed  CAS  Google Scholar 

  130. Jover, R. et al. Mismatch repair status in the prediction of benefit from adjuvant fluorouracil chemotherapy in colorectal cancer. Gut 55, 848–855 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Chowell, D. et al. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science 359, 582–587 (2018).

    Article  CAS  PubMed  Google Scholar 

  132. Kauff, N. D. et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N. Engl. J. Med. 346, 1609–1615 (2002).

    Article  PubMed  Google Scholar 

  133. Rebbeck, T. R. et al. Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J. Clin. Oncol. 22, 1055–1062 (2004).

    Article  PubMed  Google Scholar 

  134. Domchek, S. M. et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 304, 967–975 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Peffault de Latour, R. & Soulier, J. How I treat MDS and AML in Fanconi anemia. Blood 127, 2971–2979 (2016).

    Article  CAS  PubMed  Google Scholar 

  136. Hoseini, S. et al. Pediatric Fanconi anemia with secondary AML: a retrospective outcome report from the German AML-BFM Group. Blood 122, 1414 (2013).

    Google Scholar 

  137. Kentwell, M. et al. Mainstreaming cancer genetics: a model integrating germline BRCA testing into routine ovarian cancer clinics. Gynecol. Oncol. 145, 130–136 (2017).

    Article  PubMed  Google Scholar 

  138. Wright, S. et al. Patients’ views of treatment-focused genetic testing (TFGT): some lessons for the mainstreaming of BRCA1 and BRCA2 testing. J. Genet. Couns. 27, 1459–1472 (2018).

    Article  PubMed Central  Google Scholar 

  139. Vasen, H., Watson, P., Mecklin, J.-P. & Lynch, H. T. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch Syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology 116, 1453–1456 (1999).

    Article  CAS  PubMed  Google Scholar 

  140. Burn, J. et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet Oncol. 378, 2081–2087 (2011).

    Article  Google Scholar 

  141. Kwiatkowski, D. J. et al. Response to everolimus is seen in TSC-associated SEGAs and angiomyolipomas independent of mutation type and site in TSC1 and TSC2. Eur. J. Hum. Genet. 23, 1665 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Franz, D. N. et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 381, 125–132 (2013).

    Article  CAS  PubMed  Google Scholar 

  143. Bissler, J. J. et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 381, 817–824 (2013).

    Article  CAS  PubMed  Google Scholar 

  144. Kalender, M. E., Sevinc, A., Tutar, E., Sirikci, A. & Camci, C. Effect of sunitinib on metastatic gastrointestinal stromal tumor in patients with neurofibromatosis type 1: a case report. World J. Gastroenterol. 13, 2629–2632 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Rini, B. I. et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J. Clin. Oncol. 26, 5422–5428 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

All authors gratefully acknowledge funding support from the New South Wales (NSW) Office of Health and Medical Research. S.T. acknowledges funding from an Australian Postgraduate Award and a Garvan PhD top-up and Australian Genomics and Health Alliance PhD top-up scholarship (GNT1113531). M.L.B. acknowledges funding from a Cancer Institute NSW Career Development Fellowship (CDF171109). D.M.T. acknowledges funding from an Australian National Health and Medical Research Council (NHMRC) Principal Research Fellowship (APP1104364).

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  1. Cancer Division, Garvan Institute of Medical Research, Sydney, Australia

    Subotheni Thavaneswaran, Emma Rath, Anthony M. Joshua, Dominique Hess, Mark Pinese, Mandy L. Ballinger & David M. Thomas

  2. The Kinghorn Cancer Centre, St Vincent’s Hospital, Sydney, Australia

    Subotheni Thavaneswaran, Anthony M. Joshua & David M. Thomas

  3. St Vincent’s Clinical School, University of New South Wales (Medicine), Sydney, Australia

    Subotheni Thavaneswaran, Anthony M. Joshua & David M. Thomas

  4. Hereditary Cancer Clinic, Prince of Wales Hospital, Sydney, Australia

    Kathy Tucker

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S.T. researched data for the article. All authors made a substantial contribution to discussions of content. S.T. and D.M.T. wrote the manuscript, and all authors edited and/or reviewed the manuscript before submission.

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Thavaneswaran, S., Rath, E., Tucker, K. et al. Therapeutic implications of germline genetic findings in cancer. Nat Rev Clin Oncol 16, 386–396 (2019). https://doi.org/10.1038/s41571-019-0179-3

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