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.
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.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Cancer Predisposition Genes in Adolescents and Young Adults (AYAs): a Review Paper from the Italian AYA Working Group
Current Oncology Reports Open Access 23 March 2022
Nature Communications Open Access 05 May 2020
Subscribe to Nature+
Get immediate online access to Nature and 55 other Nature journal
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Garber, J. E. & Offit, K. Hereditary cancer predisposition syndromes. J. Clin. Oncol. 23, 276–292 (2005).
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).
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).
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).
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).
Schrader, K. A. et al. Germline variants in targeted tumor sequencing using matched normal DNA. JAMA Oncol. 2, 104–111 (2016).
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).
Zhang, J., Walsh, M., Wu, G. & Edmonson, M. Germline mutations in predisposition genes in pediatric cancer. N. Engl. J. Med. 374, 1390–1391 (2016).
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).
Gröbner, S. N. et al. The landscape of genomic alterations across childhood cancers. Nature 555, 321 (2018).
Kaufman, B. et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J. Clin. Oncol. 33, 244–250 (2015).
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).
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).
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).
Chang, M. T. et al. Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. Nat. Biotechnol. 34, 155–163 (2016).
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).
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).
Huang, K.-l. & Mashl, R. J. et al. Pathogenic germline variants in 10,389 adult cancers. Cell 173, 355–370 (2018).
Li Ding’s Lab. Characterization of germline variants. GitHub https://github.com/ding-lab/CharGer (2018).
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).
Inamura, K. Lung cancer: understanding its molecular pathology and the 2015 WHO classification. Front. Oncol. 7, 193 (2017).
Hyman, D. M. et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N. Engl. J. Med. 373, 726–736 (2015).
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).
Conley, B. A. & Doroshow, J. H. Molecular analysis for therapy choice: NCI MATCH. Semin. Oncol. 41, 297–299 (2014).
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).
Cunanan, K. M. et al. Basket trials in oncology: a trade-off between complexity and efficiency. J. Clin. Oncol. 35, 271–273 (2017).
Carr, T. H. et al. Defining actionable mutations for oncology therapeutic development. Nat. Rev. Cancer 16, 319 (2016).
Simon, R. & Roychowdhury, S. Implementing personalized cancer genomics in clinical trials. Nat. Rev. Drug Discov. 12, 358–369 (2013).
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).
Iyevleva, A. G. & Imyanitov, E. N. Cytotoxic and targeted therapy for hereditary cancers. Hered. Cancer Clin. Pract. 14, 17 (2016).
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).
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).
Norquist, B. et al. Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. J. Clin. Oncol. 29, 3008–3015 (2011).
Byrski, T. et al. Pathologic complete response to neoadjuvant cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res. Treat. 147, 401–405 (2014).
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).
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).
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).
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).
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).
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).
Benafif, S. & Hall, M. An update on PARP inhibitors for the treatment of cancer. Onco Targets Ther. 8, 519–528 (2015).
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).
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).
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).
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).
Mirza, M. R. et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N. Engl. J. Med. 375, 2154–2164 (2016).
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).
Robson, M. et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N. Engl. J. Med. 377, 523–533 (2017).
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).
Mateo, J. et al. DNA-repair defects and olaparib in metastatic prostate cancer. N. Engl. J. Med. 373, 1697–1708 (2015).
Helleday, T. PARP inhibitor receives FDA breakthrough therapy designation in castration resistant prostate cancer: beyond germline BRCA mutations. Ann. Oncol. 27, 755–757 (2016).
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).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02184195 (2018).
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).
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).
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).
Bowden, N. A. Nucleotide excision repair: why is it not used to predict response to platinum-based chemotherapy? Cancer Lett. 346, 163–171 (2014).
Epstein, E. H. Basal cell carcinomas: attack of the hedgehog. Nat. Rev. Cancer 8, 743–754 (2008).
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).
Tang, J. et al. Inhibiting the Hedgehog pathway in patients with the basal-cell nevus syndrome. N. Engl. J. Med. 366, 2180–2188 (2012).
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).
Kim, J. et al. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell 17, 388–399 (2010).
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).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02354261 (2018).
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).
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).
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).
Kool, M. et al. Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell 25, 393–405 (2014).
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).
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).
Scarpa, M. et al. Mismatch repair gene defects in sporadic colorectal cancer enhance immune surveillance. Oncotarget 6, 43472–43482 (2015).
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).
Banerjea, A. et al. Colorectal cancers with microsatellite instability display mRNA expression signatures characteristic of increased immunogenicity. Mol. Cancer 3, 21 (2004).
Phillips, S. et al. Tumour-infiltrating lymphocytes in colorectal cancer with microsatellite instability are activated and cytotoxic. Br. J. Surg. 91, 469–475 (2004).
Le, D. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Eng. J. Med. 372, 2509–2520 (2015).
Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).
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).
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).
Mouw, K. W. DNA damage and repair biomarkers of immunotherapy response. Cancer Discov. 7, 675–693 (2017).
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).
Mehnert, J. M. et al. Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer. J. Clin. Invest. 126, 2334–2340 (2016).
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).
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).
Lasota, J. & Miettinen, M. KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs). Semin. Diagn. Pathol. 23, 91–102 (2006).
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).
Demetri, G. D. et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N. Engl. J. Med. 347, 472–480 (2002).
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).
Chompret, A. et al. PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor. Gastroenterology 126, 318–321 (2004).
Ricci, R. et al. PDGFRA-mutant syndrome. Mod. Pathol. 28, 954–964 (2015).
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).
Postow, M. A. & Robson, M. E. Inherited gastrointestinal stromal tumor syndromes: mutations, clinical features, and therapeutic implications. Clin. Sarcoma Res. 2, 16 (2012).
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).
Hegi, M. E. et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 352, 997–1003 (2005).
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).
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).
Dombi, E. et al. Activity of selumetinib in neurofibromatosis type 1–related plexiform neurofibromas. N. Engl. J. Med. 375, 2550–2560 (2016).
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).
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).
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).
Elisei, R., Shane, L., Schlumberger, M. & Muller, S. Cabozantinib in progressive medullary thyroid cancer. J. Clin. Oncol. 31, 3639–3646 (2013).
Haddad, R. I. New developments in thyroid cancer. J. Natl Compr. Canc. Netw. 11 (Suppl.), 705–707 (2013).
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).
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).
Chen, Y. et al. Oncogenic mutations of ALK kinase in neuroblastoma. Nature 455, 971–974 (2008).
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).
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).
Tovar, E. A. & Graveel, C. R. MET in human cancer: germline and somatic mutations. Ann. Transl Med. 5, 205 (2017).
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).
Krishnaswamy, S. et al. Ethnic differences and functional analysis of MET mutations in lung cancer. Clin. Cancer Res. 15, 5714–5723 (2009).
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).
Neklason, D. W. et al. Activating mutation in MET oncogene in familial colorectal cancer. BMC Cancer 11, 424 (2011).
Tee, A. R. & Blenis, J. mTOR, translational control and human disease. Semin. Cell Dev. Biol. 16, 29–37 (2005).
Marsh, D. J. et al. Rapamycin treatment for a child with germline PTEN mutation. Nat. Clin. Pract. Oncol. 5, 357–361 (2008).
Lim, S. et al. Next-generation sequencing reveals somatic mutations that confer exceptional response to everolimus. Oncotarget 7, 10547–10556 (2016).
Robinson, J. et al. Oral rapamycin reduces tumour burden and vascularization in Lkb1(+/−) mice. J. Pathol. 219, 35–40 (2009).
Nordstrom-O’Brien, M. et al. Genetic analysis of von Hippel-Lindau disease. Hum. Mut. 31, 521–537 (2010).
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).
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).
Escudier, B. et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 23, 65–71 (2012).
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).
Marcuello, E. et al. UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. Br. J. Cancer 91, 678–682 (2004).
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).
Re, M. D., Rofi, E., Citi, V., Fidilio, L. & Danesi, R. Should CYP2D6 be genotyped when treating with tamoxifen? Pharmacogenomics 17, 1967–1969 (2016).
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).
Bhatia, S. Genetic variation as a modifier of association between therapeutic exposure and subsequent malignant neoplasms in cancer survivors. Cancer 121, 648–663 (2015).
Long, G. et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J. Clin. Oncol. 29, 1239–1246 (2011).
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).
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).
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).
Jover, R. et al. Mismatch repair status in the prediction of benefit from adjuvant fluorouracil chemotherapy in colorectal cancer. Gut 55, 848–855 (2006).
Chowell, D. et al. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science 359, 582–587 (2018).
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).
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).
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).
Peffault de Latour, R. & Soulier, J. How I treat MDS and AML in Fanconi anemia. Blood 127, 2971–2979 (2016).
Hoseini, S. et al. Pediatric Fanconi anemia with secondary AML: a retrospective outcome report from the German AML-BFM Group. Blood 122, 1414 (2013).
Kentwell, M. et al. Mainstreaming cancer genetics: a model integrating germline BRCA testing into routine ovarian cancer clinics. Gynecol. Oncol. 145, 130–136 (2017).
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).
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).
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).
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).
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).
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).
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).
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).
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).
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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
This article is cited by
Breast Cancer Research and Treatment (2022)
Cancer Predisposition Genes in Adolescents and Young Adults (AYAs): a Review Paper from the Italian AYA Working Group
Current Oncology Reports (2022)
Identification of Germline Mutations in East-Asian Young Never-Smokers with Lung Adenocarcinoma by Whole-Exome Sequencing
Nature Genetics (2021)
Nature Communications (2020)