Realizing the promise of cancer predisposition genes

Subjects

  • A Corrigendum to this article was published on 04 June 2014

Abstract

Genes in which germline mutations confer highly or moderately increased risks of cancer are called cancer predisposition genes. More than 100 of these genes have been identified, providing important scientific insights in many areas, particularly the mechanisms of cancer causation. Moreover, clinical utilization of cancer predisposition genes has had a substantial impact on diagnosis, optimized management and prevention of cancer. The recent transformative advances in DNA sequencing hold the promise of many more cancer predisposition gene discoveries, and greater and broader clinical applications. However, there is also considerable potential for incorrect inferences and inappropriate clinical applications. Realizing the promise of cancer predisposition genes for science and medicine will thus require careful navigation.

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Figure 1: Chromosomal locations of 114 cancer predisposition genes.
Figure 2: Timeline of cancer predisposition gene (CPG) discovery.
Figure 3: Overlap between somatically mutated cancer genes and cancer predisposition genes (CPGs).

References

  1. 1

    Broca, P. Traite des tumeurs. (Asselin, 1866). Broca describes the strong family history of breast cancer in his wife's relatives and, controversially for the time, proposes that it is due to hereditary factors.

    Google Scholar 

  2. 2

    Boveri, T. Zur Frage der Entstehung Maligner Tumoren. (Gustav Fischer, 1914). Boveri's seminal work proposed that genomic dysregulation is central to cancer and may be inherited in some circumstances.

    Google Scholar 

  3. 3

    Knudson, A. G., Jr. Mutation and cancer: statistical study of retinoblastoma. Proc. Natl Acad. Sci. USA 68, 820–823 (1971). A statistical study of retinoblastoma predicted it was due to two mutational events, one of which was inherited in familial and bilateral cases.

    Article  ADS  PubMed  Google Scholar 

  4. 4

    Fung, Y. K. et al. Structural evidence for the authenticity of the human retinoblastoma gene. Science 236, 1657–1661 (1987).

    Article  ADS  CAS  PubMed  Google Scholar 

  5. 5

    Varghese, J. S. & Easton, D. F. Genome-wide association studies in common cancers–what have we learnt? Curr. Opin. Genet. Dev. 20, 201–209 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. 6

    Chang, C. Q. et al. A systemic review of cancer GWAS and candidate gene meta-analyses reveals limited overlap but similar effect sizes. Eur. J. Hum. Genet. http://dx.doi.org/10.1038/ejhg.2013.161 (2013).

  7. 7

    Stadler, Z. K., Gallagher, D. J., Thom, P. & Offit, K. Genome-wide association studies of cancer: principles and potential utility. Oncology 24, 629–637 (2010).

    PubMed  Google Scholar 

  8. 8

    Zuo, L. et al. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nature Genet. 12, 97–99 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  9. 9

    Nichols, A. F., Ong, P. & Linn, S. Mutations specific to the xeroderma pigmentosum group E Ddb phenotype. J. Biol. Chem. 271, 24317–24320 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. 10

    Sijbers, A. M. et al. Xeroderma pigmentosum group F caused by a defect in a structure-specific DNA repair endonuclease. Cell 86, 811–822 (1996).

    Article  CAS  PubMed  Google Scholar 

  11. 11

    Stickens, D. et al. The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes. Nature Genet. 14, 25–32 (1996).

    Article  CAS  PubMed  Google Scholar 

  12. 12

    Pilia, G. et al. Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome. Nature Genet. 12, 241–247 (1996).

    Article  CAS  PubMed  Google Scholar 

  13. 13

    Feder, J. N. et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nature Genet. 13, 399–408 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. 14

    Whitcomb, D. C. et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nature Genet. 14, 141–145 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. 15

    Yu, C. E. et al. Positional cloning of the Werner's syndrome gene. Science 272, 258–262 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  16. 16

    Johnson, R. L. et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272, 1668–1671 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  17. 17

    Comino-Méndez, I. et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nature Genet. 43, 663–667 (2011). This article reports the first CPG to be identified through exome sequencing.

    Article  CAS  PubMed  Google Scholar 

  18. 18

    Smith, M. J. et al. Loss-of-function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas. Nature Genet. 45, 295–298 (2013).

    Article  CAS  PubMed  Google Scholar 

  19. 19

    Hanks, S. et al. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nature Genet. 36, 1159–1161 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. 20

    Armanios, M. et al. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc. Natl Acad. Sci. USA 102, 15960–15964 (2005).

    Article  ADS  CAS  PubMed  Google Scholar 

  21. 21

    Nicolaides, N. C. et al. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371, 75–80 (1994).

    Article  ADS  CAS  PubMed  Google Scholar 

  22. 22

    Miyaki, M. et al. Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nature Genet. 17, 271–272 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. 23

    Niemann, S. & Muller, U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nature Genet. 26, 268–270 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. 24

    Meijers-Heijboer, H. et al. Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nature Genet. 31, 55–59 (2002). This article reports the first clear example of a moderate penetrance hereditary CPG.

    Article  CAS  PubMed  Google Scholar 

  25. 25

    Seal, S. et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nature Genet. 38, 1239–1241 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. 26

    Rahman, N. et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nature Genet. 39, 165–167 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. 27

    Hao, H. X. et al. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 325, 1139–1142 (2009).

    Article  ADS  CAS  PubMed  Google Scholar 

  28. 28

    Loveday, C. et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nature Genet. 43, 879–882 (2011).

    Article  CAS  PubMed  Google Scholar 

  29. 29

    Lohmann, D. R. RB1 gene mutations in retinoblastoma. Hum. Mutat. 14, 283–288 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. 30

    Malkin, D. et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250, 1233–1238 (1990). In this study, the authors used a candidate gene approach to demonstrate that germline TP53 mutations confer an increased risk of multiple cancers, often referred to as Li-Fraumeni syndrome.

    Article  ADS  CAS  PubMed  Google Scholar 

  31. 31

    Huff, V. et al. Evidence for WT1 as a Wilms tumor (WT) gene: intragenic germinal deletion in bilateral WT. Am. J. Hum. Genet. 48, 997–1003 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Nishida, T. et al. Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. Nature Genet. 19, 323–324 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. 33

    Sévenet, N. et al. Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am. J. Hum. Genet. 65, 1342–1348 (1999).

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34

    Taylor, M. D. et al. Mutations in SUFU predispose to medulloblastoma. Nature Genet. 31, 306–310 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. 35

    Smith, M. L., Cavenagh, J. D., Lister, T. A. & Fitzgibbon, J. Mutation of CEBPA in familial acute myeloid leukemia. N. Engl. J. Med. 351, 2403–2407 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. 36

    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 

  37. 37

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

    Article  CAS  PubMed  Google Scholar 

  38. 38

    Niemeyer, C. M. et al. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nature Genet. 42, 794–800 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. 39

    Wiesner, T. et al. Germline mutations in BAP1 predispose to melanocytic tumors. Nature Genet. 43, 1018–1021 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. 40

    Al-Tassan, N. et al. Inherited variants of MYH associated with somatic G:CT:A mutations in colorectal tumors. Nature Genet. 30, 227–232 (2002). In this innovative approach, the mutational signature in the tumours was used to identify the underlying CPG.

    Article  CAS  PubMed  Google Scholar 

  41. 41

    Forbes, S. A. et al. The Catalogue of Somatic Mutations in Cancer (COSMIC) (Wiley, 2008). The COSMIC database is a catalogue of somatic mutations that have been identified in cancer and has proved highly useful for many aspects of research.

    Google Scholar 

  42. 42

    Hudson, T. J. et al. International network of cancer genome projects. Nature 464, 993–998 (2010).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Hindorff, L. A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl Acad. Sci. USA 106, 9362–9367 (2009).

    Article  ADS  PubMed  Google Scholar 

  44. 44

    Barrett, J. H. et al. Genome-wide association study identifies three new melanoma susceptibility loci. Nature Genet. 43, 1108–1113 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. 45

    Gao, L. B. et al. The association between ATM D1853N polymorphism and breast cancer susceptibility: a meta-analysis. J. Exp. Clin. Cancer Res. 29, 117 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Stacey, S. N. et al. A germline variant in the TP53 polyadenylation signal confers cancer susceptibility. Nature Genet. 43, 1098–1103 (2011).

    Article  CAS  PubMed  Google Scholar 

  47. 47

    Rafnar, T. et al. Sequence variants at the TERT-CLPTM1L locus associate with many cancer types. Nature Genet. 41, 221–227 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. 48

    Nelson, N. D. & Bertuch, A. A. Dyskeratosis congenita as a disorder of telomere maintenance. Mutat. Res. 730, 43–51 (2012).

    Article  CAS  PubMed  Google Scholar 

  49. 49

    Mocellin, S. et al. Telomerase reverse transcriptase locus polymorphisms and cancer risk: a field synopsis and meta-analysis. J. Natl Cancer Inst. 104, 840–854 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Teslovich, T. M. et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707–713 (2010).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Morris, A. P. et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nature Genet. 44, 981–990 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. 52

    Rahman, N. & Scott, R. H. Cancer genes associated with phenotypes in monoallelic and biallelic mutation carriers: new lessons from old players. Hum. Mol. Genet. 16, R60–R66 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. 53

    Dixit, A. et al. Sequence and structure signatures of cancer mutation hotspots in protein kinases. PLoS ONE 4, e7485 (2009).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Huff, V. Wilms' tumours: about tumour suppressor genes, an oncogene and a chameleon gene. Nature Rev. Cancer 11, 111–121 (2011).

    Article  CAS  Google Scholar 

  55. 55

    Berger, A. H., Knudson, A. G. & Pandolfi, P. P. A continuum model for tumour suppression. Nature 476, 163–169 (2011).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Villanueva, A., Newell, P. & Hoshida, Y. Inherited hepatocellular carcinoma. Best Pract. Res. Clin. Gastroenterol. 24, 725–734 (2010).

    Article  CAS  PubMed  Google Scholar 

  57. 57

    Rutter, J., Winge, D. R. & Schiffman, J. D. Succinate dehydrogenase — assembly, regulation and role in human disease. Mitochondrion 10, 393–401 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Santen, G. W., Kriek, M. & van Attikum, H. SWI/SNF complex in disorder: SWItching from malignancies to intellectual disability. Epigenetics 7, 1219–1224 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Sheppard, K., Kinross, K. M., Solomon, B., Pearson, R. B. & Phillips, W. A. Targeting PI3 kinase/AKT/mTOR signaling in cancer. Crit. Rev. Oncog. 17, 69–95 (2012).

    Article  PubMed  Google Scholar 

  60. 60

    Slade, I. et al. DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome. J. Med. Genet. 48, 273–278 (2011).

    Article  CAS  PubMed  Google Scholar 

  61. 61

    Scott, R. H., Stiller, C. A., Walker, L. & Rahman, N. Syndromes and constitutional chromosomal abnormalities associated with Wilms tumour. J. Med. Genet. 43, 705–715 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Scott, R. H. et al. Constitutional 11p15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumor. Nature Genet. 40, 1329–1334 (2008).

    Article  CAS  PubMed  Google Scholar 

  63. 63

    Gayther, S. A. & Pharoah, P. D. The inherited genetics of ovarian and endometrial cancer. Curr. Opin. Genet. Dev. 20, 231–238 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Pacini, F., Castagna, M. G., Cipri, C. & Schlumberger, M. Medullary thyroid carcinoma. Clin. Oncol. 22, 475–485 (2010).

    Article  CAS  Google Scholar 

  65. 65

    Jafri, M. & Maher, E. R. The genetics of phaeochromocytoma: using clinical features to guide genetic testing. Eur. J. Endocrinol. 166, 151–158 (2012).

    Article  CAS  PubMed  Google Scholar 

  66. 66

    Mavaddat, N. et al. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol. Biomarkers Prev. 21, 134–147 (2012).

    Article  CAS  PubMed  Google Scholar 

  67. 67

    Benusiglio, P. R. et al. CDH1 germline mutations and the hereditary diffuse gastric and lobular breast cancer syndrome: a multicentre study. J. Med. Genet. 50, 486–489 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. 68

    Rausch, T. et al. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 148, 59–71 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Aoki, Y. et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nature Genet. 37, 1038–1040 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. 71

    Hafner, C. & Groesser, L. Mosaic RASopathies. Cell Cycle 12, 43–50 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Horn, S. et al. TERT promoter mutations in familial and sporadic melanoma. Science 339, 959–961 (2013). This provides one of the clearest examples of specific promotor mutations that predispose to cancer, notably melanoma is not one of the carriers prominent in dyskeratosis congenita caused by exonic TERT mutations.

    Article  ADS  CAS  PubMed  Google Scholar 

  73. 73

    Goudie, D. R. et al. Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1. Nature Genet. 43, 365–369 (2011).

    Article  CAS  PubMed  Google Scholar 

  74. 74

    Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J. Natl Cancer Inst. 91, 1310–1316 (1999).

  75. 75

    Thompson, D. & Easton, D. Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am. J. Hum. Genet. 68, 410–419 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Ford, D. et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am. J. Hum. Genet. 62, 676–689 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Antoniou, A. et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am. J. Hum. Genet. 72, 1117–1130 (2003). This is the largest analysis of cancer risks in CPG mutation carriers, demonstrating that the average risks in relatives of cancer cases unselected for family history is lower than in those with a family history of the disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Antoniou, A. C. et al. Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am. J. Hum. Genet. 82, 937–948 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Couch, F. J. et al. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk. PLoS Genet. 9, e1003212 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Gaudet, M. M. et al. Common genetic variants and modification of penetrance of BRCA2-associated breast cancer. PLoS Genet. 6, e1001183 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Moorman, P. G. et al. Evaluation of established breast cancer risk factors as modifiers of BRCA1 or BRCA2: a multi-center case-only analysis. Breast Cancer Res. Treat. 124, 441–451 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Chompret, A. et al. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br. J. Cancer 82, 1932–1937 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Figueiredo, B. C. et al. Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation. J. Med. Genet. 43, 91–96 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. 84

    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 

  85. 85

    Turner, N. C. & Tutt, A. N. Platinum chemotherapy for BRCA1-related breast cancer: do we need more evidence? Breast Cancer Res. 14, 115 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Hunter, C. et al. A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Res. 66, 3987–3991 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. 87

    Scott, R. H. et al. Medulloblastoma, acute myelocytic leukemia and colonic carcinomas in a child with biallelic MSH6 mutations. Nature Clin. Pract. Oncol. 4, 130–134 (2007).

    Article  CAS  Google Scholar 

  88. 88

    Vencken, P. M. et al. Outcome of BRCA1- compared with BRCA2-associated ovarian cancer: a nationwide study in the Netherlands. Ann. Oncol. 24, 2036–2042 (2013).

    Article  CAS  PubMed  Google Scholar 

  89. 89

    Castro, E. et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J. Clin. Oncol. 31, 1748–1757 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Bachet, J.-B. et al. Diagnosis, prognosis and treatment of patients with gastrointestinal stromal tumour (GIST) and germline mutation of KIT exon 13. Eur. J. Cancer 49, 2531–2541 (2013).

    Article  CAS  PubMed  Google Scholar 

  91. 91

    Logan, T. F. Foretinib (XL880): c-MET inhibitor with activity in papillary renal cell cancer. Curr. Oncol. Rep. 15, 83–90 (2013).

    Article  CAS  PubMed  Google Scholar 

  92. 92

    Wells, S. A. Jr et al. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J. Clin. Oncol. 28, 767–772 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Bordeira-Carriço, R., Pego, A. P., Santos, M. & Oliveira, C. Cancer syndromes and therapy by stop-codon readthrough. Trends Mol. Med. 18, 667–678 (2012).

    Article  CAS  PubMed  Google Scholar 

  94. 94

    Aiuti, A. et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott–Aldrich syndrome. Science 341, 1233151 (2013). In this study, a lentiviral vector encoding functional WASP was used to genetically correct haematopoeitic stem cells, which were reinfused into three patients with Wiskott–Aldrich syndrome, with improved clinical symptoms.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Józwiak, S., Stein, K. & Kotulska, K. Everolimus (RAD001): first systemic treatment for subependymal giant cell astrocytoma associated with tuberous sclerosis complex. Future Oncol. 8, 1515–1523 (2012).

    Article  CAS  PubMed  Google Scholar 

  96. 96

    Tang, J. Y. 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 

  97. 97

    Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005). A synthetic lethality strategy was utilised in this study to therapeutically target the DNA repair defect in BRCA deficient cells.

    Article  ADS  CAS  Google Scholar 

  98. 98

    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 

  99. 99

    Brough, R., Frankum, J. R., Costa-Cabral, S., Lord, C. J. & Ashworth, A. Searching for synthetic lethality in cancer. Curr. Opin. Genet. Dev. 21, 34–41 (2011).

    Article  CAS  PubMed  Google Scholar 

  100. 100

    Wells, S. A. Jr, Pacini, F., Robinson, B. G. & Santoro, M. Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. J. Clin. Endocrinol. Metab. 98, 3149–3164 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Reade, C. J., Riva, J. J., Busse, J. W., Goldsmith, C. H. & Elit, L. Risks and benefits of screening asymptomatic women for ovarian cancer: a systematic review and meta-analysis. Gynecol. Oncol. 130, 674–681 (2013).

    Article  PubMed  Google Scholar 

  102. 102

    Rozen, P. & Macrae, F. Familial adenomatous polyposis: the practical applications of clinical and molecular screening. Fam. Cancer 5, 227–235 (2006).

    Article  CAS  PubMed  Google Scholar 

  103. 103

    Seevaratnam, R. et al. A systematic review of the indications for genetic testing and prophylactic gastrectomy among patients with hereditary diffuse gastric cancer. Gastric Cancer 15 (Suppl 1), 153–163 (2012).

    Article  Google Scholar 

  104. 104

    Burn, J., Mathers, J. C. & Bishop, D. T. Chemoprevention in Lynch syndrome. Fam. Cancer 12, 707–718 (2013).

    CAS  Google Scholar 

  105. 105

    Abecasis, G. R. et al. An integrated map of genetic variation from 1,092 human genomes. Nature 491, 56–65 (2012).

    Article  ADS  CAS  Google Scholar 

  106. 106

    Snape, K. et al. Predisposition gene identification in common cancers by exome sequencing: insights from familial breast cancer. Breast Cancer Res. Treat. 134, 429–433 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  107. 107

    Turnbull, C. et al. Gene–gene interactions in breast cancer susceptibility. Hum. Mol. Genet. 21, 958–962 (2012).

    Article  CAS  PubMed  Google Scholar 

  108. 108

    Zhuang, Z. et al. Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N. Engl. J. Med. 367, 922–930 (2012). Somatic gain-of-function mutations in HIF2A predispose carriers to certain tumours, including multiple tumours within an individual, but are not hereditary.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Scott, R. H. et al. Stratification of Wilms tumor by genetic and epigenetic analysis. Oncotarget 3, 327–335 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  110. 110

    Ruark, E. et al. Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature 493, 406–410 (2013).

    Article  CAS  Google Scholar 

  111. 111

    Green, R. C. et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet. Med. 15, 565–574 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Wilson, J. M. G. & Jungner, G. Principles and Practice of Screening for Disease (WHO, 1968).

    Google Scholar 

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Acknowledgements

I am very grateful to many colleagues with whom I have discussed discovery, characterization and clinical translation of CPGs over the past 15 years in particular M. Stratton, H. Hanson and C. Turnbull. I am indebted to A. Strydom for editorial assistance, S. Hanks for construction of Fig. 1 and S. Mahamdallie, B. De Souza, C. Turnbull and E. Ruark for input into the Supplementary Information.

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Rahman, N. Realizing the promise of cancer predisposition genes. Nature 505, 302–308 (2014). https://doi.org/10.1038/nature12981

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