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.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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.
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.
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.
Fung, Y. K. et al. Structural evidence for the authenticity of the human retinoblastoma gene. Science 236, 1657–1661 (1987).
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).
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).
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).
Zuo, L. et al. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nature Genet. 12, 97–99 (1996).
Nichols, A. F., Ong, P. & Linn, S. Mutations specific to the xeroderma pigmentosum group E Ddb− phenotype. J. Biol. Chem. 271, 24317–24320 (1996).
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).
Stickens, D. et al. The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes. Nature Genet. 14, 25–32 (1996).
Pilia, G. et al. Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome. Nature Genet. 12, 241–247 (1996).
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).
Whitcomb, D. C. et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nature Genet. 14, 141–145 (1996).
Yu, C. E. et al. Positional cloning of the Werner's syndrome gene. Science 272, 258–262 (1996).
Johnson, R. L. et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272, 1668–1671 (1996).
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.
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).
Hanks, S. et al. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nature Genet. 36, 1159–1161 (2004).
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).
Nicolaides, N. C. et al. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371, 75–80 (1994).
Miyaki, M. et al. Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nature Genet. 17, 271–272 (1997).
Niemann, S. & Muller, U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nature Genet. 26, 268–270 (2000).
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.
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).
Rahman, N. et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nature Genet. 39, 165–167 (2007).
Hao, H. X. et al. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 325, 1139–1142 (2009).
Loveday, C. et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nature Genet. 43, 879–882 (2011).
Lohmann, D. R. RB1 gene mutations in retinoblastoma. Hum. Mutat. 14, 283–288 (1999).
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.
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).
Nishida, T. et al. Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. Nature Genet. 19, 323–324 (1998).
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).
Taylor, M. D. et al. Mutations in SUFU predispose to medulloblastoma. Nature Genet. 31, 306–310 (2002).
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).
Chompret, A. et al. PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor. Gastroenterology 126, 318–321 (2004).
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).
Niemeyer, C. M. et al. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nature Genet. 42, 794–800 (2010).
Wiesner, T. et al. Germline mutations in BAP1 predispose to melanocytic tumors. Nature Genet. 43, 1018–1021 (2011).
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.
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.
Hudson, T. J. et al. International network of cancer genome projects. Nature 464, 993–998 (2010).
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).
Barrett, J. H. et al. Genome-wide association study identifies three new melanoma susceptibility loci. Nature Genet. 43, 1108–1113 (2011).
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).
Stacey, S. N. et al. A germline variant in the TP53 polyadenylation signal confers cancer susceptibility. Nature Genet. 43, 1098–1103 (2011).
Rafnar, T. et al. Sequence variants at the TERT-CLPTM1L locus associate with many cancer types. Nature Genet. 41, 221–227 (2009).
Nelson, N. D. & Bertuch, A. A. Dyskeratosis congenita as a disorder of telomere maintenance. Mutat. Res. 730, 43–51 (2012).
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).
Teslovich, T. M. et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707–713 (2010).
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).
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).
Dixit, A. et al. Sequence and structure signatures of cancer mutation hotspots in protein kinases. PLoS ONE 4, e7485 (2009).
Huff, V. Wilms' tumours: about tumour suppressor genes, an oncogene and a chameleon gene. Nature Rev. Cancer 11, 111–121 (2011).
Berger, A. H., Knudson, A. G. & Pandolfi, P. P. A continuum model for tumour suppression. Nature 476, 163–169 (2011).
Villanueva, A., Newell, P. & Hoshida, Y. Inherited hepatocellular carcinoma. Best Pract. Res. Clin. Gastroenterol. 24, 725–734 (2010).
Rutter, J., Winge, D. R. & Schiffman, J. D. Succinate dehydrogenase — assembly, regulation and role in human disease. Mitochondrion 10, 393–401 (2010).
Santen, G. W., Kriek, M. & van Attikum, H. SWI/SNF complex in disorder: SWItching from malignancies to intellectual disability. Epigenetics 7, 1219–1224 (2012).
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).
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).
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).
Scott, R. H. et al. Constitutional 11p15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumor. Nature Genet. 40, 1329–1334 (2008).
Gayther, S. A. & Pharoah, P. D. The inherited genetics of ovarian and endometrial cancer. Curr. Opin. Genet. Dev. 20, 231–238 (2010).
Pacini, F., Castagna, M. G., Cipri, C. & Schlumberger, M. Medullary thyroid carcinoma. Clin. Oncol. 22, 475–485 (2010).
Jafri, M. & Maher, E. R. The genetics of phaeochromocytoma: using clinical features to guide genetic testing. Eur. J. Endocrinol. 166, 151–158 (2012).
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).
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).
Rausch, T. et al. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 148, 59–71 (2012).
Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).
Aoki, Y. et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nature Genet. 37, 1038–1040 (2005).
Hafner, C. & Groesser, L. Mosaic RASopathies. Cell Cycle 12, 43–50 (2013).
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.
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).
Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J. Natl Cancer Inst. 91, 1310–1316 (1999).
Thompson, D. & Easton, D. Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am. J. Hum. Genet. 68, 410–419 (2001).
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).
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.
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).
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).
Gaudet, M. M. et al. Common genetic variants and modification of penetrance of BRCA2-associated breast cancer. PLoS Genet. 6, e1001183 (2010).
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).
Chompret, A. et al. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br. J. Cancer 82, 1932–1937 (2000).
Figueiredo, B. C. et al. Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation. J. Med. Genet. 43, 91–96 (2006).
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).
Turner, N. C. & Tutt, A. N. Platinum chemotherapy for BRCA1-related breast cancer: do we need more evidence? Breast Cancer Res. 14, 115 (2012).
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).
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).
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).
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).
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).
Logan, T. F. Foretinib (XL880): c-MET inhibitor with activity in papillary renal cell cancer. Curr. Oncol. Rep. 15, 83–90 (2013).
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).
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).
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.
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).
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).
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.
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).
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).
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).
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).
Rozen, P. & Macrae, F. Familial adenomatous polyposis: the practical applications of clinical and molecular screening. Fam. Cancer 5, 227–235 (2006).
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).
Burn, J., Mathers, J. C. & Bishop, D. T. Chemoprevention in Lynch syndrome. Fam. Cancer 12, 707–718 (2013).
Abecasis, G. R. et al. An integrated map of genetic variation from 1,092 human genomes. Nature 491, 56–65 (2012).
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).
Turnbull, C. et al. Gene–gene interactions in breast cancer susceptibility. Hum. Mol. Genet. 21, 958–962 (2012).
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.
Scott, R. H. et al. Stratification of Wilms tumor by genetic and epigenetic analysis. Oncotarget 3, 327–335 (2012).
Ruark, E. et al. Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature 493, 406–410 (2013).
Green, R. C. et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet. Med. 15, 565–574 (2013).
Wilson, J. M. G. & Jungner, G. Principles and Practice of Screening for Disease (WHO, 1968).
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.
The author declares no competing financial interests.
Reprints and permissions information is available at www.nature.com/reprints.
About this article
Cite this article
Rahman, N. Realizing the promise of cancer predisposition genes. Nature 505, 302–308 (2014). https://doi.org/10.1038/nature12981
Blood Advances (2020)
International Journal of Cancer (2020)
Der Onkologe (2020)