Architecture of Inherited Susceptibility to Common Cancer

Overview

Journal Nat Rev Cancer

Specialty Oncology

Date 2010 Apr 24

PMID 20414203

Citations 100

Authors

Olivia Fletcher

Richard S Houlston

Affiliations

Soon will be listed here.

Abstract

This Timeline article looks back at 40 years of research into the inherited genetic basis of cancer and the insights these studies have yielded. Early epidemiological research provided evidence for the 'two-hit' model of cancer predisposition. During the 1980s and 1990s linkage and positional cloning analyses led to the identification of high-penetrance cancer susceptibility genes. The past decade has seen a shift from models of predisposition based on single-gene causative mutations to multigenic models. These models suggest that a high proportion of cancers may arise in a genetically susceptible minority as a consequence of the combined effects of common low-penetrance alleles and rare disease-causing variants that confer moderate cancer risks.

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References

Peto J, Houlston R . Genetics and the common cancers. Eur J Cancer. 2001; 37 Suppl 8:S88-96. DOI: 10.1016/s0959-8049(01)00255-6. View

Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P . E-cadherin germline mutations in familial gastric cancer. Nature. 1998; 392(6674):402-5. DOI: 10.1038/32918. View

Wrensch M, Jenkins R, Chang J, Yeh R, Xiao Y, Decker P . Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility. Nat Genet. 2009; 41(8):905-8. PMC: 2923561. DOI: 10.1038/ng.408. View

Malkin D, Li F, Strong L, Fraumeni Jr J, Nelson C, Kim D . Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990; 250(4985):1233-8. DOI: 10.1126/science.1978757. View

Trevino L, Yang W, French D, Hunger S, Carroll W, Devidas M . Germline genomic variants associated with childhood acute lymphoblastic leukemia. Nat Genet. 2009; 41(9):1001-5. PMC: 2762391. DOI: 10.1038/ng.432. View

Houlston R, Webb E, Broderick P, Pittman A, Di Bernardo M, Lubbe S . Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. Nat Genet. 2008; 40(12):1426-35. PMC: 2836775. DOI: 10.1038/ng.262. View

Srivastava S, Zou Z, Pirollo K, Blattner W, Chang E . Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature. 1990; 348(6303):747-9. DOI: 10.1038/348747a0. View

Easton D . Cancer risks in A-T heterozygotes. Int J Radiat Biol. 1994; 66(6 Suppl):S177-82. DOI: 10.1080/09553009414552011. View

Nevanlinna H, Bartek J . The CHEK2 gene and inherited breast cancer susceptibility. Oncogene. 2006; 25(43):5912-9. DOI: 10.1038/sj.onc.1209877. View

10.

Zanke B, Greenwood C, Rangrej J, Kustra R, Tenesa A, Farrington S . Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat Genet. 2007; 39(8):989-94. DOI: 10.1038/ng2089. View

11.

Wiemels J, Cazzaniga G, Daniotti M, Eden O, Addison G, Masera G . Prenatal origin of acute lymphoblastic leukaemia in children. Lancet. 1999; 354(9189):1499-503. DOI: 10.1016/s0140-6736(99)09403-9. View

12.

Meyer K, Maia A, OReilly M, Teschendorff A, Chin S, Caldas C . Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer. PLoS Biol. 2008; 6(5):e108. PMC: 2365982. DOI: 10.1371/journal.pbio.0060108. View

13.

Futreal P, Coin L, Marshall M, Down T, Hubbard T, Wooster R . A census of human cancer genes. Nat Rev Cancer. 2004; 4(3):177-83. PMC: 2665285. DOI: 10.1038/nrc1299. View

14.

Seal S, Thompson D, Renwick A, Elliott A, Kelly P, Barfoot R . Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet. 2006; 38(11):1239-41. DOI: 10.1038/ng1902. View

15.

Hung R, McKay J, Gaborieau V, Boffetta P, Hashibe M, Zaridze D . A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature. 2008; 452(7187):633-7. DOI: 10.1038/nature06885. View

16.

Tomlinson I, Dunlop M, Campbell H, Zanke B, Gallinger S, Hudson T . COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer. Br J Cancer. 2009; 102(2):447-54. PMC: 2816642. DOI: 10.1038/sj.bjc.6605338. View

17.

Hethcote H, Knudson Jr A . Model for the incidence of embryonal cancers: application to retinoblastoma. Proc Natl Acad Sci U S A. 1978; 75(5):2453-7. PMC: 392572. DOI: 10.1073/pnas.75.5.2453. View

18.

Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, Ahmed M . ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet. 2006; 38(8):873-5. DOI: 10.1038/ng1837. View

19.

Erkko H, Xia B, Nikkila J, Schleutker J, Syrjakoski K, Mannermaa A . A recurrent mutation in PALB2 in Finnish cancer families. Nature. 2007; 446(7133):316-9. DOI: 10.1038/nature05609. View

20.

Thompson D, Duedal S, Kirner J, McGuffog L, Last J, Reiman A . Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst. 2005; 97(11):813-22. DOI: 10.1093/jnci/dji141. View