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PMID: 20414203 Published · ppublish English Journal Article Review

Architecture of inherited susceptibility to common cancer.

Nature reviews. Cancer ·Vol. 10 ·No. 5 ·2010-05-00 ·Pages 353-61

Fletcher O, Houlston RS

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.

MeSH Terms
Genetic Predisposition to Disease/genetics Humans Neoplasms/genetics
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Fletcher Olivia
Olivia Fletcher is at the Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, UK.
Houlston Richard S
References (107)
107 references, click to expand
  1. Genetics and the common cancers.
    Eur J Cancer. 2001 Oct;37 Suppl 8:S88-96 PMID: 11602375
  2. E-cadherin germline mutations in familial gastric cancer.
    Nature. 1998 Mar 26;392(6674):402-5 PMID: 9537325
  3. Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility.
    Nat Genet. 2009 Aug;41(8):905-8 PMID: 19578366
  4. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms.
    Science. 1990 Nov 30;250(4985):1233-8 PMID: 1978757
  5. Germline genomic variants associated with childhood acute lymphoblastic leukemia.
    Nat Genet. 2009 Sep;41(9):1001-5 PMID: 19684603
  6. Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer.
    Nat Genet. 2008 Dec;40(12):1426-35 PMID: 19011631
  7. Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome.
    Nature. 1990 Dec 20-27;348(6303):747-9 PMID: 2259385
  8. Cancer risks in A-T heterozygotes.
    Int J Radiat Biol. 1994 Dec;66(6 Suppl):S177-82 PMID: 7836845
  9. The CHEK2 gene and inherited breast cancer susceptibility.
    Oncogene. 2006 Sep 25;25(43):5912-9 PMID: 16998506
  10. Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24.
    Nat Genet. 2007 Aug;39(8):989-94 PMID: 17618283
  11. Prenatal origin of acute lymphoblastic leukaemia in children.
    Lancet. 1999 Oct 30;354(9189):1499-503 PMID: 10551495
  12. Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer.
    PLoS Biol. 2008 May 6;6(5):e108 PMID: 18462018
  13. A census of human cancer genes.
    Nat Rev Cancer. 2004 Mar;4(3):177-83 PMID: 14993899
  14. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles.
    Nat Genet. 2006 Nov;38(11):1239-41 PMID: 17033622
  15. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25.
    Nature. 2008 Apr 3;452(7187):633-7 PMID: 18385738
  16. COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer.
    Br J Cancer. 2010 Jan 19;102(2):447-54 PMID: 19920828
  17. Model for the incidence of embryonal cancers: application to retinoblastoma.
    Proc Natl Acad Sci U S A. 1978 May;75(5):2453-7 PMID: 276883
  18. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles.
    Nat Genet. 2006 Aug;38(8):873-5 PMID: 16832357
  19. A recurrent mutation in PALB2 in Finnish cancer families.
    Nature. 2007 Mar 15;446(7133):316-9 PMID: 17287723
  20. Cancer risks and mortality in heterozygous ATM mutation carriers.
    J Natl Cancer Inst. 2005 Jun 1;97(11):813-22 PMID: 15928302
  21. A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21.
    Nat Genet. 2007 Aug;39(8):984-8 PMID: 17618284
  22. The colorectal cancer risk at 18q21 is caused by a novel variant altering SMAD7 expression.
    Genome Res. 2009 Jun;19(6):987-93 PMID: 19395656
  23. Evaluating the effects of imputation on the power, coverage, and cost efficiency of genome-wide SNP platforms.
    Am J Hum Genet. 2008 Jul;83(1):112-9 PMID: 18589396
  24. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene.
    Science. 2009 Apr 10;324(5924):217 PMID: 19264984
  25. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma.
    Nature. 1986 Oct 16-22;323(6089):643-6 PMID: 2877398
  26. Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish Family-Cancer Database.
    Int J Cancer. 2002 May 10;99(2):260-6 PMID: 11979442
  27. Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer.
    Nat Genet. 2009 Sep;41(9):991-5 PMID: 19648920
  28. Polygenic susceptibility to breast cancer and implications for prevention.
    Nat Genet. 2002 May;31(1):33-6 PMID: 11984562
  29. Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24.
    Nat Genet. 2007 May;39(5):631-7 PMID: 17401366
  30. Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer.
    J Natl Cancer Inst. 1999 Jun 2;91(11):943-9 PMID: 10359546
  31. Genome-wide association study identifies five susceptibility loci for glioma.
    Nat Genet. 2009 Aug;41(8):899-904 PMID: 19578367
  32. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer.
    Nature. 1994 Mar 17;368(6468):258-61 PMID: 8145827
  33. Copy number variation at 1q21.1 associated with neuroblastoma.
    Nature. 2009 Jun 18;459(7249):987-91 PMID: 19536264
  34. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33.
    Nat Genet. 2010 Mar;42(3):224-8 PMID: 20101243
  35. A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia.
    Nat Genet. 2008 Oct;40(10):1204-10 PMID: 18758461
  36. The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer.
    Nat Genet. 2009 Aug;41(8):882-4 PMID: 19561607
  37. Identification and characterization of the familial adenomatous polyposis coli gene.
    Cell. 1991 Aug 9;66(3):589-600 PMID: 1651174
  38. Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Anglian Breast Cancer Study Group.
    Br J Cancer. 2000 Nov;83(10):1301-8 PMID: 11044354
  39. Calibrating the performance of SNP arrays for whole-genome association studies.
    PLoS Genet. 2008 Jun 27;4(6):e1000109 PMID: 18584036
  40. Fine mapping and functional analysis of a common variant in MSMB on chromosome 10q11.2 associated with prostate cancer susceptibility.
    Proc Natl Acad Sci U S A. 2009 May 12;106(19):7933-8 PMID: 19383797
  41. Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland.
    N Engl J Med. 2000 Jul 13;343(2):78-85 PMID: 10891514
  42. Mutation of a mutL homolog in hereditary colon cancer.
    Science. 1994 Mar 18;263(5153):1625-9 PMID: 8128251
  43. Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics.
    PLoS Genet. 2008 Apr 25;4(4):e1000054 PMID: 18437204
  44. Lung cancer susceptibility locus at 5p15.33.
    Nat Genet. 2008 Dec;40(12):1404-6 PMID: 18978790
  45. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer.
    Nat Genet. 2009 Sep;41(9):986-90 PMID: 19648918
  46. A common coding variant in CASP8 is associated with breast cancer risk.
    Nat Genet. 2007 Mar;39(3):352-8 PMID: 17293864
  47. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer.
    Cell. 1993 Dec 17;75(6):1215-25 PMID: 8261515
  48. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1.
    Nat Genet. 2008 May;40(5):616-22 PMID: 18385676
  49. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24.
    Nat Genet. 2007 May;39(5):645-9 PMID: 17401363
  50. Common and rare variants in multifactorial susceptibility to common diseases.
    Nat Genet. 2008 Jun;40(6):695-701 PMID: 18509313
  51. Genome-wide association study identifies novel breast cancer susceptibility loci.
    Nature. 2007 Jun 28;447(7148):1087-93 PMID: 17529967
  52. Breast and other cancers in families with ataxia-telangiectasia.
    N Engl J Med. 1987 May 21;316(21):1289-94 PMID: 3574400
  53. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer.
    Nat Genet. 2007 Jul;39(7):870-4 PMID: 17529973
  54. ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma.
    Nat Genet. 2008 Jul;40(7):886-91 PMID: 18488027
  55. Genetic mapping of a second locus predisposing to hereditary non-polyposis colon cancer.
    Nat Genet. 1993 Nov;5(3):279-82 PMID: 7903889
  56. The future of genetic studies of complex human diseases.
    Science. 1996 Sep 13;273(5281):1516-7 PMID: 8801636
  57. Identification of the breast cancer susceptibility gene BRCA2.
    Nature. 1995 Dec 21-28;378(6559):789-92 PMID: 8524414
  58. Multiple ADH genes are associated with upper aerodigestive cancers.
    Nat Genet. 2008 Jun;40(6):707-9 PMID: 18500343
  59. Implications of familial colorectal cancer risk profiles and microsatellite instability status.
    J Clin Oncol. 2009 May 1;27(13):2238-44 PMID: 19307499
  60. A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk.
    Nat Genet. 2007 Nov;39(11):1315-7 PMID: 17934461
  61. Localization of the gene for familial adenomatous polyposis on chromosome 5.
    Nature. 1987 Aug 13-19;328(6131):614-6 PMID: 3039373
  62. Sequence variant on 8q24 confers susceptibility to urinary bladder cancer.
    Nat Genet. 2008 Nov;40(11):1307-12 PMID: 18794855
  63. Identification of deletion mutations and three new genes at the familial polyposis locus.
    Cell. 1991 Aug 9;66(3):601-13 PMID: 1678319
  64. Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors.
    Nat Genet. 2002 Feb;30(2):227-32 PMID: 11818965
  65. Comprehensive resequence analysis of a 136 kb region of human chromosome 8q24 associated with prostate and colon cancers.
    Hum Genet. 2008 Sep;124(2):161-70 PMID: 18704501
  66. p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition.
    Cancer Res. 2001 Aug 1;61(15):5718-22 PMID: 11479205
  67. Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk.
    Nat Genet. 2008 Jan;40(1):26-8 PMID: 18084292
  68. A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2.
    Nat Genet. 2009 Sep;41(9):996-1000 PMID: 19648919
  69. Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women.
    Breast Cancer Res. 2007;9(6):R83 PMID: 18053174
  70. Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer.
    Nat Genet. 2007 Jul;39(7):865-9 PMID: 17529974
  71. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene.
    Nat Genet. 2007 Feb;39(2):165-7 PMID: 17200668
  72. Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC.
    Nat Genet. 1997 Sep;17(1):79-83 PMID: 9288102
  73. Most rare missense alleles are deleterious in humans: implications for complex disease and association studies.
    Am J Hum Genet. 2007 Apr;80(4):727-39 PMID: 17357078
  74. The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling.
    Nat Genet. 2009 Aug;41(8):885-90 PMID: 19561604
  75. Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi.
    Nat Genet. 2009 Aug;41(8):915-9 PMID: 19578365
  76. Genome-wide association study identifies three loci associated with melanoma risk.
    Nat Genet. 2009 Aug;41(8):920-5 PMID: 19578364
  77. Chromosome 8q23.3 and 11q23.1 variants modify colorectal cancer risk in Lynch syndrome.
    Gastroenterology. 2009 Jan;136(1):131-7 PMID: 19010329
  78. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations.
    Nat Genet. 2002 May;31(1):55-9 PMID: 11967536
  79. Multiple newly identified loci associated with prostate cancer susceptibility.
    Nat Genet. 2008 Mar;40(3):316-21 PMID: 18264097
  80. Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia.
    Nat Genet. 2009 Sep;41(9):1006-10 PMID: 19684604
  81. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease.
    Nature. 2008 Apr 3;452(7187):638-642 PMID: 18385739
  82. Carcinogenesis in MYH-associated polyposis follows a distinct genetic pathway.
    Cancer Res. 2003 Nov 15;63(22):7595-9 PMID: 14633673
  83. Deciphering the impact of common genetic variation on lung cancer risk: a genome-wide association study.
    Cancer Res. 2009 Aug 15;69(16):6633-41 PMID: 19654303
  84. Colonic cancer arising in polyposis coli.
    J Med Genet. 1969 Dec;6(4):376-8 PMID: 5365944
  85. Sequence variants at the TERT-CLPTM1L locus associate with many cancer types.
    Nat Genet. 2009 Feb;41(2):221-7 PMID: 19151717
  86. Common 5p15.33 and 6p21.33 variants influence lung cancer risk.
    Nat Genet. 2008 Dec;40(12):1407-9 PMID: 18978787
  87. Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk.
    Nat Genet. 2010 Feb;42(2):132-6 PMID: 20062064
  88. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.
    Science. 1994 Oct 7;266(5182):66-71 PMID: 7545954
  89. Breast cancer susceptibility-A new look at an old model.
    Cancer Cell. 2002 Jun;1(5):411-2 PMID: 12124169
  90. Clinical implications of the colorectal cancer risk associated with MUTYH mutation.
    J Clin Oncol. 2009 Aug 20;27(24):3975-80 PMID: 19620482
  91. Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers.
    Am J Hum Genet. 2008 Apr;82(4):937-48 PMID: 18355772
  92. The gene for familial polyposis coli maps to the long arm of chromosome 5.
    Science. 1987 Dec 4;238(4832):1411-3 PMID: 3479843
  93. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer.
    Cell. 1993 Dec 3;75(5):1027-38 PMID: 8252616
  94. Explaining the familial colorectal cancer risk associated with mismatch repair (MMR)-deficient and MMR-stable tumors.
    Clin Cancer Res. 2007 Jan 1;13(1):356-61 PMID: 17200375
  95. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13.
    Science. 1994 Sep 30;265(5181):2088-90 PMID: 8091231
  96. Genetic study of breast cancer: identification of a high risk group.
    Cancer. 1974 Oct;34(4):1090-7 PMID: 4424650
  97. NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses.
    Lancet. 2005 Aug 20-26;366(9486):649-59 PMID: 16112301
  98. Germline p16 mutations in familial melanoma.
    Nat Genet. 1994 Sep;8(1):15-21 PMID: 7987387
  99. Genetic mapping of a locus predisposing to human colorectal cancer.
    Science. 1993 May 7;260(5109):810-2 PMID: 8484120
  100. The strength of selection on ultraconserved elements in the human genome.
    Am J Hum Genet. 2007 Apr;80(4):692-704 PMID: 17357075
  101. Linkage of early-onset familial breast cancer to chromosome 17q21.
    Science. 1990 Dec 21;250(4988):1684-9 PMID: 2270482
  102. Assignment of a locus for familial melanoma, MLM, to chromosome 9p13-p22.
    Science. 1992 Nov 13;258(5085):1148-52 PMID: 1439824
  103. A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer.
    Am J Hum Genet. 2002 Aug;71(2):432-8 PMID: 12094328
  104. A common variant associated with prostate cancer in European and African populations.
    Nat Genet. 2006 Jun;38(6):652-8 PMID: 16682969
  105. Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands.
    J Natl Cancer Inst. 1994 Nov 2;86(21):1600-8 PMID: 7932824
  106. Copy number variations and cancer.
    Genome Med. 2009 Jun 16;1(6):62 PMID: 19566914
  107. Identification of FAP locus genes from chromosome 5q21.
    Science. 1991 Aug 9;253(5020):661-5 PMID: 1651562
Article Info
Journal
Nature reviews. Cancer
Abbr.
Nat Rev Cancer
ISSN
1474-1768
DOI
10.1038/nrc2840
Published
2010-05-00
Pages
353-61
Language
English
Region
England
NLM ID
101124168
Subset
IM
External Links
PubMed source DOI: 10.1038/nrc2840 View journal details
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