Genome-wide association studies in common cancers--what have we learnt?

Genome-wide association studies (GWAS) have led to the identification of more than 100 common, low-penetrance loci for cancer. At these loci, common genetic variants are associated with moderate increases in risk, typically <1.5-fold. Almost all loci lie in genomic regions not previously suspected to be involved in cancer. A plausible functional basis for a few loci, such as FGFR2 for breast cancer and MSMB for prostate cancer, has been elucidated, but the majority are not understood and suggest new mechanisms of carcinogenesis. Most loci are specific to a single cancer type, and are often subtype specific (e.g. ER-positive breast cancer). There are notable differences in the genetic architecture for different cancer types, with a greater contribution of common variants for prostate cancer. The clinical utility of variants to predict individual disease risk of disease is currently limited, but this may change as more variants are identified.

[1]  Ali Amin Al Olama,et al.  Identification of seven new prostate cancer susceptibility loci through a genome-wide association study , 2009, Nature Genetics.

[2]  Giske Ursin,et al.  FGFR2 variants and breast cancer risk: fine-scale mapping using African American studies and analysis of chromatin conformation. , 2009, Human molecular genetics.

[3]  A. Whittemore,et al.  A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2 , 2009, Nature Genetics.

[4]  Ali Amin Al Olama,et al.  Multiple newly identified loci associated with prostate cancer susceptibility , 2008, Nature Genetics.

[5]  Esko Ukkonen,et al.  The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling , 2009, Nature Genetics.

[6]  J. Carpten,et al.  Evidence for two independent prostate cancer risk–associated loci in the HNF1B gene at 17q12 , 2008, Nature Genetics.

[7]  N. Camp,et al.  Meta Association of Colorectal Cancer Confirms Risk Alleles at 8q24 and 18q21 , 2009, Cancer Epidemiology Biomarkers & Prevention.

[8]  Jaana M. Hartikainen,et al.  A common coding variant in CASP8 is associated with breast cancer risk , 2007, Nature Genetics.

[9]  Paolo Vineis,et al.  A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25 , 2008, Nature.

[10]  Dieter Niederacher,et al.  Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. , 2008, American journal of human genetics.

[11]  B. Ponder,et al.  Polygenes, risk prediction, and targeted prevention of breast cancer. , 2008, The New England journal of medicine.

[12]  Ying Wang,et al.  A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. , 2009, American journal of human genetics.

[13]  A. Whittemore,et al.  Multiple regions within 8q24 independently affect risk for prostate cancer , 2007, Nature Genetics.

[14]  Christopher I Amos,et al.  Common 5p15.33 and 6p21.33 variants influence lung cancer risk , 2008, Nature Genetics.

[15]  D. English,et al.  Identification of new genetic risk factors for prostate cancer. , 2009, Asian journal of andrology.

[16]  R. Hayes,et al.  Comprehensive resequence analysis of a 97 kb region of chromosome 10q11.2 containing the MSMB gene associated with prostate cancer , 2009, Human Genetics.

[17]  S. Weinstein,et al.  Fine mapping and functional analysis of a common variant in MSMB on chromosome 10q11.2 associated with prostate cancer susceptibility , 2009, Proceedings of the National Academy of Sciences.

[18]  W. Willett,et al.  Multiple loci identified in a genome-wide association study of prostate cancer , 2008, Nature Genetics.

[19]  P. Kantoff,et al.  Evaluation of the 8q24 prostate cancer risk locus and MYC expression. , 2009, Cancer research.

[20]  K. Hemminki,et al.  Familial cancers in a nationwide family cancer database: age distribution and prevalence. , 1999, European journal of cancer.

[21]  A. Whittemore,et al.  Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men , 2006, Proceedings of the National Academy of Sciences.

[22]  R. Eeles,et al.  The potential value of microseminoprotein‐β as a prostate cancer biomarker and therapeutic target , 2010, The Prostate.

[23]  Julian Peto,et al.  A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3 , 2008, Nature Genetics.

[24]  John L Hopper,et al.  Multiple loci with different cancer specificities within the 8q24 gene desert. , 2008, Journal of the National Cancer Institute.

[25]  T. Spector,et al.  Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi , 2009, Nature Genetics.

[26]  Kari Stefansson,et al.  Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility , 2009, Nature Genetics.

[27]  P. Pharoah,et al.  Polygenic susceptibility to breast cancer: current state-of-the-art. , 2009, Future oncology.

[28]  A. Sigurdsson,et al.  Common variants on chromosome 5p12 confer susceptibility to estrogen receptor–positive breast cancer , 2008, Nature Genetics.

[29]  M. Beckmann,et al.  Risk of estrogen receptor-positive and -negative breast cancer and single-nucleotide polymorphism 2q35-rs13387042. , 2009, Journal of the National Cancer Institute.

[30]  J. Haines,et al.  Genome-wide association study identifies a novel breast cancer susceptibility locus at 6q25.1 , 2009, Nature Genetics.

[31]  M. Thun,et al.  Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2 , 2009, Nature Genetics.

[32]  D. Kerr,et al.  Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk , 2008, Nature Genetics.

[33]  M. Spitz,et al.  Deciphering the impact of common genetic variation on lung cancer risk: a genome-wide association study. , 2009, Cancer research.

[34]  B. Ponder,et al.  Allele-Specific Up-Regulation of FGFR2 Increases Susceptibility to Breast Cancer , 2008, PLoS biology.

[35]  W. Willett,et al.  A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer , 2007, Nature Genetics.

[36]  J. Malvehy,et al.  Genome-wide association study identifies three loci associated with melanoma risk , 2009, Nature Genetics.

[37]  J. Kaprio,et al.  Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. , 2000, The New England journal of medicine.

[38]  P. Kantoff,et al.  Evaluation of 8q24 and 17q Risk Loci and Prostate Cancer Mortality , 2009, Clinical Cancer Research.

[39]  B. Trock,et al.  Individual and cumulative effect of prostate cancer risk‐associated variants on clinicopathologic variables in 5,895 prostate cancer patients , 2009, The Prostate.

[40]  Steven Gallinger,et al.  Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer , 2008, Nature Genetics.

[41]  Peter Kraft,et al.  Identification of a new prostate cancer susceptibility locus on chromosome 8q24 , 2009, Nature Genetics.

[42]  P. Gregersen,et al.  Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33 , 2008, Proceedings of the National Academy of Sciences.

[43]  D. Gudbjartsson,et al.  Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes , 2007, Nature Genetics.

[44]  R. Eeles,et al.  Genome-wide association studies in cancer. , 2008, Human molecular genetics.

[45]  G. Mills,et al.  Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1 , 2008, Nature Genetics.

[46]  Christopher A. Haiman,et al.  The 8q24 cancer risk variant rs6983267 demonstrates long-range interaction with MYC in colorectal cancer , 2009, Nature Genetics.

[47]  Kari Stefansson,et al.  Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations , 2009, Nature Genetics.

[48]  D. Gudbjartsson,et al.  Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor–positive breast cancer , 2007, Nature Genetics.

[49]  Deborah Hughes,et al.  A genome-wide association study of testicular germ cell tumor , 2009, Nature Genetics.

[50]  Peter Kraft,et al.  Heterogeneity of Breast Cancer Associations with Five Susceptibility Loci by Clinical and Pathological Characteristics , 2008, PLoS genetics.

[51]  A. Gylfason,et al.  A common variant associated with prostate cancer in European and African populations , 2006, Nature Genetics.

[52]  Oliver Sieber,et al.  A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21 , 2007, Nature Genetics.

[53]  Paolo Vineis,et al.  Sequence variants at the TERT-CLPTM1L locus associate with many cancer types , 2009, Nature Genetics.

[54]  Mads Thomassen,et al.  Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers. , 2009, Human molecular genetics.

[55]  Oliver Sieber,et al.  A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk , 2007, Nature Genetics.

[56]  I. Deary,et al.  Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21 , 2008, Nature Genetics.

[57]  P. Fearnhead,et al.  Genome-wide association study of prostate cancer identifies a second risk locus at 8q24 , 2007, Nature Genetics.

[58]  Daniel F. Gudbjartsson,et al.  A variant associated with nicotine dependence, lung cancer and peripheral arterial disease , 2008, Nature.

[59]  Hongling Liao,et al.  Long-range enhancers on 8q24 regulate c-Myc , 2010, Proceedings of the National Academy of Sciences.

[60]  Ali Amin Al Olama,et al.  Multiple loci on 8q24 associated with prostate cancer susceptibility , 2009, Nature Genetics.

[61]  W. Willett,et al.  A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1) , 2009, Nature Genetics.

[62]  Stephen J Chanock,et al.  Genome-wide association studies in cancer--current and future directions. , 2010, Carcinogenesis.

[63]  Nandita Mitra,et al.  Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer , 2009, Nature Genetics.

[64]  Lester L. Peters,et al.  Genome-wide association study identifies novel breast cancer susceptibility loci , 2007, Nature.

[65]  Steven Gallinger,et al.  Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24 , 2007, Nature Genetics.

[66]  Christopher I Amos,et al.  The CHRNA5-A3 region on chromosome 15q24-25.1 is a risk factor both for nicotine dependence and for lung cancer. , 2008, Journal of the National Cancer Institute.

[67]  Nazneen Rahman,et al.  Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations , 2002, Nature Genetics.

[68]  Julian Peto,et al.  Refinement of the basis and impact of common 11q23.1 variation to the risk of developing colorectal cancer. , 2008, Human molecular genetics.

[69]  G. Casey,et al.  Association of common genetic variants in SMAD7 and risk of colon cancer. , 2009, Carcinogenesis.

[70]  D. Clayton.  Prediction and Interaction in Complex Disease Genetics: Experience in Type 1 Diabetes , 2009, PLoS genetics.

[71]  Tony Fletcher,et al.  Sequence variant on 8q24 confers susceptibility to urinary bladder cancer , 2008, Nature Genetics.

[72]  Kevin M. Bradley,et al.  Common sequence variants on 2p15 and Xp11.22 confer susceptibility to prostate cancer , 2008, Nature Genetics.

[73]  D. Gudbjartsson,et al.  Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24 , 2007, Nature Genetics.