Genome‐wide Association Studies of Cancers


Advances in high‐throughput genotyping technologies have enabled the efficient systematic screening of single‐nucleotide polymorphisms (SNPs) throughout the human genome for disease associations in genome‐wide association studies (GWAS). Many human complex diseases have been interrogated by GWAS; these include autoimmune and chronic inflammatory diseases, neurological and neuropsychiatric diseases, cardiovascular diseases and cancers among others. Presently, more than 60 cancer GWAS have been published and numerous novel SNPs and genetic loci were found to be associated with various cancers such as breast, prostate and colorectal cancers. These SNP associations were supported by robust statistical evidence. The GWAS of cancers have so far focused only on SNPs. Other germline genetic variations such as small insertions and deletions (indels), copy number variations (CNVs) and tandem repeat polymorphisms should also be investigated for their associations with cancers in the future.

Key Concepts:

  • Cancer is similar to other complex diseases in that it is a consequence of complex interactions between multiple genetic factors and environmental exposures.

  • The genetic susceptibility of cancer has been previously established by epidemiological, twin and familial aggregation studies.

  • The implication of a genetic component in the aetiology of cancer has driven enormous research endeavours to identify the genetic risk factors.

  • The candidate gene association and linkage analysis approaches to identifying these genetic risk factors has, however, generated inconsistent results in the past.

  • Notable advances have been achieved in recent years by genome‐wide association studies (GWAS) – where several hundred–thousand single nucleotide polymorphisms (SNPs) throughout the human genome are interrogated for disease associations.

  • Numerous novel genetic loci or genes have been implicated in a variety of cancers by GWAS.

  • This significant progress in dissecting the germline genetic component of cancers is credited to the development of high‐throughput genotyping technologies, which has enabled GWAS to be done more efficiently on thousands of samples.

  • Similar to other complex diseases, most of the GWAS‐identified SNPs for cancers have small effect sizes (OR <1.5) and collectively only account for a small fraction of the heritability of cancers.

  • Several practical steps to further uncover additional genetic loci for cancers include (a) extending GWAS in different populations, (b) meta‐analysis, (c) subgroup analysis and (d) a second tier of replication.

  • In addition, other approaches should also be considered such as investigating rare variants or less common SNPs, targeted resequencing of the GWAS‐identified loci, copy number variations and homozygosity mapping analysis.

Keywords: cancer genetics; single nucleotide polymorphisms (SNPs); high‐throughput genotyping technologies; genome‐wide association studies (GWAS); cancer genome sequencing

Figure 1.

Steps to further uncover additional genetic loci for cancers.



Amos CI, Wu X, Broderick P et al. (2008) Genome‐wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nature Genetics 40: 616–622.

Assie G, LaFramboise T, Platzer P et al. (2008) Frequency of germline genomic homozygosity associated with cancer cases. Journal of the American Medical Association 299: 1437–1445.

Bacolod MD, Schemmann GS, Wang S et al. (2008) The signatures of autozygosity among patients with colorectal cancer. Cancer Research 68: 2610–2621.

Baird (2010) Variation at the TERT locus and predisposition for cancer. Expert Reviews in Molecular Medicine 12: e16.

Barrett JC, Hansoul S, Nicolae DL et al. (2008) Genome‐wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nature Genetics 40: 955–962.

Bei JX, Li Y, Jia WH et al. (2010) A genome‐wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci. Nature Genetics 42: 599–603.

Bishop DT, Demenais F, Iles MM et al. (2009) Genome‐wide association study identifies three loci associated with melanoma risk. Nature Genetics 41: 920–925.

Broderick P, Carvajal‐Carmona L, Pittman AM et al. (2007) A genome‐wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nature Genetics 39: 1315–1317.

Broderick P, Wang Y, Vijayakrishnan J et al. (2009) Deciphering the impact of common genetic variation on lung cancer risk: a genome‐wide association study. Cancer Research 69: 6633–6641.

Conrad DF, Pinto D, Redon R et al. (2010) Origins and functional impact of copy number variation in the human genome. Nature 464: 704–712.

Cook EH Jr and Scherer SW (2008) Copy‐number variations associated with neuropsychiatric conditions. Nature 455: 919–923.

Crowther‐Swanepoel D, Broderick P, Di Bernardo MC et al. (2010) Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk. Nature Genetics 42: 132–136.

Czene K, Lichtenstein P and Hemminki K (2002) Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish family cancer database. International Journal of Cancer 99: 260–266.

Dickson SP, Wang K, Krantz I et al. (2010) Rare variants create synthetic genome‐wide associations. PLoS Biology 8: e1000294.

Diskin SJ, Hou C, Glessner JT et al. (2009) Copy number variation at 1q21.1 associated with neuroblastoma. Nature 459: 987–991.

Easton DF, Pooley KA, Dunning AM et al. (2007) Genome‐wide association study identifies novel breast cancer susceptibility loci. Nature 447: 1087–1093.

Eeles RA, Kote‐Jarai Z, Al Olama AA et al. (2009) Identification of seven new prostate cancer susceptibility loci through a genome‐wide association study. Nature Genetics 41: 1116–1121.

Enciso‐Mora V, Hosking FJ and Houlston RS (2010) Risk of breast and prostate cancer is not associated with increased homozygosity in outbred populations. European Journal of Human Genetics 18: 909–914.

Fransen K, Visschedijk MC, van Sommeren S et al. (2010) Analysis of SNPs with an effect on gene expression identifies UBE2L3 and BCL3 as potential new risk genes for Crohn's disease. Human Molecular Genetics 19: 3482–3488.

Galvan A, Ioannidis JP and Dragani TA (2010) Beyond genome‐wide association studies: genetic heterogeneity and individual predisposition to cancer. Trends in Genetics 26: 132–141.

Garcia‐Closas M and Chanock S (2008) Genetic susceptibility loci for breast cancer by estrogen receptor status. Clinical Cancer Research 14: 8000–8009.

Greenman C, Stephens P, Smith R et al. (2007) Patterns of somatic mutation in human cancer genomes. Nature 446: 153–158.

Gudmundsson J, Sulem P, Manolescu A et al. (2007a) Genome‐wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nature Genetics 39: 631–637.

Gudmundsson J, Sulem P, Steinthorsdottir V et al. (2007b) Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nature Genetics 39: 977–983.

Hartman M, Loy EY, Ku CS et al. (2010) Molecular epidemiology and its current clinical use in cancer management. Lancet Oncology 11: 383–390.

Hirschhorn JN (2005) Genetic approaches to studying common diseases and complex traits. Pediatric Research 57: 74R–77R.

Hirschhorn JN and Daly MJ (2005) Genome‐wide association studies for common diseases and complex traits. Nature Reviews. Genetics 6: 95–108.

Hirschhorn JN, Lohmueller K, Byrne E et al. (2002) A comprehensive review of genetic association studies. Genetics in Medicine 4: 45–61.

Hosking FJ, Papaemmanuil E, Sheridan E et al. (2010) Genome‐wide homozygosity signatures and childhood acute lymphoblastic leukemia risk. Blood 115: 4472–4477.

Houlston RS, Webb E, Broderick P et al. (2008) Meta‐analysis of genome‐wide association data identifies four new susceptibility loci for colorectal cancer. Nature Genetics 40: 1426–1435.

Hsiung CA, Lan Q, Hong YC et al. (2010) The 5p15.33 locus is associated with risk of lung adenocarcinoma in never‐smoking females in Asia. PLoS Genetics 6: e1001051.

Hung RJ, McKay JD, Gaborieau V et al. (2008) A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 452: 633–637.

Hunter DJ, Kraft P, Jacobs KB et al. (2007) A genome‐wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nature Genetics 39: 870–874.

Ioannidis JP, Loy EY, Poulton R et al. (2009) Researching genetic versus non‐genetic determinants of disease: a comparison and proposed unification. Science Translational Medicine 1: 7ps8.

Johansen CT, Wang J, Lanktree MB et al. (2010) Excess of rare variants in genes identified by genome‐wide association study of hypertriglyceridemia. Nature Genetics 42: 684–687.

Kanetsky PA, Mitra N, Vardhanabhuti S et al. (2009) Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer. Nature Genetics 41: 811–815.

Kiemeney LA, Sulem P, Besenbacher S et al. (2010) A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer. Nature Genetics 42: 415–419.

Koboldt DC, Ding L, Mardis ER et al. (2010) Challenges of sequencing human genomes. Briefings in Bioinformatics 11: 484–498.

Kuiper RP, Ligtenberg MJ, Hoogerbrugge N et al. (2010) Germline copy number variation and cancer risk. Current Opinion in Genetics and Development 20: 282–289.

Landi MT, Chatterjee N, Yu K et al. (2009) A genome‐wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. American Journal of Human Genetics 85: 679–691.

Lencz T, Lambert C, DeRosse P et al. (2007) Runs of homozygosity reveal highly penetrant recessive loci in schizophrenia. Proceedings of the National Academy of Sciences of the USA 104: 19942–19947.

Ley TJ, Mardis ER, Ding L et al. (2008) DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature 456: 66–72.

Lichtensteinm P, Holm NV, Verkasalo PK et al. (2000) Environmental and heritable factors in the causation of cancer – analyses of cohorts of twins from Sweden, Denmark, and Finland. New England Journal of Medicine 343: 78–85.

Manolio TA, Collins FS, Cox NJ et al. (2009) Finding the missing heritability of complex diseases. Nature 461: 747–753.

McCarroll SA, Huett A, Kuballa P et al. (2008) Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease. Nature Genetics 40: 1107–1112.

McKay JD, Hung RJ, Gaborieau V et al. (2008) Lung cancer susceptibility locus at 5p15.33. Nature Genetics 40: 1404–1406.

McPherson R, Pertsemlidis A, Kavaslar N et al. (2007) A common allele on chromosome 9 associated with coronary heart disease. Science 316: 1488–1491.

Nalls MA, Guerreiro RJ, Simon‐Sanchez J et al. (2009) Extended tracts of homozygosity identify novel candidate genes associated with late‐onset Alzheimer's disease. Neurogenetics 10: 183–190.

Nejentsev S, Walker N, Riches D et al. (2009) Rare variants of IFIH1 a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324: 387–389.

Pleasance ED, Cheetham RK, Stephens PJ et al. (2010) A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 463: 191–196.

Pomerantz MM, Ahmadiyeh N, Jia L et al. (2009) The 8q24 cancer risk variant rs6983267 shows long‐range interaction with MYC in colorectal cancer. Nature Genetics 41: 882–884.

Rafnar T, Sulem P, Stacey SN et al. (2009) Sequence variants at the TERT‐CLPTM1L locus associate with many cancer types. Nature Genetics 41: 221–227.

Rapley EA, Turnbull C, Al Olama AA et al. (2009) A genome‐wide association study of testicular germ cell tumor. Nature Genetics 41: 807–810.

Shete S, Hosking FJ, Robertson LB et al. (2009) Genome‐wide association study identifies five susceptibility loci for glioma. Nature Genetics 41: 899–904.

Shlien A and Malkin D (2010) Copy number variations and cancer susceptibility. Current Opinion in Oncology 22: 55–63.

Spain SL, Cazier JB, CORGI Consortium et al. (2009) Colorectal cancer risk is not associated with increased levels of homozygosity in a population from the United Kingdom. Cancer Research 69: 7422–7429.

Stacey SN, Manolescu A, Sulem P et al. (2007) Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor‐positive breast cancer. Nature Genetics 39: 865–869.

Sun J, Zheng SL, Wiklund F et al. (2009) Sequence variants at 22q13 are associated with prostate cancer risk. Cancer Research 69: 10–15.

Takata R, Akamatsu S, Kubo M et al. (2010) Genome‐wide association study identifies five new susceptibility loci for prostate cancer in the Japanese population. Nature Genetics 42: 751–754.

Tenesa A, Farrington SM, Prendergast JG et al. (2008) Genome‐wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21. Nature Genetics 40: 631–637.

Thomas G, Jacobs KB, Yeager M et al. (2008) Multiple loci identified in a genome‐wide association study of prostate cancer. Nature Genetics 40: 310–315.

Thorgeirsson TE, Geller F, Sulem P et al. (2008) A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 452: 638–642.

Tomlinson I, Webb E, Carvajal‐Carmona L et al. (2007) A genome‐wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nature Genetics 39: 984–988.

Tomlinson IP, Webb E, Carvajal‐Carmona L et al. (2008) A genome‐wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nature Genetics 40: 623–630.

Turnbull C, Ahmed S, Morrison J et al. (2010) Genome‐wide association study identifies five new breast cancer susceptibility loci. Nature Genetics 42: 504–507.

Tuupanen S, Turunen M, Lethonen R et al. (2009) The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling. Nature Genetics 41: 885–890.

Wain LV, Armour JA and Tobin MD (2009) Genomic copy number variation, human health, and disease. Lancet 374: 340–350.

Walters RG, Jacquemont S, Valsesia A et al. (2010) A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature 463: 671–675.

Wang Y, Broderick P, Matakidou A et al. (2010) Role of 5p15.33 (TERT‐CLPTM1L), 6p21.33 and 15q25.1 (CHRNA5‐CHRNA3) variation and lung cancer risk in never‐smokers. Carcinogenesis 31: 234–238.

Wang Y, Broderick P, Webb E et al. (2008) Common 5p15.33 and 6p21.33 variants influence lung cancer risk. Nature Genetics 40: 1407–1409.

Wellcome Trust Case Control Consortium, Craddock N, Hurles ME et al. (2010) Genome‐wide association study of CNVs in 16 000 cases of eight common diseases and 3000 shared controls. Nature 464: 713–720.

Willer CJ, Speliotes EK, Loos RJ et al. (2009) Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nature Genetics 41: 25–34.

Yang TL, Guo Y, Zhang LS et al. (2010) Runs of homozygosity identify a recessive locus 12q21.31 for human adult height. Journal of Clinical Endocrinology and Metabolism 95: 3777–3782.

Yeager M, Orr N, Hayes RB et al. (2007) Genome‐wide association study of prostate cancer identifies a second risk locus at 8q24. Nature Genetics 39: 645–649.

Zanke BW, Greenwood CM, Rangrej J et al. (2007) Genome‐wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nature Genetics 39: 989–994.

Zeggini E, Scott LJ, Saxena R et al. (2008) Meta analysis of genome‐wide association data and large‐scale replication identifies additional susceptibility loci for type 2 diabetes. Nature Genetics 40: 638–645.

Zeggini E, Weedon MN, Lindgren CM et al. (2007) Replication of genome‐wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316: 1336–1341.

Zheng W, Long J, Gao Y et al. (2009) Genome‐wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nature Genetics 41: 324–328.

Further Reading

Bodmer W and Tomlinson I (2010) Rare genetic variants and the risk of cancer. Current Opinion in Genetics and Development 20: 262–267.

Ioannidis JP, Castaldi P and Evangelou E (2010) A compendium of genome‐wide associations for cancer: critical synopsis and reappraisal. Journal of the National Cancer Institute 102: 846–858.

Stadler ZK, Thom P, Robson ME et al. (2010) Genome‐wide association studies of cancer. Journal of Clinical Oncology 28: 4255–4267.

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Ku, Chee Seng, Naidoo, Nasheen, Hartman, Mikael, and Pawitan, Yudi(Dec 2010) Genome‐wide Association Studies of Cancers. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022659]