Allele frequency and effect sizes for genetic variants associated with colorectal cancer. Allele frequencies and ORs are taken from published literature where available and are not depicted to scale. Associations identified through GWA or GWA follow-up studies are shown with solid colored bars; all others are shaded from dark (top) to light (bottom). 

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... is manifested. Published GWAs in cancer are summarized in supplementary Table 1A, available at Carcinogenesis Online. Over 150 associations at P , 5 Â 10 À 8 have been identified with a variety of cancer phenotypes, however, the functional implications of these variants are often unclear. As seen for other complex diseases, the vast majority of cancer-associated variants identified in GWA studies are either intronic (39%) or intergenic (52%). Effect sizes associated with these common variants are modest (median OR 1.25, 75% with OR , 1.5) (8), consistent with the idea that variants with large effect sizes could be subject to selection pressure (13), though selection pressures are thought to have changed dramatically over the course of human evolution. Associations with OR . 2 were observed for SNPs associated with prostate cancer, testicular cancer and myelo- proliferative neoplasms. Most variants identified to date are cancer type and, in some cases, subtype specific, though important exceptions include TERT , CLPTM1L , TP53 and the 8q24 region. In addition to true differences in the genetic architecture of various cancers, the tumor-specific productivity of the GWA approach may reflect the ability to assemble large sample sizes with enough statistical power to identify variants of small effect; the genetic heterogeneity of some tumor types relative to others; the relative contribution of genetic and environmental factors or the differing selection pressures on cancers showing major differences in incidence or course by age or sex. Few studies have followed-up variants from GWA studies in families, either to study unexplained disease or as genetic modi- fiers of known variants. The overwhelming majority of studies have included cancer risk as the primary GWAS endpoint. A minority of studies have looked at survival, prognosis or treatment response in individuals with cancer, with limitations due to small sample size or lack of replication (14–20). To date, the gaps in genetic architecture reflect the areas where genotyping technology is still being developed and/or applied. Thus, the contribution of rare variants other than those segregating in affected families has yet to be defined but may well be clarified as very high density SNP arrays (2 million or more SNPs), exome and whole genome sequencing become feasible in population-based studies. For reasons that are largely unknown, epidemiologic studies of some cancer types have been more successful at identifying less common, high penetrance variants and others at identifying high frequency susceptibility alleles of smaller effect. Linkage scans of prostate and testicular cancer, for example, have identified only a limited number of highly penetrant variants (21), although GWA studies of prostate cancer have identified the largest number of variants to date (1). Studies of breast and colorectal cancer have identified high-risk mutations in BRCA1 , BRCA2 and APC , MLH1 and MSH2 , respectively, and fewer susceptibility alleles overall. Below, we highlight specific results from the four most common cancers—breast, colorectal, prostate and lung. We discuss findings from both candidate gene studies and GWAS, recognizing that many GWAS findings may still be re- garded as preliminary until functional consequences are identified. Over two dozen loci and variants have been implicated in susceptibility to breast cancer (Figure 2). Fewer than 10% of breast cancer cases are attributed to rare, high-penetrance genes, with a similar estimate attributed to SNPs identified through GWA studies (supplementary Table 1B is available at Carcinogenesis Online) (1,2). BRCA1 and BRCA2 , the two most well-characterized genes, are associated with greater than a 10-fold increase of breast cancer risk relative to the general population (22). The other rare and highly penetrant loci are reported in rare hereditary cancer syndromes such as Li-Fraumeni syndrome and Cowden’s syndrome. An intermediate risk group of breast cancer variants—in ATM , BRIP1 , CHEK2 , PALB2 and RAD51C generally confer a 2- to 3-fold increased risk of breast cancer. Minor allele frequencies for these variants are typically , 0.1%, although there are some notable exceptions (for example, CHEK2 has a frequency of $ 1% in the Ashkenazi Jewish population) (2). GWA-identified variants to date have shown ORs , 1.5 and are frequent (most with risk allele frequencies of . 20%). In contrast to the rare and intermediate effect variants, where functional significance is often recognized (for example, in tumor suppressor or loss-of-function mutations), the GWA loci harbor susceptibility variants whose functions are largely unknown. In fact, some, such as the variants in 8q24.21, are in regions of the genome that are devoid of known genes. As in breast cancer, several key loci in colorectal cancer were discovered in familial or syndromic cases (including APC , MUTYH and mismatch repair genes MLH1 , MSH2 , MSH6 and PMS2 ; Figure 3, supplementary Table 1C is available at Carcinogenesis Online). To- gether, these loci account for $ 20% of the genetic predisposition to colorectal cancer (23). A handful of low to moderate penetrance variants, including APC -I1307K, BLM , HRAS1 , TGF b R1 , HFE , CCND1 and MTHFR , have also been identified in candidate gene association studies (23). GWA studies have identified a number of common variants (those at BMP4 , CDH1 , EIF3H , RHPN2 , SMAD7 , 8q24, 10p14, 11q23.1 and 20p12.3), which are associated with small increases in relative risk and which cumulatively account for $ 6% of the excess familial risk (24). Prostate cancer demonstrates strong familial clustering (25) but high penetrance genes have yet to be identified and replicated. The most likely candidate so far is BRCA2 , which is associated with a 20-fold increased risk relative to the general population. Linkage studies show a number of susceptibility loci with modest LOD scores; however, most were not replicated across studies (26).The GWA study approach has been fruitful in identifying many replicated variants, all with OR , 2 and most with OR , 1.3 (Figure 4; supplementary Table 1D is available at Carcinogenesis Online). In addition to variants in the EHBP1 , IGF1/IGF2 (11p15), ITGA6 , KLK3 , LMTK2 , MSMB , NKX3.1 , NUDT10/NUDT11 , PDLIM5 , SLC22A3 , TCF2 , THADA and TET2 genes, many of these variants are in intergenic regions at 3p12, 3q21, 8q24, 11q13, 17q24, 19q13 and 22q13.2. Furthermore, the cumulative effects of these loci explain at least 20% of the familial risk (27). Interestingly, several of these variants localize to distinct linkage disequilibrium blocks on 8q24 (28). GWA studies have identified more signals for prostate cancer than for any other cancer type. This may reflect the true underlying genetic architecture of prostate cancer (reasonably common variants with modest effect sizes) and/or the ways in which prostate cancer has been particularly amenable to the GWA approach, including reduced influence of environmental factors, limited disease subtype heterogeneity and long survival after diagnosis. Notably, the variants identified thus far do not distinguish between less and more aggressive tumor types (29), suggesting that they may be more involved in the initiation of cancer than its severity or course. Finally, that prostate cancer presents largely in older age suggests that alleles predisposing to prostate cancer may be under less se- lective pressure than those that predispose to cancers at younger ages (27) or that age-related senescence plays a key role in etiology. However, the overall picture is probably more complicated, as genotypes are selected based on the phenotypes they produce and focusing on a variant’s influence on a single cancer ignores possible pleiotropic effects (30). The etiology of lung cancer is recognized to be strongly environmental, although there is increasing evidence that genetic factors may also play a role. Family and linkage studies have identified high- penetrance variants in TP53 , RB1 and 6q23–25 (31–33). More recently, GWA studies have consistently identified three loci at genome-wide significance (Figure 5; supplementary Table 1E is available at Carcinogenesis Online)—variants at 5p15.33 ( TERT-CLPTM1L ), 6p21( BAT3, APOM )/6p22.1 ( TRNAA-UGC ) and 15q25.1 ( CHRNA3 , CHRNA4 and CHRNA5 ), which explain $ 7% of the familial risk of lung cancer (27). Interestingly, 15q25.1 variants are also associated with smoking behavior, a risk factor for lung cancer. Part of the association of 15q25.1 variants with lung cancer can probably be explained by associations with smoking behavior; however, not all studies agree whether they have some degree of independent effects (34–36). Specific variants have also been consistently identified for strong lung cancer risk factors, such as smoking quantity, smoking initiation or cessation (37,38) but have not met strict definitions of genome-wide significance. The emerging picture of the genetic architecture of cancer is complex and varies somewhat by cancer type, as discussed above. Adding to this complexity are several additional dimensions, including allelic heterogeneity, phenotypic heterogeneity and pleiotropy. Allelic heterogeneity, or the association of a single trait with multiple variants within the same gene or locus, has been described for several cancers. For example, within the 8q24 region, five loci are independently associated with prostate cancer susceptibility (28,39).Additionally, these loci may be population specific, reflecting differences in linkage disequilibrium (Figure 6) as well as disease risks conferred (39). Allelic heterogeneity is evident across the spectrum of rare and common variation, as for colorectal cancer and variants in the APC gene (23). In the presence of allelic heterogeneity, the value of any one approach, whether GWA-, family- or candidate gene-based, is limited; results from all of these study ...