Association Studies Of Cancer Research Articles

Risk of urinary bladder cancer is associated with 8q24 variant rs9642880[T] in multiple racial/ethnic groups: results from the Los Angeles-Shanghai case-control study.

Multiple chromosome 8q24 genotypic variants are strongly implicated in several cancers. Recent genome-wide association studies of urinary bladder cancer report risk to be associated with the T allele of rs9642880 on 8q24 among individuals of European descent. We examined associations between bladder cancer risk and genotypes defined by rs9642880 and each of 8 additional 8q24 variants associated with risk of other cancers, in both high-risk non-Hispanic white and low-risk Chinese participants enrolled in a large population-based case-control study conducted in Los Angeles County and Shanghai. We confirmed association of rs9642880 T with bladder cancer risk not only among non-Hispanic whites but also among Chinese participants [overall per-allele relative risk estimate 1.32 (95% CI, 1.16-1.50; P = 0.000024)]. Subgroup analyses suggested that effects of rs9642880 are largely confined to nonsmokers and former smokers, and may be particularly important in the etiology of noninvasive papillary tumors. There was little indication that 8q24 SNPs associated with other cancer types--rs7008482, rs7000448, rs6983561, rs6983267, rs13281615, rs13254738, or rs10090154--are associated with bladder cancer risk. Bladder cancer risk is associated specifically with variation in the discrete 8q24 region containing rs9642880. Factors other than rs9642880 genotypes seem to underlie differences in bladder cancer risk between non-Hispanic whites and Chinese. Characterization of functional consequences of genetic variation in the discrete region including rs9642880 is needed to understand biological basis of this bladder cancer-specific 8q24 association in these racial/ethnic groups characterized by both high and low risk of bladder cancer.

Genome-wide analysis of CGIs in bladder cancer identifies novel epigenetic biomarkers for diagnosis and follow-up

Epigenetic modifications have been shown to contribute to the pathogenesis of various cancers including bladder cancer. Hypermethylation in cancer is often found in CGIs in the 50 regions of genes. Although the list of aberrantly methylated genes in cancer is expanding, only a few genes so far were investigated for their usefulness as tumor biomarkers for early diagnosis and risk assessment of bladder cancer. Thus, a genome-wide screening of aberrant methylation of CGIs is needed to identify bladderspecific epigenetic markers. In this study, we performed a genome-wide screening for DNA methylation in different bladder cancer subtypes using differential methylation hybridization coupled with Agilent 244k human CpG island microarrays. We next validated the genome-wide data on a 384-plex custom Illumina Golden Gate Methylation Assay, which is based on bisulfite conversion. We found and validated a large number of possible novel epigenetic biomarkers for early detection and prognosis of bladder cancer. We also observed that subgroups of bladder tumors cluster separately due to their different methylation patterns, suggesting possible differences in pathogenesis. Our data clearly showed that the adjacent CpG loci within a CGI were comethylated. In contrast, CGIs neighboring a methylated island were usually not methylated. The data showed no bias toward promoter methylation, as the relative proportion of methylated islands in genes was similar to those encompassing promoter regions. We observed that 70% of the methylated genes are downregulated in bladder cancer. Moreover, gene body methylation also seems to be negatively correlated with gene expression. Interestingly, we found an overrepresentation of methylated genes in those genes that are the target of polycomb group protein complexes in embryonic stem cells. Further validation of selected CGIs on a separate group of bladder cancers on a custom Illumina Golden Gate Methylation assay allowed us to confirm 70% of CGIs differentiating bladder cancers from normal cells, besides validating CGIs discriminating subgroups of bladder tumors. In conclusion, this is the first genome-wide study on bladder cancer, which identified potential methylation target genes that provide putative biomarkers that may be correlated with disease course, as well as insight into the pathogenesis of bladder cancer subtypes. CLINICAL IMPACT OF GENOME-WIDE ASSOCIATION STUDIES FOR CANCER

Clinical impact of genome-wide association studies for cancer

Clinical impact of genome-wide association studies for cancer

Abstract PR-4: Genetic heterogeneity in colorectal cancer associations in African Americans

Abstract Background: Genome-wide association studies of colorectal cancer (CRC) have identified risk variants in 10 genomic regions. None of these studies included African Americans, who have the highest incidence and mortality from CRC in the U.S. For the 10 genomic regions, we performed an association study in African and European Americans. Methods: We genotyped 22 single nucleotide polymorphisms (SNPs) in DNA samples from 1194 patients with CRC (795 African Americans and 399 European Americans) and 1352 controls (985 African Americans and 367 European Americans). At chromosome 8q24.21 region 3, we analyzed five additional SNPs from 1000 African American cases and 1393 controls. Association testing was done using multivariate logistic regression controlling for ancestry, age, and sex. Results: Whereas effects sizes and directions of association for all SNPs tested in European Americans were consistent with previously published studies, the associations ran in the opposite direction for 9 of 22 SNPs tested in African Americans. Among African Americans, the SNP rs6983267 at 8q24.21 was not associated with CRC (OR=1.18; P=0.12); instead, the 8q24.21 SNP rs7014346 (OR=1.15; p=0.03) was associated with CRC in this population. On chromosome 15q13.3, rs10318 was associated with CRC in both populations. On chromosome 10p14, the opposite allele of rs10795668 was associated with CRC in African Americans (OR=1.35; P=0.04). On chromosome 11 q23.1, rs3802842 was significantly associated with rectal cancer risk only among African Americans (OR 1.34; P=0.01); a similar observation was made in previous studies of Europeans. Among European Americans, SNPs on chromosomes 8q24.21,11 q23.1, and 16q22.1 were associated with CRC, in agreement with previous reports. Conclusion: There is genetic heterogeneity in CRC associations in Americans of African vs. European descent. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):PR-4.

A combined analysis of genome-wide association studies in breast cancer

In an attempt to identify common disease susceptibility alleles for breast cancer, we performed a combined analysis of three genome-wide association studies (GWAS), involving 2,702 women of European ancestry with invasive breast cancer and 5,726 controls. Tests for association were performed for 285,984 SNPs. Evidence for association with SNPs in genes in specific pathways was assessed using a permutation-based approach. We confirmed associations with loci reported by previous GWAS on 1p11.2, 2q35, 3p, 5p12, 8q24, 10q23.13, 14q24.1 and 16q. Six SNPs with the strongest signals of association with breast cancer, and which have not been reported previously, were typed in two further studies; however, none of the associations could be confirmed. Suggestive evidence for an excess of associations was found for genes involved in the regulation of actin cytoskeleton, glycan degradation, alpha-linolenic acid metabolism, circadian rhythm, hematopoietic cell lineage and drug metabolism. Androgen and oestrogen metabolism, a pathway previously found to be associated with the development of postmenopausal breast cancer, was marginally significant (P=0.051 [unadjusted]). These results suggest that further analysis of SNPs in these pathways may identify associations that would be difficult to detect through agnostic single SNP analyses. More effort focused in these aspects of oncology can potentially open up promising avenues for the understanding of breast cancer and its prevention.

Genome‐wide association studies of pigmentation and skin cancer: a review and meta‐analysis

Recent genome-wide association studies (GWAS) identified genetic loci associated with pigmentation, nevi, and skin cancer. We performed a review and meta-analysis of GWAS results, grouping them into four categories: (i) loci associated with pigmentation (hair, eye, and/or skin color), cutaneous UV-response (sun sensitivity and/or freckling), and skin cancer; (ii) loci associated with nevi and melanoma; (iii) loci associated with pigmentation and/or cutaneous UV-response but not skin cancer; and (iv) loci associated distinctly with skin cancer, mostly basal cell carcinoma, but not pigmentation or cutaneous UV-response. These findings suggest at least two pathways for melanoma development (via pigmentation and via nevi), and two pathways for basal cell carcinoma development (via pigmentation and independent of pigmentation). However, further work is necessary to separate the association with skin cancer from the association with pigmentation. As with any GWAS, the identified loci may not include the causal variants and may need confirmation by direct genome sequencing.

The 5p15.33 Locus Is Associated with Risk of Lung Adenocarcinoma in Never-Smoking Females in Asia

Genome-wide association studies of lung cancer reported in populations of European background have identified three regions on chromosomes 5p15.33, 6p21.33, and 15q25 that have achieved genome-wide significance with p-values of 10−7 or lower. These studies have been performed primarily in cigarette smokers, raising the possibility that the observed associations could be related to tobacco use, lung carcinogenesis, or both. Since most women in Asia do not smoke, we conducted a genome-wide association study of lung adenocarcinoma in never-smoking females (584 cases, 585 controls) among Han Chinese in Taiwan and found that the most significant association was for rs2736100 on chromosome 5p15.33 (p = 1.30×10−11). This finding was independently replicated in seven studies from East Asia totaling 1,164 lung adenocarcinomas and 1,736 controls (p = 5.38×10−11). A pooled analysis achieved genome-wide significance for rs2736100. This SNP marker localizes to the CLPTM1L-TERT locus on chromosome 5p15.33 (p = 2.60×10−20, allelic risk = 1.54, 95% Confidence Interval (CI) 1.41–1.68). Risks for heterozygote and homozygote carriers of the minor allele were 1.62 (95% CI; 1.40–1.87), and 2.35 (95% CI: 1.95–2.83), respectively. In summary, our results show that genetic variation in the CLPTM1L-TERT locus of chromosome 5p15.33 is directly associated with the risk of lung cancer, most notably adenocarcinoma.

Genetic Heterogeneity in Colorectal Cancer Associations Between African and European Americans

Genome-wide association studies of colorectal cancer (CRC) have identified risk variants in 10 genomic regions. None of these studies included African Americans, who have the highest incidence and mortality from CRC in the United States. For the 10 genomic regions, we performed an association study of Americans of African and European descent. We genotyped 22 single nucleotide polymorphisms (SNPs) in DNA samples from 1194 patients with CRC (795 African Americans and 399 European Americans) and 1352 controls (985 African Americans and 367 European Americans). At chromosome 8q24.21 region 3, we analyzed 6 SNPs from 1000 African American cases and 1393 controls. Association testing was done using multivariate logistic regression controlling for ancestry, age, and sex. Among African Americans, the SNP rs6983267 at 8q24.21 was not associated with CRC (odds ratio, 1.18; P = .12); instead, the 8q24.21 SNP rs7014346 (odds ratio, 1.15; P = .03) was associated with CRC in this population. At 15q13.3, rs10318 was associated with CRC in both populations. At 11q23.1, rs3802842 was significantly associated with rectal cancer risk only among African Americans (odds ratio, 1.34; P = .01); this observation was made in previous studies. Among European Americans, SNPs at 8q24.21, 11q23.1, and 16q22.1 were significantly associated with CRC, and the odds ratios were of the same magnitude and direction for all SNPs tested, consistent with previously published studies. In contrast, in African Americans, the opposite allele of rs10795668 at 10p14 was associated with colorectal cancer (odds ratio, 1.35; P = .04), and altogether the odds ratios were in the opposite direction for 9 of the 22 SNPs tested. There is genetic heterogeneity in CRC associations in Americans of African versus European descent.

Genetic and Clinical Predictors for Breast Cancer Risk Assessment and Stratification Among Chinese Women

Most of the genetic variants identified from genome-wide association studies of breast cancer have not been validated in Asian women. No risk assessment model that incorporates both genetic and clinical predictors is currently available to predict breast cancer risk in this population. We analyzed 12 single-nucleotide polymorphisms (SNPs) identified in recent genome-wide association studies mostly of women of European ancestry as being associated with the risk of breast cancer in 3039 case patients and 3082 control subjects who participated in the Shanghai Breast Cancer Study. All participants were interviewed in person to obtain information regarding known and suspected risk factors for breast cancer. The c statistic, a measure of discrimination ability with a value ranging from 0.5 (random classification) to 1.0 (perfect classification), was estimated to evaluate the contribution of genetic and established clinical predictors of breast cancer to a newly established risk assessment model for Chinese women. Clinical predictors included in the model were age at menarche, age at first live birth, waist-to-hip ratio, family history of breast cancer, and a previous diagnosis of benign breast disease. The utility of the models in risk stratification was evaluated by estimating the proportion of breast cancer patients in the general population that could be accounted for above a given risk threshold as predicted by the models. All statistical tests were two-sided. Eight SNPs (rs2046210, rs1219648, rs3817198, rs8051542, rs3803662, rs889312, rs10941679, and rs13281615), each of which reflected a genetically independent locus, were found to be associated with the risk of breast cancer. A dose-response association was observed between the risk of breast cancer and the genetic risk score, which is an aggregate measure of the effect of these eight SNPs (odds ratio for women in the highest quintile of genetic risk score vs those in the lowest = 1.85, 95% confidence interval = 1.58 to 2.18, P(trend) = 2.5 x 10(-15)). The genetic risk score, the waist-to-hip ratio, and a previous diagnosis of benign breast disease were the top three predictors of the risk of breast cancer, each contributing statistically significantly (P < .001) to the full risk assessment model. The model, with a c statistic of 0.6295 after adjustment for overfitting, showed promise for stratifying women into different risk groups; women in the top 30% risk group accounted for nearly 50% of the breast cancers diagnosed in the general population. A risk assessment model that includes both genetic markers and clinical predictors may be useful to classify Asian women into relevant risk groups for cost-efficient screening and other prevention programs.

Mediating effects of smoking and chronic obstructive pulmonary disease on the relation between the CHRNA5‐A3 genetic locus and lung cancer risk

Recent genome-wide association studies of lung cancer have shown that the CHRNA5-A3 region on chromosome 15q24-25.1 is strongly associated with an increased risk of lung cancer and nicotine dependence, and is thought to be associated with chronic obstructive pulmonary disease as well. However, it has not been established whether the association between genetic variants and lung cancer risk is a direct one or one mediated by nicotine dependence. The authors applied a rigorous statistical approach, mediation analysis, to examine the mediating effect of smoking behavior and self-reported, physician-diagnosed emphysema (chronic obstructive pulmonary disease [COPD]) on the relation between the CHRNA5-A3 region genetic variant rs1051730 and the risk of lung cancer. Our results showed that rs1051730 is directly associated with lung cancer risk, but it is also associated with lung cancer risk through its effect on both smoking behavior and COPD. Furthermore, we showed that COPD is a mediating phenotype that explains part of the effect of smoking behavior on lung cancer. Our results also suggested that smoking behavior is a mediator of the relation between rs1051730 and COPD risk. Smoking behavior and COPD are mediators of the association between the single nucleotide polymorphism (SNP) rs1051730 and the risk of lung cancer. Also, COPD is a mediator of the association between smoking behavior and lung cancer. Finally, smoking behavior also has mediating effects on the association between the SNP and COPD.

Abstract PL02-05: Genome-wide association studies in cancer: What have we found and what next

Abstract Cancer genetics has moved into a new era of discovering germ-line genetic variants that influence risk for specific cancers as a consequence of large-scale annotation of common genetic variation across the human genome. With the advent of fixed genotyping platforms and the investment in well-designed molecular epidemiology studies, the focus has shifted away from candidate gene studies towards large scale GWAS. In the process, we have seen clear evidence that substantial replication efforts are needed to conclusively identify new signals associated with cancer etiology. These studies seek to discover markers for disease, but rarely directly identify the variants biologically underlying the observed effect. Consequently, GWAS have primarily identified surrogate markers that necessitate follow-up fine mapping and laboratory analyses. So far, the published literature in cancer has reported approximately 100 novel regions of the genome associated with cancer etiology. GWAS have also demonstrated that the spectrum of cancers could have distinct genomic architectures, which reflects differential contributions of alleles with a range of frequencies and effect sizes. For nearly all regions, the estimated per allele effect sizes are less than 1.3 and the susceptibility alleles are common, with minor allele frequencies greater than 5%. The notable exception is for testicular cancer, which has a very strong tendency towards familial aggregation. In the GWAS of testicular cancer, common genetic markers on chromosome 12q21.32 were found to have per allele estimated risks of greater than 2.5; there is a plausible candidate gene in this region, KITLG. Still, because each common allele appears to confer a small effect, we are beginning to better appreciate the complex nature of common genetic variants that contribute to primary carcinogenesis. Furthermore, it is unlikely that there are many other common alleles with large effects for the common diseases, such as breast, colorectal, lung or prostate cancer because a sufficiently large enough number of cases and controls have been scanned. It is notable that the distribution of the number of regions identified by GWAS varies greatly by cancers, and does not appear to closely mimic hereditary estimates based on twins or family aggregation. For instance, GWAS have identified nearly 30 regions in the genome associated with prostate cancer, all of which are associated with early and aggressive cancers. On the other hand, for lung cancer, only three have been identified and one of them on chromosome 15q24/25 is also strongly associated with smoking behavior phenotypes. These observations raise the likelihood that for some cancers, a substantial environmental effect, such as smoking and lung cancer inhibits the ability to discover low penetrance, common alleles for these diseases. Because GWAS have been conducted in more than a dozen cancers, it is interesting to note that multiple cancers have mapped to two distinct regions, 8q24 and 5p15.33. The former, a ~600MB region centromeric to the MYC gene harbors a series of independent markers associated with breast, colorectal, prostate and urinary bladder cancer as well as chronic lymphocytic leukemia. Similarly, an unexpected spectrum of GWAS have pointed to common variants in a region of chromosome 5p15.33, which harbors the TERT-CLPTM1L locus; these include lung cancer (specifically adenocarcinoma), brain tumors, skin cancer (melanoma and basal cell carcinoma) and pancreatic cancer. This region also harbors less common mutations linked to acute myelogenous leukemia, dyskeratosis congenital (an inherited bone marrow failure syndrome) and pulmonary fibrosis. For each of the regions conclusively identified by GWAS, a series of follow-up studies are needed to fine map the most promising variants, preferably in different populations that can point investigators towards variants for studies designed to investigate plausibility for the association. Subsequently, laboratory investigation will be required to investigate each region that can lead to new insights into pathways and mechanisms underlying the association. To date, the reported GWAS have concentrated on regions associated with cancer etiology and not survival or other clinical outcomes. These suggests that common genetic variation may influence distinct processes important for carcinogenesis as opposed to those associated with disease progression. Though there has been considerable discussion of the promise of common variants as markers for disease risk, it is too early to apply the common variants detected in cancer GWAS to clinical and public health venues. Further studies are needed to map the markers and assess the relationship of multiple markers in sufficiently large studies. In addition, the analytical approach should account for the exposures to environmental and lifestyle choices that interact with germ-line genetic variants. The success of GWAS has opened new horizons for exploration and highlighted the complex genomic architecture of disease susceptibility. Citation Format: Stephen J. Chanock. Genome-wide association studies in cancer: What have we found and what next [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr PL02-05

Abstract 3773: Ability to predict breast cancer in asian women using a polygenic susceptibility model

Abstract Ability to predict breast cancer in Asian women using a polygenic susceptibility model Background Recently identified susceptibility alleles from Genome wide Association Studies (GWAS) for breast cancer suggest a new venue to both prevention and treatment of the disease. Given variations in allele frequency between populations this ability may vary. Methods We examined the possibility for individualized disease prevention and for population screening in Asian women based on common breast cancer risk alleles. We tested using simulations and available allele frequencies from the Singapore Genome Variation Project how these markers perform together with known environmental risk factors for the disease. Results Our analysis suggests that the risk profile generated by 13 single nucleotide polymorphisms (SNP) as identified thru GWAS does not provide sufficient discrimination to warrant individualized prevention. They may however be useful in risk stratification for screening programs especially together with a few reproductive risk factors for disease in breast cancer prevention in the general population (Table 1). Conclusions The clinical use of single, common, low-penetrance genes is limited, but 13 validated SNPs in combination with a few readily available reproductive factors may distinguish women who are at high risk for breast cancer from those who are at low risk, particularly in the context of population screening. Table 1: Proportion of cases of breast cancer explained by the proportion of the population at highest risk for the disease. Estimates based on 13 currently known susceptibility alleles by ethnic group and number of SNPS.Proportion of general population at risk above a given level Proportion of Cases at risk above a given level Chinese 13 SNPsMalay 13 SNPsIndian 13 SNPsChinese 13 SNPs &amp; Environment 20%30.6%30.9%32.2%33.5% 40%53.1%53.5%54.9%56.0% 60%71.9%72.4%73.5%74.2% 80%87.8%88.1%88.6%89.0% Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3773.

Abstract 3863: Fine mapping and comprehensive resequencing analysis of a region of chromosome 11q13 reveals multiple independent loci associated with prostate cancer

Abstract Two genome-wide association studies of prostate cancer identified single nucleotide polymorphism (SNP) markers in a region of chromosome 11q13. As part of the Cancer Genetic Markers of Susceptibility (CGEMS) Initiative the region flanking the most significant marker, rs10896449, was fine mapped using common single nucleotide polymorphisms (SNPs) selected from a two-staged tagging strategy. Of the 120 SNPs analyzed in 10,272 cases and 9,123 controls of European origin, single locus analysis identified 18 SNPs below genome-wide significance (P &amp;lt; 10−8); rs10896449, initially reported remained most significant (P = 7.94 × 10−19). Multi-locus models that included the 18 significant SNPs sequentially identified a second association at rs12793759 (OR = 1.14 P = 4.76 × 10−5), independent of rs10896449 that remained significant after adjustment for multiple testing within the region. A third signal, rs10896438 (OR = 1.07, P = 5.92 × 10−3), independent of both rs10896449 and rs12793759 was detected. To comprehensively catalog genetic variants in strong LD with the above SNPs as well as to determine the region's LD pattern, next-generation sequence analysis of 123 kb (chr11: 68,642,755 - 68,765,690) was performed in 75 individuals of European origin. 447 SNPs with minor allele frequency (MAF) &amp;gt; 1% were identified, which included 180 novel SNPs. Based on r2 &amp;gt; 0.8, 105 SNPs are needed to monitor SNPs with MAF &amp;gt; 1%, whereas 62 SNPs are required for MAF &amp;gt; 5%. 51 SNPs with MAF &amp;gt; 5% are not monitored with r2 &amp;gt; 0.8; 24 singletons (most of which were monitored with r2 &amp;gt; 0.6) and 27 SNPs in 9 correlation bins (r2 &amp;gt; 0.8). For the strongest hits, rs10896449, rs12793759 and rs10896438, 26, 6 and 18 SNPs are correlated with r2 &amp;gt; 0.8, respectively. Our results illustrate the complex architecture of the common genetic variants conferring prostate cancer risk on chromosome 11q13. The fine mapping and sequence analysis point towards a subset of SNPs worthy of follow-up studies designed to understand the molecular basis of the susceptibility alleles. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3863.

Abstract 2849: A functional promoter variant (rs2075533 C&amp;gt;T) in TNFSF8 involved in apoptosis contributes to decreased risk of lung cancer — a finding from Texas lung cancer genome-wide association study

Abstract Although genome-wide association studies (GWASs) of lung cancer have identified several significant variants associated with risk of lung cancer, few variants in known biological pathways involved in the etiology of lung cancer have been yet implicated. In this study, we further explored the variants in the extrinsic apoptosis pathway, a fundamental pathway in lung cancer etiology, in 1,154 lung cancer cases and 1,137 cancer-free controls, all being ever-smokers, from the Texas lung cancer (TLC) GWAS (using the Illumina Human370 chip, in which 611 tagSNPs in 41 genes in the apoptosis extrinsic pathway were included. An association analysis using Plink1.06 showed that 10 of these 611 SNPs were associated with risk of lung cancer with a p value &amp;lt;10−2. Among the tagSNPs with the smallest p values, we selected the TNFSF8 gene for further analysis. To search for the tagged functional SNPs, we applied MACH1.0 to impute 52 additional SNPs in the 48-kb region around TNFSF8 based on the genotypes of 10 tagSNPs from the TLC-GWAS database and the genotypes in the same region from the Hapmap database. With further SNP function prediction analyses using SNPinfo and TFSEARCH bioinformatics software, we found that a SNP, −861 C&amp;gt;T (rs2075533), located in the promoter region of TNFSF8 may be a functional SNP. In subsequent functional validation by the luciferase transfection assay, the T allele of this SNP significantly decreased expression of the luciferase reporter constructs by 5-10 fold in all H1299, Hela and HCT116 cell lines tested, compared with the C allele. Our findings implicated a possible novel role of TNFSF8 in the development of lung cancer. Further investigation is warranted to determine whether TNFSF8 rs2075533 alone or in combination with other SNPs contribute to the risk of lung cancer. (Supported by NIH grants R01CA131274, CA055769, CA127219, and R01ES011740) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2849.

Abstract 4719: Genome-wide association studies of pigmentation and skin cancer: A meta-analysis

Abstract We performed a meta-analysis of summary results from 13 genome-wide association studies (GWAS) examining pigmentation and sun sensitivity traits, nevi, melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma identified from PubMed through November 1, 2009. Two of these expanded upon findings from other GWAS and were therefore included. We grouped the significant loci from the GWAS into four categories: (1) loci associated with pigmentation (hair, eye and/or skin color), freckling, sun sensitivity traits, and skin cancer, (2) loci associated with nevi and melanoma, (3) loci associated with pigmentation and/or sun sensitivity but not skin cancer, and (4) loci distinctly associated with basal cell carcinoma (BCC) but not pigmentation, sun sensitivity, or other skin cancers. (1) GWAS confirmed the known association of SNPs in MC1R (melanocortin-1 receptor) with hair color, sun sensitivity, freckling, melanoma, and BCC. SNPs in TYR (tyrosinase), ASIP (agouti signaling protein), TYRP1 (tyrosinase-related protein 1), and SLC45A2 (solute carrier family 45, member 2) were also associated with pigmentation factors and skin cancer (melanoma and BCC for TYR and ASIP; melanoma for TYRP1; and melanoma, BCC, and squamous cell carcinoma for SLC45A2). Since three of the seven skin cancer GWAS did not adjust for pigmentation or sun sensitivity factors, we cannot conclusively separate the effects on skin cancer from the effects on pigmentation for these SNPs. (2) Two loci around the MTAP (methylthioadenosine phosphorylase) and PLA2G6 (phospholipase A2, group VI) genes were associated with nevi and melanoma. (3) The loci associated with pigmentation and/or sun sensitivity but not melanoma or BCC included four genes, namely TPCN2 (two-pore segment channel 2), KITLG (kit ligand), SLC24A4 (solute carrier family 24, member 4), and OCA2 (oculocutaneous albinism type II). IRF4 (interferon regulatory factor 4), SLC24A5 (solute carrier family 24, member 5), and HERC2 (hect domain and rcc1-like domain 2) were associated with pigmentation but not tested for skin cancers in these GWAS. (4) Finally, there were six loci distinctly associated with BCC around the following genes: PADI6 (peptidylarginine deiminase, type VI), RHOU (ras homolog gene family, member u), TERT-CLPTM1L (telomerase reverse transcriptase-CLPTM1-like protein), KLF14 (kruppel-like factor 14), CDKN2A/B (cyclin-dependent kinase inhibitor 2A/B), and KRT5 (keratin 5). Interestingly, SNPs on chromosome 16 span a region including three genes: MC1R, FANCA (fanconi anemia complementation group A), and CDK10 (cyclin-dependent kinase 10). Upon further sequencing of MC1R and adjustment for additional MC1R variants not included in the platform used in these GWAS, SNPs in CDK10 and FANCA were no longer significant. This signifies the importance of prior knowledge of melanoma risk factors (like MC1R) even in an apparent “agnostic” approach as in GWAS. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4719.

Interleukin 10 polymorphisms differentially influence the risk of gastric cancer in East Asians and Caucasians

Background: Although a number of association studies of gastric cancer (GC) risk have been conducted worldwide, their results have been inconsistent among different populations. The association between GC incidence and Helicobacter pylori ( H. pylori) infection is somewhat of an enigma that has yet to be clearly explained. Geographically-restricted positive selection due to unique environmental pressures often result in large allele frequency differences between populations. Thus, population differences need to be investigated when attempting to identify genes that contribute to phenotypes that differ greatly between populations. Methods: We analyzed population differences in 18 polymorphisms of 12 GC-associated or immune response-related genes from 3 ethnic groups comprising 50 Koreans, 46 Indians, and 60 Caucasians; these groups differed in H. pylori seropositivity and susceptibility to GC. Results: An interleukin 10 ( IL10) polymorphism demonstrated a significantly different genotype distribution ( F ST = 0.306, P = 0.014), indicating a large difference between the Korean and Caucasian populations. The odds ratio of IL10 polymorphism allele between the populations was 38.32 (95% confidence interval, 11.49–127.83). Conclusion: This finding, taken together with previous evidence, provides a possible explanation for previous discrepant association results and supports the idea that IL10 gene polymorphisms can differentially affect GC development among populations.

Abstract ED3-1: Genome-wide association studies in cancer: Insights in cancer etiology

Abstract Genome-wide association studies (GWAS) in cancer have already discovered over 100 novel regions of the genome associated with cancer risk. For nearly all regions conclusively identified by GWAS, the estimated per allele effect sizes are less than 1.3 and the susceptibility alleles are common, with minor allele frequencies greater than 5%. Each common allele appears to confer a small effect overall, underscoring the complex nature of common genetic variants that contribute to primary carcinogenesis. Interestingly, none of the variant markers associated with etiology have been strongly associated with outcomes, such as metastatic disease or survival, which suggests that common genetic variation may influence distinct processes important for carcinogenesis as opposed to those associated with disease progression. GWAS have also demonstrated that the spectrum of cancers could have distinct genomic architectures (e.g., differential contributions of alleles with a range of frequencies and effect sizes). GWAS have identified perhaps as many as 30 regions in the genome associated with prostate cancer, whereas for lung cancer, only three so far, and one of them on chromosome 15q24/25 is also strongly associated with smoking behavior phenotypes. This observation could be related to the strong environmental effect of smoking on lung cancer. It is also notable that GWAS have mapped multiple cancers to two distinct regions, 8q24 and 5p15.33. Consequently, follow-up studies are needed to map the most promising variants, preferably in different populations that can point investigators towards the optimal variants for studies designed to investigate plausibility for the association. Consequently, parallel laboratory investigation of each region can lead to new insights into novel pathways and mechanisms associated with carcinogenesis. Though there has been considerable discussion of the promise of common variants as markers for disease risk, it is too early to apply the common variants to clinical and public health venues. The success of GWAS has opened new horizons for exploration and highlighted the complex genomic architecture of disease susceptibility. Citation Information: Clin Cancer Res 2010;16(7 Suppl):ED3-1

A functional polymorphism in MSMB gene promoter is associated with prostate cancer risk and serum MSMB expression

To explore the reported association of SNP marker rs10993994 with prostate cancer identified by two independent in two genome-wide association studies (GWAS) further, we performed a case-control study in southern Chinese Han population. Consequently, we detected the serum levels of MSMB expression with different genotypes in the cases and controls to characterize the functional consequences of rs10993994. Two hundred fifty-one prostate cancer and 258 control subjects were included in the cancer association study and 90 serum samples were used to test the expression of the MSMB by Enzyme-linked immunosorbent assay (ELISA). We found that the T allele displayed an increased prevalence of prostate cancer compared with the C allele (OR = 1.30, 95% CI = 1.01-1.67, P = 0.040). Moreover, the prostate cancer patients carrying CT/TT genotype had significantly decreased serum MSMB levels compared to those with CC genotype (16.32 +/- 3.98 microg/L vs. 19.33 +/- 4.27 microg/L, P = 0.022). rs10993994 in MSMB promoter affects serum MSMB expression, contributes to the genetic predisposition to prostate cancer in southern Chinese Han population.

Novel breast cancer risk alleles and interaction with ionizing radiation among U.S. radiologic technologists.

As genome-wide association studies of breast cancer are replicating findings and refinement studies are narrowing the signal location, additional efforts are necessary to elucidate the underlying functional relationships. One approach is to evaluate variation in risk by genotype based on known breast carcinogens, such as ionizing radiation. Given the public health concerns associated with recent increases in medical radiation exposure, this approach may also identify potentially susceptible subpopulations. We examined interaction between 27 newly identified breast cancer risk alleles (identified within the NCI Cancer Genetic Markers of Susceptibility and the Breast Cancer Association Consortium genome-wide association studies) and occupational and medical diagnostic radiation exposure among 859 cases and 1083 controls nested within the United States Radiologic Technologists cohort. We did not find significant variation in the radiation-related breast cancer risk for the variant in RAD51L1 (rs10483813) on 14q24.1 as we had hypothesized. In exploratory analyses, we found that the radiation-associated breast cancer risk varied significantly by linked markers in 5p12 (rs930395, rs10941679, rs2067980 and rs4415084) in the mitochondrial ribosomal protein S30 (MRPS30) gene (P(interaction) = 0.04). Chance, however, may explain these findings, and as such, these results need to be confirmed in other populations with low to moderate levels of radiation exposure. Even though a complete understanding of the way(s) in which these variants may increase breast cancer risk remains elusive, this approach may yield clues for further investigation.

Abstract A124: Genome-wide association identified susceptibility loci as modifiers of colorectal cancer risk in Lynch syndrome

Abstract Purpose: The purpose of this study was to determine whether 5 common low-penetrance variants identified in recent genome-wide association studies (GWAS) for colorectal cancer modify colorectal cancer risk in people with Lynch syndrome. People with Lynch syndrome are genetically predisposed to colorectal cancer owing to an inherited DNA mismatch repair (MMR) gene mutation; however, disease expression varies, pointing to the role of modifying factors. A study of Dutch Lynch syndrome families (Wijnen et al., 2009) examined 6 GWAS-identified markers and found that 2 of them—rs16892766 (8q23.3) and rs3802842 (11q23.1)—were associated with colorectal cancer risk. However, other risk variants have yet to be characterized in Lynch syndrome. A replication study of 3 markers in subjects enrolled irrespective of whether they were MMR gene mutation carriers (Poynter et al., 2007) found that 2 risk variants in the 8q24 region (rs10505477 and rs6983267) and 1 variant in the 9p24 region (rs719725) were associated with colorectal cancer risk. Methods: In a retrospective cohort study, we analyzed 278 people with Lynch syndrome and a confirmed MMR gene mutation from the M. D. Anderson Lynch syndrome registry. We genotyped the 5 aforementioned risk variants—rs16892766, rs3802842, rs10505477, rs6983267, and rs719725—and analyzed the association between each risk variant and colorectal cancer using Cox proportional hazards regression while adjusting for sex, MMR gene mutation status, and familial correlation. Results: Of the 278 subjects from 128 families with 11,702 person years of follow-up, 146 subjects had colorectal cancer, and the remaining subjects were unaffected. In a codominant model, rs16892766 was significantly associated with colorectal cancer (hazard ratio [HR]: 1.61; 95% confidence interval [CI]: 1.10–2.35). Similarly, rs3802842 exhibited a marginally significant trend in an additive model (Ptrend = 0.07), and the association was most clearly evident among carriers of mutations in the MLH1 MMR gene in a codominant model (HR: 1.98; 95% CI: 1.18–3.33). Conclusion: Our study replicates the previous finding of an association between 2 GWAS-identified susceptibility loci and risk of colorectal cancer in people with Lynch syndrome. Although people with Lynch syndrome have a strong predisposition to colorectal cancer due to the underlying MMR mutation, these common genetic variants may further modify their colorectal cancer risk, particularly in carriers of multiple risk alleles. These and other low-penetrance susceptibility loci are likely to have future application in personalized risk prediction in identifying individuals who are most susceptible so that they can be provided more rigorous cancer-prevention strategies. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A124.