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Coding region variants that are shared by Family I affected members III:6 and III:7

Clinical characteristics of familial myeloma probands who were studied with germline whole exome sequencing.

Polymorphisms in DNA double-strand break repair gene XRCC2 may play an important role in colorectal cancer etiology, specifically in disease subtypes. Associations of XRCC2 variants and colorectal cancer were investigated by tumor site and tumor instability status in a four-center collaboration including three U.K. case-control studies (Sheffield, Leeds, and Dundee) and a U.S. case-control study of cases from high-risk Utah pedigrees (total: 1,252 cases and 1,422 controls). The 14 variants studied were tagging single nucleotide polymorphisms (SNP) selected from National Institute of Environmental Health Sciences/HapMap data supplemented with SNPs identified from sequencing of 125 cases chosen to represent multiple colorectal cancer groups (familial, metastatic disease, and tumor subsite). Monte Carlo significance testing using Genie software provided valid meta-analyses of the total resource that includes family-based data. Similar to reports of colorectal cancer and other cancer sites, the rs3218536 R188H allele was not associated with increased risk. However, we observed a novel, highly significant association of a common SNP, rs3218499G>C, with increased risk of rectal tumors (odds ratio, 2.1; 95% confidence interval, 1.3-3.3; Pχ2 = 0.0006) versus controls, with the largest risk found for female rectal cases (odds ratio, 3.1; 95% confidence interval, 1.6-6.1; Pχ2 = 0.0006). This difference was significantly different to that for proximal and distal colon cancers (Pχ2 = 0.02). Our investigation supports a role for XRCC2 in colorectal cancer tumorigenesis, conferring susceptibility to rectal tumors. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2476–84)

PCA and gene based rare synonymous variant comparison analyses of European ancestry Multiple Myeloma cases and controls

SUPPLEMENTAL TABLE: Effect of homozygosity at the three HLA class I loci -A, -B and -C and five HLA class I loci -DRB1, DQA1, DQB1, DPA1, and DPB1 on susceptibility to four NHL subtypes (DLBCL, FL, CLL/SLL, and MZL) stratified by GWAS platform (analyses adjusted for sex, age, and ancestry/principal components)

KDM1A mutation promotes enrichment of LSK and HoxA9 leukemia stem cell signatures in near haploid hypodiploid acute lymphoblastic leukemia.

DNA repair enzymes function in major pathways to reverse DNA damage, including base excision repair (BER). Missense polymorphisms in BER repair genes may contribute to differences in DNA repair capacity, specific mutations, and susceptibility to cancer in the presence of exposure to carcinogens such as cigarette smoking. In a study of 1,604 incident colon cancer cases and 1,969 matched population-based controls genotyped for BER variants OGG1 (S326C) and XRCC1 (R194W, R280H, and R399Q), we found no associations with colon cancer overall. However, a 2-fold increased risk of BRAF V600E tumor mutation was observed in current and former cigarette smokers homozygous for the OGG1 polymorphism (odds ratio, 2.2; 95% confidence interval, 1.02-4.9, recessive model); similar associations were not observed for microsatellite instability, CpG island methylator phenotype, KRAS2 mutations, or TP53 mutations. The XRCC1 R194W polymorphism was associated with a modest increased risk of TP53 tumor mutations in those who regularly smoked cigarettes (odds ratio, 1.4; 95% confidence interval, 1.02-1.9). These findings point to the importance of studying tumor mutations when examining DNA repair polymorphisms and cigarette smoke exposure to identify potentially relevant associations with colorectal cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(12):3384–8)

Supplementary Table 2 from Genetic Variants in XRCC2: New Insights Into Colorectal Cancer Tumorigenesis

Supplementary Table 1 from Assessing Tumor Mutations to Gain Insight into Base Excision Repair Sequence Polymorphisms and Smoking in Colon Cancer

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

Supplementary Table 3 from Genetic Variants in XRCC2: New Insights Into Colorectal Cancer Tumorigenesis

Supplementary Table 2 from Assessing Tumor Mutations to Gain Insight into Base Excision Repair Sequence Polymorphisms and Smoking in Colon Cancer

Supplementary Table 1 from Genetic Variants in XRCC2: New Insights Into Colorectal Cancer Tumorigenesis

1. RNAseq DESeq2 differentially expressed gene list for mouse GSK-LSD1 treated and control plasma cells; 2. The compiled list of differentially expressed genes from 1000 permutation analyses; comparing KDM1A mutation carrier MM tumors and randomly picked MM tumors from KDM1A wild-type patients. 3. Genes up- or downregulated in common between GSK-LSD1 mouse plasma cells and MMRF MM tumors from KDM1A mutation carriers; 4. ClueGo pathway analysis.

Given the frequent and largely incurable occurrence of multiple myeloma, identification of germline genetic mutations that predispose cells to multiple myeloma may provide insight into disease etiology and the developmental mechanisms of its cell of origin, the plasma cell (PC). Here, we identified familial and early-onset multiple myeloma kindreds with truncating mutations in lysine-specific demethylase 1 (LSD1/KDM1A), an epigenetic transcriptional repressor that primarily demethylates histone H3 on lysine 4 and regulates hematopoietic stem cell self-renewal. In addition, we found higher rates of germline truncating and predicted deleterious missense KDM1A mutations in patients with multiple myeloma unselected for family history compared with controls. Both monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma cells have significantly lower KDM1A transcript levels compared with normal PCs. Transcriptome analysis of multiple myeloma cells from KDM1A mutation carriers shows enrichment of pathways and MYC target genes previously associated with myeloma pathogenesis. In mice, antigen challenge followed by pharmacologic inhibition of KDM1A promoted PC expansion, enhanced secondary immune response, elicited appearance of serum paraprotein, and mediated upregulation of MYC transcriptional targets. These changes are consistent with the development of MGUS. Collectively, our findings show that KDM1A is the first autosomal-dominant multiple myeloma germline predisposition gene providing new insights into its mechanistic roles as a tumor suppressor during post-germinal center B-cell differentiation.Significance: KDM1A is the first germline autosomal dominant predisposition gene identified in multiple myeloma and provides new insights into multiple myeloma etiology and the mechanistic role of KDM1A as a tumor suppressor during post-germinal center B-cell differentiation. Cancer Res; 78(10); 2747–59. ©2018 AACR.

Additional methods, statistical and resource information to assist readers about how experiments and analyses were conducted.

Introduction: Women with extremely dense breast tissue on mammography have a higher risk of breast cancer compared to similarly-aged women with less dense breast tissue. Tamoxifen therapy has been observed to reduce breast density among both pre- and postmenopausal women with HR+ breast cancer and may predict benefit of therapy. Studies of aromatase inhibitor (AI) therapy and breast density change, however, are limited and results inconclusive. Factors associated with breast density change with ET, and effect of duration of ET on breast density change, have not been well studied. Methods: Using the Utah Population Database, women were identified who underwent screening mammography in 2005-2016 and who had no personal history of breast cancer. Those who were subsequently diagnosed with HR+ breast cancer and treated in one of the major health care systems in Utah (Intermountain Healthcare or University of Utah Health) were included in the analysis. ET prescription information and duration of ET were obtained from provider records and the Utah All-Payer Claims Database. Women with mammography results in the electronic medical record both before and within 3 years after the breast cancer diagnosis were included. BI-RADS density classification from mammogram reports 6-12 months, 13-24 months, and 25-36 months after ET initiation were compared to pre-diagnosis BI-RADS density classification. Breast density reduction was defined as a decrease of ≥1 BI-RADS category compared to baseline. Fisher’s exact test was used to examine ET and breast density reduction among women ≥55y and Results: In total, 1328 women with HR+ breast cancer and baseline BI-RADS breast density categories B-D were included. Women with BI-RADS density category A(almost entirely fatty) were excluded. A majority (61%) were age ≥55y at diagnosis, were non-Hispanic white (90%), and had BMI ≥25 kg/m2 (56%); 15% had a first-degree family history of breast cancer. At baseline, 602 (44%) women had scattered fibroglandular densities (BI-RADS category B), 697 (50%) had heterogeneously dense breasts (BI-RADS category C), and 83 (6%) had extremely dense breasts (BI-RADS category D). Half were treated with AI only (49%), 21% with tamoxifen only, and 29% with both during follow-up. In both the age ≥55y and Conclusion: Baseline breast density is associated with a demonstrable reduction in breast density during ET. Our findings suggest that AI therapy can reduce breast density similar to that seen with tamoxifen therapy. Table 1 Breast Density (BD) changes among women who underwent mammography 6-12 months, 13-24 months, and 25-36 months after ET initiationBaseline BDN≥55 years oldPTotal Citation Format: Mei Wei, Lisa Pappas, Emily Guinto, Carol Sweeney, Nicola Camp, Phoebe Freer, Saundra Buys, N. Lynn Henry, Karen Curtin. Mammographic breast density changes with endocrine therapy (ET) in women with hormone receptor positive (HR+) breast cancer in a Utah population [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-08-10.

Background: Incidence of small-intestine neuroendocrine tumors (SINT) has been increasing in the United States over the past 40 years, with higher incidence in Utah than elsewhere. As information about how these tumors arise is limited, elucidating lifestyle factors associated with SINT in a statewide cohort could potentially identify those at risk to help mitigate their effects. Methods: Cases of SINT with a carcinoid histology (8240 or 8241) diagnosed in Utah from 1996 to 2014 with no prior history of cancer within 5 years (n = 433) were matched to population controls (1:10 ratio). Tobacco and alcohol exposures before case diagnosis were identified from International Classification of Diseases codes in statewide medical records and from self-reported data captured at patient encounters beginning in 1996. Multivariate logistic regression was used to estimate risk of SINT associated with tobacco and alcohol in cases compared with controls. Results: An increased risk of SINT was observed in tobacco-exposed individuals compared with unexposed [OR, 1.44; 95% confidence interval (CI), 1.11–1.86; P = 0.006]. Those who were exposed to alcohol exhibited an increased risk of SINT (OR, 1.62; 95% CI, 1.05–2.49; P = 0.03). Conclusions: This study supports tobacco and alcohol use as risk factors for SINT, independent of family history. However, low rates of smoking and alcohol use in Utah coupled with higher rates of SINT suggest other factors may contribute to development of these tumors. Impact: Although tobacco and alcohol modestly contribute to risk, our study suggests in addition to greater detection of tumors, other as-of-yet undefined exposures may drive rising SINT incidence.

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes. Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

Given the frequent and largely incurable occurrence of multiple myeloma, identification of germline genetic mutations that predispose cells to multiple myeloma may provide insight into disease etiology and the developmental mechanisms of its cell of origin, the plasma cell (PC). Here, we identified familial and early-onset multiple myeloma kindreds with truncating mutations in lysine-specific demethylase 1 (LSD1/KDM1A), an epigenetic transcriptional repressor that primarily demethylates histone H3 on lysine 4 and regulates hematopoietic stem cell self-renewal. In addition, we found higher rates of germline truncating and predicted deleterious missense KDM1A mutations in patients with multiple myeloma unselected for family history compared with controls. Both monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma cells have significantly lower KDM1A transcript levels compared with normal PCs. Transcriptome analysis of multiple myeloma cells from KDM1A mutation carriers shows enrichment of pathways and MYC target genes previously associated with myeloma pathogenesis. In mice, antigen challenge followed by pharmacologic inhibition of KDM1A promoted PC expansion, enhanced secondary immune response, elicited appearance of serum paraprotein, and mediated upregulation of MYC transcriptional targets. These changes are consistent with the development of MGUS. Collectively, our findings show that KDM1A is the first autosomal-dominant multiple myeloma germline predisposition gene providing new insights into its mechanistic roles as a tumor suppressor during post-germinal center B-cell differentiation. Significance: KDM1A is the first germline autosomal dominant predisposition gene identified in multiple myeloma and provides new insights into multiple myeloma etiology and the mechanistic role of KDM1A as a tumor suppressor during post-germinal center B-cell differentiation. Cancer Res; 78(10); 2747–59. ©2018 AACR.

Background: Women with high breast density have a 4-6 fold increased risk of breast cancer compared to women with low breast density. There is a strong inverse association between body mass index (BMI) and breast density, so we hypothesized that some of the racial/ethnic variation in mammographic density may reflect differences in the prevalence of high BMI or the strength of the association between BMI and mammographic density by race/ethnicity. Methods: We leveraged data from the Utah Population Database (UPDB) mammography cohort, including 140,200 non-Hispanic White (NHW) women, 703 non-Hispanic Black (NHB) women, 15,560 Hispanic women, 713 American Indian/Alaskan Native (AIAN) women, 2,525 Asian women, and 434 Native Hawaiian/Pacific Islander (NHPI) women with a screening mammogram obtained 2005-2019. We estimated the association between BMI and binary mammographic density (BI-RADS A & B versus C & D) using logistic regression adjusted for age, education, and parity in Utah. Menopausal status was not available, so we used age 55 as a proxy. We considered effect modification by running stratified analyses and conducting a likelihood ratio test of models with and without an interaction between BMI and race/ethnicity. We also calculated population attributable risks (PAR%). Results: The prevalence of high BMI differed by race/ethnicity with the highest BMI among NHPI women (29.4% overweight and 52.2% obese) and lowest BMI among Asian women (17.9% overweight and 5.7% obese). Results from multivariable models were consistent with a strong inverse association between BMI and mammographic density (ORBMI>30v≤25=0.21, 95% CI=0.21-0.22, p-trend Discussion: We observed the strongest evidence of racial/ethnic differences in BMI when comparing the two groups most commonly studied together: Asians and NHPIs. While we present only limited evidence to suggest that BMI is differentially associated with breast density by race/ethnicity, differences in the prevalence of high BMI were substantial. Overall, our findings suggest that risk factor prevalence should not be overlooked when evaluating potential contributors to cancer disparities. Citation Format: Mollie E. Barnard, Tarun Martheswaran, Karen Curtin, Jennifer A. Doherty. Body mass index and mammographic density by race and ethnicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 32.

Background: Mammographic density is an important breast cancer risk factor, yet data on mammographic density is limited for some racial/ethnic groups, including Native Hawaiians and Pacific Islanders (NHPI). Obesity is highly prevalent in the NHPI population and prior work, primarily in non-Hispanic White (NHW) women, has reported that high body mass index (BMI) is inversely associated with mammographic density but positively associated with risk of breast cancer. We used data from the Utah Population Database (UPDB) to estimate the association between BMI and mammographic density in Utah's NHPI population and evaluate if the association differs for NHPI women compared to NHW women. Methods: We included women ages 18-79 years with at least one mammogram from 2005-2012 and no history of breast cancer. Data on BMI and race/ethnicity were collected from the UPDB, and mammographic density was evaluated using Breast Imaging Reporting and Data System (BIRADS) scores. We estimated the association between BMI and BIRADS using multinomial logistic regression adjusted for age and stratified at age 55 (a proxy for menopausal status). Heterogeneity by race/ethnicity was evaluated using likelihood ratio tests. Results: Our analyses included data from 102 Native Hawaiian, 112 Samoan, 344 other Pacific Islander, and 143,259 NHW women. High mammographic density (BIRADS=4) was less common among Samoan women (2.7%) and other Pacific Islanders (4.7%) compared to NHW women (5.8%), but more common among Native Hawaiians (11.8%). Age-standardized BMI was highest in Samoan women (mean=32.3, SD=6.3) followed by other Pacific Islander women (mean=31.2, SD=7.1) then Native Hawaiian women (mean=27.8, SD=6.4), and lowest among NHW women (mean=26.1, SD=5.4). Among women younger than age 55, a one-unit increase in BMI was associated with 0.76 (95% CI=0.69-0.84) times lower odds of high (BIRADS=4) versus low (BIRADS=1) breast density in NHPI women. The comparable odds ratio (OR) in NHW women was 0.66 (95% CI=0.65-0.66; p-heterogeneity=6.9 × 10^-10). For women age 55 and older, the association between BMI and mammographic density was stronger among NHPI women, OR=0.62 (95%CI=0.45-0.84), compared to NHW women, OR=0.70 (95%CI=0.69-0.72; p-heterogeneity=0.018). Discussion: Mammographic density differs among racial/ethnic subgroups of the NHPI population with Native Hawaiians having the highest mammographic density. Given the high prevalence of obesity in the NHPI population and evidence that the association between BMI and mammographic density may differ by race/ethnicity, more research is needed to understand how BMI and mammographic density influence risk of breast cancer in understudied racial/ethnic minorities, such as NHPIs. Citation Format: Mollie E. Barnard, Tarun Martheswaran, Jennifer A. Doherty, Karen Curtin. Body mass index and mammographic density among Native Hawaiians and Pacific Islanders [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3485.

Background: Mammographic breast density (MBD) and family history are consistently associated with breast cancer risk, and breast density may account for a proportion of susceptibility to this disease. MBD has been shown to correlate in small cohort studies of twins and siblings. However, MBD has not been studied on a large scale in multi-generation families. We investigated the familial relative risk of MBD in the Utah population, as clustering of breast density in extended relatives may provide evidence for the role of genetics in breast density and inform screening recommendations. Methods: Using the Utah Population Database (UPDB), an extensive genealogical database linked to medical records) we identified 189,812 women ages 35-85 with pedigree information, who underwent digital mammography between 2005-2012, with no history of breast/ovarian cancer and no indication of tamoxifen/aromatase inhibitor use. Individuals with unusually frequent screening (>1/yr) or with inconsistent MBD assessments were not included. Subjects were categorized according to Breast Imaging-Reporting and Data System (BI-RADS®) composition classification at index mammogram available in radiology records of Intermountain Healthcare and University of Utah Healthcare systems, representing the majority of mammograms in Utah, as: (I) 0-25% fibroglandular densities (mostly fat); (II) 26-50% fibroglandular (scattered densities); (III) 51-75% fibroglandular (heterogeneously dense); or, (IV) >75% fibroglandular densities (extremely dense). Familial recurrence risks of MBD classification and breast cancer were estimated using Cox regression models in relatives (mothers, daughters, and sisters or 1st-degree; aunts, nieces, grandmothers, and granddaughters or 2nd-degree; first- and second-cousins) of probands classified as BI-RADS I (N=18,170) or BI-RADS IV (N=11,787), compared to those in the most common classifications, BI-RADS II (N=79,825) and III (N=80,030) combined. Women in the comparison group were randomly selected and matched 5:1 to probands on birth year. Results: Relatives of women with a history of extremely dense breasts (BI-RADS IV) were at increased relative risk (RR) of extremely dense breasts compared to women in BI-RADS II/III: 1st-degree, RR=2.3 (95%CI 2.0-2.7, P Conclusions: BI-RADS composition categories available from radiology records in the UPDB appear to be useful in assessing familial risk of MBD at the population level. Our results may inform screening guidelines in more distant as well as close relatives of women with a history of extremely dense breasts, whose families may be more susceptible to breast cancer. Citation Format: Karen Curtin, Leigh Neumayer, Matthew B Morgan, Matthew A Stein, Nicola J Camp, Geraldine P Mineau, Kerry G Rowe, Saundra S Buys. Familial risk of breast density in extended Utah pedigrees [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-07-07.

Genome-wide association studies (GWAS) have identified SMAD7 on 8q21 as being associated with colorectal cancer. We evaluated single nucleotide polymorphisms (SNP) in the SMAD7 gene, including rs4939827, rs12953717, and rs4464148, previously identified from GWAS in a large population-based case-control study of colon cancer. We observed that rs12953717 was associated with a statistically significant increased risk of colon cancer [odds ratio, 1.38; 95% confidence intervals (CI), 1.13–1.68; P linear trend < 0.01] for the TT genotype compared with the CC genotype, whereas the CC genotype of the rs4939827 SNP was inversely associated with colon cancer (0.77; 95% CI, 0.64–0.93) relative to the TT genotype. There were no significant differences in association for either of these polymorphisms when stratified by age, tumor site, sex, or family history. The odds ratios between SMAD7 and colon cancer among individuals reporting recent aspirin/nonsteroidal anti-inflammatory drug use was 0.60 (95% CI, 0.43–0.85) for the CC genotype of the rs4939827 polymorphism and 1.69 (95% CI, 1.20–2.38) for the TT genotype of the rs1295371 polymorphism. This result compares to odds ratios of 0.86 (95% CI, 0.68–1.09) for rs4939827 and 1.22 (95% CI, 0.96–1.56) among individuals who did not use aspirin/nonsteroidal anti-inflammatory drugs. An assessment of SMAD7 genotypes with tumor markers did not reveal any significant differences by KRAS2, TP53, CpG island methylator phenotype, or microsatellite instability status. No significant associations were observed for the rs4464148 SNP or other SNPs evaluated in the SMAD7. These results corroborate the findings of GWAS in colon cancer pointing to SMAD7 and reinforce interest in SNPs in this gene. Cancer Res; 70(4); 1479–85

DNA repair enzymes function in major pathways to reverse DNA damage, including base excision repair (BER). Missense polymorphisms in BER repair genes may contribute to differences in DNA repair capacity, specific mutations, and susceptibility to cancer in the presence of exposure to carcinogens such as cigarette smoking. In a study of 1,604 incident colon cancer cases and 1,969 matched population-based controls genotyped for BER variants OGG1 (S326C) and XRCC1 (R194W, R280H, and R399Q), we found no associations with colon cancer overall. However, a 2-fold increased risk of BRAF V600E tumor mutation was observed in current and former cigarette smokers homozygous for the OGG1 polymorphism (odds ratio, 2.2; 95% confidence interval, 1.02-4.9, recessive model); similar associations were not observed for microsatellite instability, CpG island methylator phenotype, KRAS2 mutations, or TP53 mutations. The XRCC1 R194W polymorphism was associated with a modest increased risk of TP53 tumor mutations in those who regularly smoked cigarettes (odds ratio, 1.4; 95% confidence interval, 1.02-1.9). These findings point to the importance of studying tumor mutations when examining DNA repair polymorphisms and cigarette smoke exposure to identify potentially relevant associations with colorectal cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(12):3384–8)

Polymorphisms in DNA double-strand break repair gene XRCC2 may play an important role in colorectal cancer etiology, specifically in disease subtypes. Associations of XRCC2 variants and colorectal cancer were investigated by tumor site and tumor instability status in a four-center collaboration including three U.K. case-control studies (Sheffield, Leeds, and Dundee) and a U.S. case-control study of cases from high-risk Utah pedigrees (total: 1,252 cases and 1,422 controls). The 14 variants studied were tagging single nucleotide polymorphisms (SNP) selected from National Institute of Environmental Health Sciences/HapMap data supplemented with SNPs identified from sequencing of 125 cases chosen to represent multiple colorectal cancer groups (familial, metastatic disease, and tumor subsite). Monte Carlo significance testing using Genie software provided valid meta-analyses of the total resource that includes family-based data. Similar to reports of colorectal cancer and other cancer sites, the rs3218536 R188H allele was not associated with increased risk. However, we observed a novel, highly significant association of a common SNP, rs3218499G>C, with increased risk of rectal tumors (odds ratio, 2.1; 95% confidence interval, 1.3-3.3; Pχ2 = 0.0006) versus controls, with the largest risk found for female rectal cases (odds ratio, 3.1; 95% confidence interval, 1.6-6.1; Pχ2 = 0.0006). This difference was significantly different to that for proximal and distal colon cancers (Pχ2 = 0.02). Our investigation supports a role for XRCC2 in colorectal cancer tumorigenesis, conferring susceptibility to rectal tumors. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2476–84)

Background: Genome-wide association studies of colorectal cancer (CRC) have identified genetic variants that reproducibly associate with CRC. Associations of 12 single nucleotide polymorphisms at 8q24, 9p24, and 18q21 (SMAD7) and CRC were investigated in a three-center collaborative study including two U.K. case-control cohorts (Sheffield and Leeds) and a U.S. case-control study of CRC cases from high-risk Utah pedigrees. Methods: Our combined resource included 1,092 CRC case subjects and 1,060 age- and sex-matched controls. Meta statistics and Monte Carlo significance testing using Genie software provided a valid combined analysis of our mixed independent and related case-control resource. We also evaluated whether these associations differed by sex, age at diagnosis, family history, or tumor site. Results: At 8q24, we observed two independent significant associations at single nucleotide polymorphisms located in two different risk regions of 8q24: rs6983267 in region 3 [Ptrend = 0.01; per allele odds ratio (OR), 1.17; 95% confidence intervals (95% CI), 1.03-1.32] and rs10090154 in region 5 (Ptrend = 0.05; per allele OR, 1.24; 95% CI, 1.01-1.51). At 18q21, associations were observed in distal colon tumors but not in proximal or rectal cancers: rs4939827 (Ptrend = 0.007; per allele OR, 0.77; 95% CI, 0.64-0.93; case-case pdiff = 0.03) and rs12953717 (Ptrend = 0.01; per allele OR, 1.27; 95% CI, 1.06-1.52). We were unable to detect any associations at 9p24 with CRC. Conclusions: Our investigation confirms that variants across multiple risk regions of 8q24 are associated with CRC, and that associations at 18q21 differ by tumor site. (Cancer Epidemiol Biomarkers Prev 2009;18(2):616–21)

Interleukin-6 is a cytokine thought to be involved in inflammation, insulin, and estrogen-related pathways. We evaluate genetic variation in the IL6 gene with risk of breast cancer. We also evaluate breast cancer associations with aspirin and nonsteroidal anti-inflammatory drugs. A breast cancer case-control study (n = 1,527 non-Hispanic white cases, 1,601 non-Hispanic white controls, 798 Hispanic/Native American cases, and 924 Hispanic/Native American controls) was conducted among women living in the southwestern United States (4-Corner's Breast Cancer Study). Five IL6 single nucleotide polymorphisms (SNP) and IL6 haplotypes based on these SNPs were evaluated. Allele frequencies were significantly different between non-Hispanic white and Hispanic/Native American women. Among postmenopausal women not recently exposed to hormones, the AG/GG genotypes of rs1800797 (−596A>G) and the GC/CC genotypes of rs1800795 (−174G>C) significantly reduced risk of breast cancer among non-Hispanic white women [odds ratio (OR), 0.69; 95% confidence interval (95% CI), 0.48-1.00 and OR, 0.68; 95% CI, 0.47-0.99, respectively] and Hispanic/Native American women (OR, 0.48; 95% CI, 0.28-0.83 and OR, 0.44; 95% CI, 0.26-0.99, respectively). Haplotypes of the five IL6 SNPs further defined these associations. Recent aspirin use significantly decreased risk of breast cancer among postmenopausal Hispanic/Native American women not recently exposed to hormones (OR, 0.56; 95% CI, 0.33-0.96). Among non-Hispanic white, the inverse association with aspirin was not statistically significant. IL6 genotype and haplotype significantly modified the association between aspirin and breast cancer, with the greatest effect modification being among women not recently exposed to hormones [P interaction = 0.06 (for non-Hispanic white) and 0.04 (for Hispanic/Native American) and SNP rs1800796 or −572G>C]. These data suggest that IL6 is associated with breast cancer risk and modifies the association between estrogen and aspirin and breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(4):747–55)

Inherited variants of the vitamin D receptor (VDR) gene may influence cancer risk by altering the effect of vitamin D on cell growth and homeostasis. Studies have examined genotypes for common VDR polymorphisms, including a single nucleotide polymorphism (SNP) detected by Bsm1, a polyadenosine [poly(A)] repeat polymorphism, and a SNP detected by Fok1, as candidates for susceptibility to cancer, but most have not evaluated haplotypes for these markers. We investigated haplotypes for these polymorphisms in case-control studies of colon cancer (1,811 cases and 1,451 controls) and rectal cancer (905 cases and 679 controls). We used the expectation-maximization algorithm to estimate haplotypes for White, Hispanic, African-American, and Asian subjects, tested for differences in VDR haplotype distribution, and calculated odds ratios (OR) for association between haplotype and cancer. The distribution of haplotypes differed by race or ethnic group, but four common haplotypes accounted for the majority of alleles in all groups. VDR haplotype distributions differed between colon cancer cases and controls (P = 0.0004). The common haplotype bLF, containing Bsm1 b (Bsm1 restriction site present), poly(A) long (18-22 repeats), and Fok1 F (restriction site absent) was associated with increased risk of colon cancer, OR 1.15 (95% confidence interval, 1.03-1.28), as was the rare haplotype BLF, containing Bsm1 B (restriction site absent), poly(A) long, and Fok1 F (OR, 2.40; 95% confidence interval, 1.43-4.02). No case-control differences were detected for rectal cancer. In this analysis, haplotypes of the VDR influenced risk of colon cancer, but haplotype variables had only slightly better ability to explain case-control differences than genotype variables. (Cancer Epidemiol Biomarkers prev 2006;15(4):744–9)

Introduction: Insulin, insulin-like growth factor (IGF), and IGF binding protein (IGFBP) are involved in cell growth and proliferation and are thought to be important in the etiology of colorectal cancer. We hypothesize that genetic polymorphisms of insulin receptor substrates (IRS-1 and IRS-2), IGF-I, and IGFBP-3 alter colorectal cancer risk because of their roles in the insulin-related signaling pathway. Methods: Data from a population-based incident case-control study of 1,346 colon cancer cases and 1,544 population-based controls and 952 rectal cancer cases and 1,205 controls were used to evaluate associations. Genetic polymorphisms of four genes were investigated: an IGF1 CA repeat, the IGFBP3 −202 A > C, the IRS1 G972R, and the IRS2 G1057D. Results: Having at least one R allele (GR or RR) for IRS1 G972R was associated with an increased risk of colon cancer [odds ratio 1.4, 95% confidence interval (95% CI) 1.1-1.9]. The IRS2 G972R heterozygote GD genotype significantly reduced risk of colon cancer (odds ratio 0.8, 95% CI 0.6-0.9). Neither the IGF1 nor the IGFBP3 variants was associated independently with colon cancer, but there was an association when examined with IRS1. Individuals with an IRS1 R allele and IGF1 non-192 allele were at a 2-fold increased risk of colon cancer (95% CI 1.2-4.4). There was a 70% (95% CI 1.02-2.8) increased risk of colon cancer with an IRS1 R allele and the IGFBP3 AC or CC genotype. The IRS2 GD genotype reduced risk of colon cancer, except among those with an IRS1 R allele. No significant associations were seen in analyses of main effects or interactions of these variants and rectal cancer risk. Conclusions: Both IRS1 and IRS2 variants were associated with colon cancer risk independently. Associations were slightly stronger when polymorphisms in multiple genes were evaluated in conjunction with other genes rather than individually. These data suggest that the insulin-related pathway may be important in the etiology of colon cancer but not rectal cancer.

5,10-methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism, diverting metabolites toward methylation reactions or nucleotide synthesis. Using data from an incident case-control study (1608 cases and 1972 controls) we investigated two polymorphisms in the MTHFR gene, C677T and A1298C, and their associations with risk of colon cancer. All of the combined genotypes were evaluated separately, and the 1298AA/677CC (wild-type/wild-type) group was considered the reference group. Among both men and women, the 677TT/1298AA (variant/wild-type) genotype was associated with a small reduction in risk [men: odds ratio (OR), 0.7, 95% confidence interval (CI), 0.5–1.0; women: OR, 0.8, 95% CI, 0.5–1.2]. However, the 677CC/1298CC (wild-type/variant) genotype was associated with a statistically significant lower risk among women (OR, 0.6; 95% CI, 0.4–0.9) but not men. When the polymorphisms were considered individually, for A1298C a significant risk reduction associated with the homozygous variant CC genotype was seen among women only (OR, 0.6; 95% CI, 0.5–0.9), and nonstatistically significant reduced risks were observed for the variant 677 TT genotypes among both men and women. Stratification by nutrient intakes showed inverse associations with higher intakes of folate, vitamin B2, B6, B12, and methionine among women with the MTHFR 677CC/1298AA genotypes, but not those with 677TT/1298AA. We observed opposite risk trends for both MTHFR variants, depending on whether women used hormone-replacement therapy or not (P for interaction = In summary, this study supports recent findings that the MTHFR A1298C polymorphism may be a predictor of colon cancer risk and have functional relevance. The possible interaction with hormone-replacement therapy warrants additional investigation.

Genome-wide association studies (GWAS) of multiple myeloma (MM) in Northern Europeans have identified seven novel risk loci (2p23.3, 3p22.1, 3q26.2, 6p21.33, 7p15.3, 17p11.2, 22q13.1). We performed a multiethnic meta-analysis of these regions in 1,274 MM patients and 1,486 controls of European ancestry (EA) and 1,049 MM patients and 7,080 controls of African ancestry (AA), leveraging the differential linkage-disequilibrium of these populations in order to better localize the putative functional variants. We observed directionally consistent effects for all seven index SNPs in both populations, with four significantly associated (p Table 1.Most significant associations for each region in the multiethnic meta-analysis.Individuals of European AncestryIndividuals of African AncestryMulitethnic Metar2 with IndexcCHRSNPRAaFreqbORP-valueFreqbORP-valueORP-valueP-het2rs732075G0.591.222.0×10−30.621.122.0×10−21.162.6×10−40.280.09/0.283rs73069394A0.191.243.0×10−30.621.181.5×10−21.201.3×10−50.550.77/0.963rs12637184G0.761.136.0×10−20.921.192.7×10−11.151.0×10−20.640.94/1.007rs4487645C0.671.237.0×10−40.891.485.5×10−51.308.7×10−80.07-d17rs34562254A0.121.452.4×10−50.131.212.2×10−31.312.5×10−60.120.33/0.9022rs139400T0.491.224.0×10−40.531.172.1×10−31.191.2×10−60.630.63/0.96aRisk allelebFrequency of the risk allele in European and African ancestry studiescr2 metrics based on 1000 Genomes Project AFR/EUR populationsdIndex SNP Citation Format: Kristin A. Rand, Chi Song, Eric Dean, Daniel Serie, Karen Curtin, Dennis Hazelett, Amie E. Hwang, Xin Sheng, Alex Stram, David J. Van Den Berg, Carol Ann Huff, Leon Bernal-Mizrachi, Michael H. Tomasson, Sikander Ailawadhi, Anneclaire De Roos, Seema Singhal, Karen Pawlish, Edward Peters, Catherine Bock, David V. Conti, Graham Colditz, Todd Zimmerman, Scott Huntsman, John Graff, African Ancestry Prostate Cancer GWAS Consortium,African Ancestry Breast Cancer GWAS Consortium, Stephen J. Chanock, Michael Lieber, Jayesh Mehta, Eric A. Klein, Nalini Janakiraman, Richard K. Severson, Angela R. Brooks-Wilson, Vincent Rajkumar, Elizabeth E. Brown, Laurence Kolonel, Susan Slager, Brian E. Henderson, Graham G. Giles, John J. Spinelli, Brian Chiu, Kenneth C. Anderson, Jeffrey Zonder, Robert Z. Orlowski, Sagar Lonial, Nicola Camp, Celine Vachon, Elad Ziv, Dan O. Stram, Christopher A. Haiman, Wendy Cozen. Multiple myeloma susceptibility loci examined in African and European ancestry populations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4629. doi:10.1158/1538-7445.AM2015-4629

Introduction: 5-Lipoxygenase-activating protein (FLAP) binds to arachidonic acid (AA) and activates arachidonate 5-lipoxygenase (ALOX5). ALOX5 is upregulated in colon cancer and is involved in the synthesis of leukotriene A4, which plays an important role in immunity and inflammation. ALOX5 also competes with the prostaglandin H synthases PTGS1 and PTGS2, which convert AA into prostaglandins. NSAIDs reduce the risk of colorectal neoplasia and inhibit PTGS1 and PTGS2. We investigated associations between ALOX5 and FLAP and risk of colorectal neoplasia, as well as potential NSAID interactions in three independent study populations that capture the range of colorectal carcinogenesis by including both adenoma and cancer cases. Methods: A linkage-disequilibrium (LD)-based tagSNP selection algorithm (r2=0.90, MAF=4%) identified 32 tagSNPs in FLAP, representing common genetic variation in Europeans. ALOX5 lacked resequencing data, and we were only able to look at candidate polymorphisms. We used an identical Illumina platform to investigate FLAP SNPs and 1 ALOX5 candidate SNP in three US population-based case-control studies of colon cancer (1424 cases/1780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). VNTR polymorphisms in both genes were also genotyped. Multiple logistic regression analysis was used, adjusting for age, sex, center and restricted to Caucasians (>90% of all study participants). A p value < 0.05 without multiple comparison adjustment was considered statistically significant. Results: The variant ALOX5 allele of rs4986832 G>A showed a significant trend towards decreased risk of rectal cancer (ORhzv=0.65; 95% CI 0.43-0.98; p-trend=0.04). For FLAP, several SNPs showed increased risk of colorectal neoplasia across all three studies, with the strongest associations for: rs12429692 A>T ORhzv=2.05, 95% CI 1.20-3.53 in adenoma (global p=0.01); rs17239025 G>C ORhet/hzv=1.43, 95% CI 1.01-2.04 in rectal cancer (global p=0.05, p-trend=0.04); rs17222919 A>C ORhzv=1.55, 95% CI 1.00-2.42 in rectal cancer (p-trend=0.05). The inverse association with NSAID use was stronger among those with the wildtype genotype for rs9551960 A>G (rectal cancer p-interaction=0.05) and rs17239025 G>C (colon cancer p-int=0.02), whereas those with variant genotypes had greater NSAID risk reduction of rectal cancer for rs9315053 A>C (p-int=0.03), rs9508832 G>A (p-int=0.02), and rs9506352 G>A (p-int=0.04). Conclusion: We show evidence that genetic variability in ALOX5 and FLAP may affect risk of colorectal neoplasia. These results suggest that, in ALOX5, rs4986832 is associated with a decreased risk of rectal cancer, whereas FLAP SNPs rs12429692, rs17239025 and rs17222919 increase colorectal neoplasia risk. Additionally, we provide evidence that genetic variability in FLAP may modify the protective association of NSAID use against colorectal neoplasia. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3761. doi:10.1158/1538-7445.AM2011-3761

Introduction: Arachidonate lipoxygenase (ALOX) enzymes generate potent inflammatory mediators via the metabolism of arachidonic acid. Genetic polymorphisms in the lipoxygenase gene family have been implicated in cancer and inflammatory diseases such as asthma, bone loss, and atherosclerosis. NSAIDs, which reduce colorectal cancer risk, induce apoptosis in colon cancer cells via upregulation of ALOX15. We hypothesize that polymorphisms in lipoxygenases ALOX12 and ALOX15 may influence colorectal neoplasia risk and protective NSAIDs effects. Methods: A linkage-disequilibrium (LD)-based tagSNP-selection algorithm (r2=0.90, MAF=4%) identified tagSNPs in ALOX12 and ALOX15 representing common genetic variation in Europeans. We genotyped 17 SNPs in ALOX12 and 21 SNPs in ALOX15 in three independent study populations that capture the range of colorectal carcinogenesis by including adenoma, colon, and rectal cancer cases. We investigated these SNPs in relation to colorectal neoplasia risk and potential interactions with NSAID use in three US population-based case-control studies of colon cancer (n=1424/1780 cases/controls), rectal cancer (n=583/775), and colorectal adenoma (n=485/578). Multiple logistic regression analysis was used, adjusting for age, sex, and study site, and restricted to Caucasians (>90% of all study participants). A p value < 0.05 without multiple comparison adjustment was considered statistically significant. Results: In ALOX12, rs11571364 was associated with a modestly increased risk of colon cancer among variant allele carriers (OR: 1.23, 95% CI: 1.01-1.51). A risk increase was also seen in rectal cancer, but was not statistically significant (OR: 1.26, 95% CI: 0.92-1.71). The homozygous variant genotype of another SNP in ALOX12 showed a possible reduced risk of rectal cancer (rs2073438, OR: 0.66, 95% CI: 0.42-1.04), but not colon cancer or adenomas. No significant interactions between SNPs in ALOX12 and NSAID use were observed in any of the three studies. In ALOX15, rs2619112 showed a suggested increase in rectal cancer risk. However, the risk was more elevated among those with a heterozygous genotype (OR: 1.37; 95% CI: 1.06-1.77) than among those with a homozygous variant genotype (OR: 1.13, 95% CI: 0.83-1.55). We detected a significant interaction between this SNP and NSAID use. Among NSAID non-users, the homozygous genotype was associated with increased rectal cancer risk (OR: 1.24). Among NSAID users, the homozygous wildtype and homozygous variant genotypes were associated with decreased risk, but there was no association among heterozygous NSAID users (p-interaction=0.04). Conclusion: Polymorphisms in ALOX12 and ALOX15 are associated with risk of rectal and colon cancer, but not colorectal adenomas. An ALOX15 SNP previously associated with bone mineral density levels and coronary artery disease risk was associated with rectal cancer risk and showed possible interaction with NSAID use. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3756. doi:10.1158/1538-7445.AM2011-3756

Introduction: Glutathione peroxidases (GPXs) are selenium-dependent enzymes that scavenge hydroperoxides linked to oxidative stress, prostaglandin synthesis, inflammation and proliferation. Because these processes are important in carcinogenesis, we hypothesized that genetic variability in the GPXs may influence colorectal neoplasia risk. We investigated candidate polymorphisms and tagSNPs in GPX1-4 in relation to colorectal neoplasia in three independent study populations capturing the range of colorectal carcinogenesis. Methods: A linkage-disequilibrium (LD)-based tagSNP selection algorithm (r2=0.90, MAF=4%) identified 24 tagSNPs, including the candidates (GPX1 P200L and GPX4 2573 C>T), representing common genetic variation in Europeans. We used an identical Illumina platform to investigate GPX SNPs in three US population-based case-control studies of colon cancer (1424 cases/1780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). For gene-level associations, we conducted principal components analysis (PCA). Multiple logistic regression was used for single SNPs, adjusting for age, sex, and study center, restricted to Caucasians (>90% of all study populations). Results: In PCA, GPX3 was significant for rectal cancer at p=0.03. Without correction for multiple testing, five polymorphisms in GPX2 and GPX3 were associated with significant differences in rectal cancer risk at α=0.05 (see Table). GPX3 rs8177406 also reduced risk in rectal polyps. The candidate GPX1 P200L showed a marginally increased risk for LP/LL vs. PP (1.22, 0.98-1.52, p=0.06). No other SNPs in GPX1-4 showed significant associations for rectal cancer or adenomas. No associations were observed for colon cancer. Conclusion: These data provide evidence that genetic variability in GPX2 and GPX3 contributes to risk of rectal cancer but not of colon cancer and thus provide additional support for unique etiological mechanisms for colon and rectal cancer.Table.Selected tagSNPs in GPX1, GPX2 and GPX3 and risk of rectal cancer, adjusted for age, sex, and study center*SNPGenotypeCasesControlsOR95%CIp (2df)p-trendGPX1rs105045**CC252367 2834 C>T, P200LCT or TT3013601.220.981.520.06NAGPX2rs2277502**GG4595741.00.. 2834 G>AGA or AA1141890.770.600.990.04NA rs4902347**GG4565741.00.. 1756 G>AGA or AA1141880.780.601.000.05NAGPX3rs3828599CC3404091.00.. 1580 C->TCT2142980.850.681.07 TT29660.520.330.830.010.01 rs736775CC2372821.00 9133 C->TCT2753540.910.721.15 TT701380.590.420.830.010.01 rs8177447CC4135001.00 7241 C->TCT1552350.790.621.01 TT14350.480.260.910.020.01* r2 < 0.70, except rs2277502 and rs4902347 (r2 > 0.90)** Dominant model is shown because there were 10 or fewer subjects with the homozygous variant model 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 933.

Introduction: Pancreatic phospholipase A2 (also known as PLA2G1B or PLA2A) catalyzes the release of fatty acids from dietary phospholipids for adsorption in the small intestine. Some of the polyunsaturated fatty acids removed from the intestinal lumen are precursors to eicosanoids, which are linked to inflammation, cell proliferation and colorectal carcinogenesis. We suspect that genetic variation at the PLA2A locus might affect colorectal neoplasia and thus we evaluated the association of PLA2A tagSNPs with colorectal neoplasia risk in three independent study populations capturing the range of colorectal carcinogenesis. Methods: A linkage-disequilibrium (LD)-based tagSNP selection algorithm (r2=0.90, MAF=4%) identified 3 tagSNPs in PLA2A. We genotyped these SNPs on the same Illumina platform in 3 US population-based case-control studies of colon cancer (1424 cases/1780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). LD was calculated among Caucasian controls for each study. For gene-level associations, we conducted principal components analysis (PCA) and haplotype analysis. Multiple logistic regression was used for single SNPs, adjusting for age, sex, and study center, restricted to Caucasians (>90% of all study populations). Results: Two PLA2A variants were statistically significantly associated with reduced risk of rectal cancer (rs5637, 3702G>A Ser98Ser, p-trend = 0.03 and rs9657930, 1593C>T p-trend = 0.01, see table). Linkage disequilibrium between the SNPs was modest (r2 Conclusion: The results suggest that genetic variability in PLA2A affects susceptibility to rectal but not colon cancer. Additional observational and functional follow-up studies are needed.Table.Selected tagSNPs in PLA2A and risk of rectal cancer, adjusted for age, sex, and study centerSNPGenotypeCasesControlsOR95%CIp (2df)p-trendrs56373702 G>AGG4285361.00.. Ser98SerGA1472150.850.661.08 AA8230.430.190.980.060.03 rs9657930CC4886141.00.. 1593 C>TCT891480.750.561.00 TT3100.390.111.430.050.01 rs2070873GG4365741.00.. 3027 G>TGT1391811.000.781.29 TT6190.420.171.060.150.36Principal component analysis p= 0.02 Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 934.

First results from genome-wide association studies (GWAS) have demonstrated considerable success in identifying genetic variants associated with colorectal cancer (CRC). To date, 10 CRC susceptibility loci have been identified. However, these marginal single nucleotide polymorphism (SNP) associations explain only ∼6% of the heritable variation underlying CRC risk. We employed a pathway-based approach using our recently developed Gene-set Ridge Regression in Association Studies (GRASS) method to assess whether sets of functionally related genes are enriched for SNPs associated with colon cancer risk. We used GWAS data from three studies: The Women's Health Initiative (WHI; 483 cases and 530 controls); the Prostate, Lung, Colon and Ovarian Cancer Screening Trial (PLCO; 546 cases and 1177 controls); and the Diet, Activity and Lifestyle population-based case-control study (DALS; 698 cases and 719 controls). Samples were genotyped on Illumina HumanHap 300K + 240K, 550K or 610K platforms. After applying stringent quality control criteria, our final analysis included 392,361 SNPs. We used genomic partition to assign SNPs to nearby genes and defined pathways using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. We restricted our analysis to 170 pathways with 10 or more genes (range 10-253 genes). Our GRASS method uses eigenSNPs derived from principal components analysis within each gene. Regularized regression is performed for each pathway, using a novel group ridge penalty function. The penalty function results in selection of the most representative eigenSNPs within genes while assessing the association of all the genes, within a pathway, with disease risk. Permutations are used to standardize the test statistics and obtain p-values. The false discovery rate (FDR) was calculated using the Benjamini-Hochberg method. We analyzed WHI, PLCO and DALS separately, adjusting for age, sex, and genetic ancestry derived from principal components analysis, and performed a meta-analysis to combine the results. Five pathways were significant at a p-value cutoff of 0.05. The top pathway, the transforming growth factor beta (TGF-beta) signaling pathway (p-value=0.009), also met a FDR cutoff of 20%. This pathway remained significant (p=0.014) after excluding the known CRC susceptibility loci and all SNPs with linkage disequilibrium r2>0.2 with those 10 loci. The top genes in the pathway were TFGB1, SMAD4, FST, TFGB2, INHBA, PITX2, BMPR2 and PP2R2B (all p 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 4733.