Citations

Abstract As pathways of the immune system play an important role in multiple malignancies, we assessed the association between single-nucleotide polymorphisms (SNPs) in inflammation-related genes and risk of ovarian cancer in a multi-site case-control study. Using a custom array, we genotyped 930 epithelial ovarian cancer cases and 1,037 controls for SNPs in ALOX12, ALOX15, ALOX5, CCL11, CCL2, CCL3, CCR3, CRP, CXCL16, IL10, IL15RA, IL18, IL1A, IL1B, IL1RN, IL4R, IL6, IL6R, IL7R, IL8RA, IL8RB, IL9, NOS3, PTGS1, PTGS2, TLR2, and TNF. After analysis by logistic regression, SNPs with p<0.10 were evaluated in an independent data set of 3,143 cases and 2,102 controls from the Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI) collaboration. Combined analysis revealed association with interleukin 1, alpha (IL1A) SNPs (rs17561 and rs4848300, r2=0.990, p=0.005) which varied by histological subtype (heterogeneity p=0.03). For example, IL1A rs17561, which results in a missense change in amino acid at position 114 and correlates with multiple inflammatory phenotypes, was inversely associated with risk of clear cell, mucinous, and endometrioid subtypes, but not with the serous subtype (Table 1). Additional data on IL1A rs17561 in an even larger collection of ovarian cancer cases and controls are pending and will be analyzed soon. We also found that genotype at rs1864414 in ALOX5 (arachidonate 5-lipoxygenase) was associated with decreased risk combined across subtypes (OR 0.86, 95% CI 0.78-0.95; p=0.002). Thus, inherited variation in IL1A and ALOX5 appears to have a role in ovarian cancer risk, though it is limited to rarer subtypes for IL1A. These data add to existing literature on the importance of inflammation in tumorigenesis and growing evidence of subtype-specific traits in ovarian cancer and may provide important clues on prevention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2603. doi:1538-7445.AM2012-2603

Abstract Ovarian carcinoma is a significant cause of cancer mortality in women in the United States. Increasing evidence has demonstrated that differential methylation status in lymphocyte DNA may be linked to risk of carcinogenesis. We are investigating the differential DNA methylation in germline DNA obtained from pre-treatment ovarian cancer cases (n=256) and individually-age matched controls (n=274) using the Illumina Infinium Human Methylation 27K BeadChip. We are first studying methylation and the common moderate-risk alleles for ovarian cancer on chromosomes 2q31, 3q25, 8q24, 9p22, 17q21, and 19p13. Within each locus, we correlated single nucleotide polymorphism (SNP) genotypes with methylation values at relevant nearby CpG sites. Preliminary results are available on the first set of 84 cases and 90 controls. At 2q31, cases with TG or TT genotype at rs2072590 were hypomethylated at HOXD1 (a homeobox transcription factor) compared to cases with GG genotype (mean beta TG/TT=0.08, GG=0.09, p=0.034); and at 17q21, cases with AG or GG genotype at rs9303542 were hypomethylated at SKAP1 (a T-cell adaptor protein) compared to cases with AA genotype (mean beta AG/GG=0.14, AA=0.16, p=0.045). At these two loci, similar trends were seen among controls. Logistic regression adjusted for age and methylation chip was then used to assess the association between SNP genotype and ovarian cancer risk, with and without inclusion of the relevant methylation value. At HOXD1 rs2072590, the per-allele ovarian cancer risk of 1.34 attenuated to 1.25 with inclusion of the HOXD1 methylation value as a covariate, suggesting that the disease association may be mediated in part through methylation. Though based on preliminary data, results are consistent with a role for inherited variation on germline methylation at HOXD1 and SKAP1. Analysis of methylation on additional genotyped cases and controls is underway. Finally, because, trans effects may also exist, we are assessing relationships between genotype and methylation at other loci throughout the genome. Such correlative molecular studies have the potential to help elucidate mechanisms underlying associations from genome-wide association studies. 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 5616. doi:10.1158/1538-7445.AM2011-5616

Abstract The importance of inflammation pathways to the development of many human cancers prompted us to examine the associations between single-nucleotide polymorphisms (SNP) in inflammation-related genes and risk of ovarian cancer. In a multisite case–control study, we genotyped SNPs in a large panel of inflammatory genes in 930 epithelial ovarian cancer cases and 1,037 controls using a custom array and analyzed by logistic regression. SNPs with P < 0.10 were evaluated among 3,143 cases and 2,102 controls from the Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI) post-GWAS collaboration. Combined analysis revealed association with SNPs rs17561 and rs4848300 in the interleukin gene IL1A which varied by histologic subtype (Pheterogeneity = 0.03). For example, IL1A rs17561, which correlates with numerous inflammatory phenotypes, was associated with decreased risk of clear cell, mucinous, and endometrioid subtype, but not with the most common serous subtype. Genotype at rs1864414 in the arachidonate 5-lipoxygenase ALOX5 was also associated with decreased risk. Thus, inherited variation in IL1A and ALOX5 seems to affect ovarian cancer risk which, for IL1A, is limited to rarer subtypes. Given the importance of inflammation in tumorigenesis and growing evidence of subtype-specific features in ovarian cancer, functional investigations will be important to help clarify the importance of inherited variation related to inflammation in ovarian carcinogenesis. Cancer Res; 72(5); 1064–9. ©2012 AACR.

Abstract Multiple genome-wide association studies have identified several susceptibility variants for colon cancer at 8q24. However, the functional roles of these variants have yet to be elucidated. Here, we evaluated the potential role of these markers in tumor progression and examined association with commonly observed structural abnormalities in this region, c-MYC amplification and chromosome fragility at FRA8C and FRA8D. We first replicated the previously reported association by testing 1,178 cases and 1,009 clinic-based controls with eight markers localized to three specific regions at 8q24. We observed significant associations with colon cancer risk with markers rs13254738 (ordinal odds ratio, 0.82; 95% confidence interval, 0.072-0.94; Ptrend = 0.0037) and rs6983267 (ordinal odds ratio, 1.17; 95% confidence interval, 1.03-1.32, Ptrend = 0.013). Survival analysis was done using a separate set of 460 cases to evaluate the clinical significance of these markers. Overall, univariate analysis did not detect survival differences for any of the markers. We also tested a subset of the 460 cases (n = 380) for structural abnormalities at or near the c-MYC locus using fluorescence in situ hybridization analysis. Furthermore, we evaluated a small number of cases homozygous for the rs6983267 alleles to test for differences in fragile site induction. None of the 8q markers correlated with amplification at the c-MYC locus as detected by fluorescence in situ hybridization, and no clear pattern of breakage was observed at the FRA8C and FRA8D sites. In this study, we confirm the association for several single nucleotide polymorphisms at 8q24 in colon cancer but have not detected any structural role relating to c-MYC amplification or chromosomal fragility. Finally, these risk alleles do not seem to be associated with survival. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2492–500)

AbstractPrevious studies suggest that enzymes involved in the androgen metabolic pathway are susceptibility factors for prostate cancer. Estrogen metabolites functioning as genotoxins have also been proposed as risk factors. In this study, we systematically tested the hypothesis that common genetic variations for those enzymes involved in the androgen and estrogen metabolic pathways increase risk for sporadic and familial prostate cancer. From these two pathways, 46 polymorphisms (34 single nucleotide polymorphisms, 10 short tandem repeat polymorphisms, and 2 null alleles) in 25 genes were tested for possible associations. Those genes tested included PRL, LHB, CYP11A1, HSD3B1, HSD3B2, HSD17B2, CYP17, SRD5A2, AKR1C3, UGT2B15, AR, SHBG, and KLK3 from the androgen pathway and CYP19, HSD17B1, CYP1A1, CYP1A2, CYP1B1, COMT, GSTP1, GSTT1, GSTM1, NQO1, ESR1, and ESR2 from the estrogen pathway. A case-control study design was used with two sets of cases: familial cases with a strong prostate cancer family history (n = 438 from 178 families) and sporadic cases with a negative prostate cancer family history (n = 499). The controls (n = 493) were derived from a population-based collection. Our results provide suggestive findings for an association with either familial or sporadic prostate cancer with polymorphisms in four genes: AKR1C3, HSD17B1, NQO1, and GSTT1. Additional suggestive findings for an association with clinical variables (disease stage, grade, and/or node status) were observed for single nucleotide polymorphisms in eight genes: HSD3B2, SRD5A2, SHBG, ESR1, CYP1A1, CYP1B1, GSTT1, and NQO1. However, none of the findings were statistically significant after appropriate corrections for multiple comparisons. Given that the point estimates for the odds ratio for each of these polymorphisms are <2.0, much larger sample sizes will be required for confirmation. (Cancer Epidemiol Biomarkers Prev 2007;16(5):969–78)

ABSTRACTThe objectives of this study were to evaluate soybean [Glycine max (L.) Merr.] agronomic and quality traits and to examine correlations among traits in an interspecific soybean population. The agronomic traits included maturity, plant canopy height, canopy spread, leaflet length, leaflet width, seed yield, and seed size. The seed quality traits were sucrose, raffinose, and stachyose content. A total of 308 recombinant inbred lines (RIL) were developed from the cross between a large‐seeded Glycine max breeding line (V71‐370) and a small‐seeded Glycine soja Sieb. & Zucc. accession (PI 407162). Normal distribution was observed for most of the traits with a slight skewness towards the G. soja parent. Most correlation coefficients were highly significant, such as the positive correlation between yield and sucrose and between seed size and sucrose. Genotype × environment interaction was significant for all of the agronomic traits but not for sugar contents. Maturity, seed size, and sucrose content were highly heritable, whereas plant height, canopy spread, leaflet length, leaflet width, yield, stachyose content, and raffinose content had relatively low broad‐sense heritabilities. Our findings suggest that the lack of genotype × location effects on sugar content favors progress through selection, but the strong correlation among the sugars may hinder progress in selecting lines that are high in sucrose but low in raffinose and stachyose over different environmental conditions. The information on heritabililty and interrelationships among the agronomic and seed quality traits will be helpful to breeders in constructing their breeding populations and implementing selection strategies.