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Ovarian cancer risk associated with inherited inflammation-related variants.

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 (P(heterogeneity) = 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.

SUBMITTER: White KL

PROVIDER: S-EPMC3293997 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Ovarian cancer risk associated with inherited inflammation-related variants.

White Kristin L KL Schildkraut Joellen M JM Palmieri Rachel T RT Iversen Edwin S ES Berchuck Andrew A Vierkant Robert A RA Rider David N DN Charbonneau Bridget B Cicek Mine S MS Sutphen Rebecca R Birrer Michael J MJ Pharoah Paul P D PP Song Honglin H Tyrer Jonathan J Gayther Simon A SA Ramus Susan J SJ Wentzensen Nicolas N Yang Hannah P HP Garcia-Closas Montserrat M Phelan Catherine M CM Cunningham Julie M JM Fridley Brooke L BL Sellers Thomas A TA Goode Ellen L EL

Cancer research 20120126 5

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 contr ...[more]

PMID: 22282663

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Project description:BACKGROUND:Mitochondria are the site of oxidative phosphorylation, a process which generates reactive oxygen species (ROS). Elevated ROS levels can lead to oxidative stress, a cellular state implicated in carcinogenesis. It is hypothesized that alternations in mitochondrial (MT) DNA, including heritable MT single nucleotide polymorphisms (MT-SNPs), have the potential to change the capacity of MT function, leading to increased oxidative stress and cancer risk. We investigated if common MT-SNPs and/or haplogroups and are associated with invasive serous ovarian cancer (OvCa) risk. METHODS:A panel of 64 MT-SNPs designed to tag all common variation in the European MT genome (minor allele frequency (MAF) >1%, r^2 >0.8) was genotyped in study participants of European descent using the Sequenom MassARRAY iPlex Gold® system (Sequenom Inc, CA, USA). Invasive serous OvCa cases (n?=?405) and frequency age-matched controls (n?=?445) were drawn from a population-based case-control study of OvCa in western Canada. Binary logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (C.I.) for carriage of the minor versus major allele by case-control status. MitoTool was used to test the relationship between European haplogroup status and case-control status using Fisher's exact test. RESULTS:The most significant disease-SNP association was for rs2857285, a synonymous MT-SNP in ND4 (OR?=?4.84, 95% CI: 1.03-22.68, P?=?0.045). After adjustment for multiple testing using a Bonferroni correction of the Type 1 error this MT-SNP was not significant. No other MT-SNP had a P-value?<?0.05. European haplogroup status was not associated with case status. Most MT-SNPs (73%) genotyped had a MAF <5%. CONCLUSION:Common European MT-SNPs (MAF?>?5%) and haplogroups were not associated with invasive serous OvCa risk in this study; however, most European MT-SNPs have a low MAF (<5%), which we were underpowered to adequately assess. Larger studies are needed to clarify the role of low MAF MT-SNPs (MAF?<?5%) in invasive serous OvCa risk.

Dataset Information

Ovarian cancer risk associated with inherited inflammation-related variants.

Publications

Ovarian cancer risk associated with inherited inflammation-related variants.

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