ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: A comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas

<b>Objective</b> <i>ABCB1</i> encodes the multi-drug efflux pump P-glycoprotein (P-gp) and has been implicated in multi-drug resistance. We comprehensively evaluated this gene and flanking regions for an association with clinical outcome in epithelial ovarian cancer (EOC).<p></p> <b>Methods</b> The best candidates from fine-mapping analysis of 21 <i>ABCB1</i> SNPs tagging C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642) were analysed in 4616 European invasive EOC patients from thirteen Ovarian Cancer Association Consortium (OCAC) studies and The Cancer Genome Atlas (TCGA). Additionally we analysed 1,562 imputed SNPs around ABCB1 in patients receiving cytoreductive surgery and either ‘standard’ first-line paclitaxel–carboplatin chemotherapy (n = 1158) or any first-line chemotherapy regimen (n = 2867). We also evaluated ABCB1 expression in primary tumours from 143 EOC patients.<p></p> <b>Result</b> Fine-mapping revealed that rs1128503, rs2032582, and rs1045642 were the best candidates in optimally debulked patients. However, we observed no significant association between any SNP and either progression-free survival or overall survival in analysis of data from 14 studies. There was a marginal association between rs1128503 and overall survival in patients with nil residual disease (HR 0.88, 95% CI 0.77–1.01; p = 0.07). In contrast, <i>ABCB1</i> expression in the primary tumour may confer worse prognosis in patients with sub-optimally debulked tumours.<p></p> <b>Conclusion</b> Our study represents the largest analysis of <i>ABCB1</i> SNPs and EOC progression and survival to date, but has not identified additional signals, or validated reported associations with progression-free survival for rs1128503, rs2032582, and rs1045642. However, we cannot rule out the possibility of a subtle effect of rs1128503, or other SNPs linked to it, on overall survival.<p></p&gt

Cell cycle genes and ovarian cancer susceptibility: a tagSNP analysis

BACKGROUND: Dysregulation of the cell cycle is a hallmark of many cancers including ovarian cancer, a leading cause of gynaecologic cancer mortality worldwide.METHODS: We examined single nucleotide polymorphisms (SNPs) (n = 288) from 39 cell cycle regulation genes, including cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors, in a two-stage study. White, non-Hispanic cases (n = 829) and ovarian cancer-free controls (n = 941) were genotyped using an Illumina assay.RESULTS: Eleven variants in nine genes (ABL1, CCNB2, CDKN1A, CCND3, E2F2, CDK2, E2F3, CDC2, and CDK7) were associated with risk of ovarian cancer in at least one genetic model. Seven SNPs were then assessed in four additional studies with 1689 cases and 3398 controls. Association between risk of ovarian cancer and ABL1 rs2855192 found in the original population [odds ratio, ORBB vs AA 2.81 (1.29-6.09), P = 0.01] was also observed in a replication population, and the association remained suggestive in the combined analysis [ORBB vs AA 1.59 (1.08-2.34), P = 0.02]. No other SNP associations remained suggestive in the replication populations.CONCLUSION: ABL1 has been implicated in multiple processes including cell division, cell adhesion and cellular stress response. These results suggest that characterization of the function of genetic variation in this gene in other ovarian cancer populations is warranted. British Journal of Cancer (2009) 101, 1461-1468. doi: 10.1038/sj.bjc.6605284 www.bjcancer.com Published online 8 September 2009 (C) 2009 Cancer Research U

Mediterranean Diet and Breast Density in the Minnesota Breast Cancer Family Study

Mediterranean populations’ lower breast cancer incidence has been attributed to a traditional Mediterranean diet, but few studies have quantified Mediterranean dietary pattern intake in relation to breast cancer. We examined the association of a Mediterranean diet scale (MDS) with mammographic breast density as a surrogate marker for breast cancer risk. Participants completed a dietary questionnaire and provided screening mammograms for breast density assessment using a computer-assisted method. Among 1,286 women, MDS was not clearly associated with percent density in multivariate linear regression analyses. Because of previous work suggesting dietary effects limited to smokers, we conducted stratified analyses and found MDS and percent density to be significantly, inversely associated among current smokers (β = –1.68, P = 0.002) but not among nonsmokers (β = –0.08, P = 0.72; P for interaction = 0.008). Our results confirm a previous suggestion that selected dietary patterns may be protective primarily in the presence of procarcinogenic compounds such as those found in tobacco smoke

Extended LTA, TNF, LST1 and HLA Gene Haplotypes and Their Association with Rubella Vaccine-Induced Immunity

Recent studies have suggested the importance of HLA genes in determining immune responses following rubella vaccine. The telomeric class III region of the HLA complex harbors several genes, including lymphotoxin alpha (LTA), tumor necrosis factor (TNF) and leukocyte specific transcript -1 (LST1) genes, located between the class I B and class II DRB1 loci. Apart from HLA, little is known about the effect of this extended genetic region on HLA haplotypic backgrounds as applied to immune responses.We examined the association between immune responses and extended class I-class II-class III haplotypes among 714 healthy children after two doses of rubella vaccination. These extended haplotypes were then compared to the HLA-only haplotypes. The most significant association was observed between haplotypes extending across the HLA class I region, ten-SNP haplotypes, and the HLA class II region (i.e. A-C-B-LTA-TNF-LST1-DRB1-DQA1-DQB1-DPA1-DPB1) and rubella-specific antibodies (global p-value of 0.03). Associations were found between both extended A*02-C*03-B*15-AAAACGGGGC-DRB1*04-DQA1*03-DQB1*03-DPA1*01-DPB1*04 (p = 0.002) and HLA-only A*02-C*03-B*15-DRB1*04-DQA1*03-DQB1*03-DPA1*01-DPB1*04 haplotypes (p = 0.009) and higher levels of rubella antibodies. The class II HLA-only haplotype DRB1*13-DQA1*01-DQB1*06-DPA1*01-DPB1*04 (p = 0.04) lacking LTA-TNF-LST1 SNPs was associated with lower rubella antibody responses. Similarly, the class I-class II HLA-only A*01-C*07-B*08-DRB1*03-DQA1*05-DQB1*02-DPA1*01-DPB1*04 haplotype was associated with increased TNF-alpha secretion levels (p = 0.009). In contrast, the extended AAAACGGGGC-DRB1*01-DQA1*01-DQB1*05-DPA1*01-DPB1*04 (p = 0.01) haplotype was found to trend with decreased rubella-specific IL-6 secretion levels.These data suggest the importance of examining both HLA genes and genes in the class III region as part of the extended haplotypes useful in understanding genomic drivers regulating immune responses to rubella vaccine

No association between a candidate TCF7L2 variant and risk of breast or ovarian cancer

<p>Abstract</p> <p>Background</p> <p>TCF7L2 is a transcription factor involved in Wnt/β-catenin signaling which has a variant known to be associated with risk of Type 2 diabetes and, in some studies, with risk of certain cancers, including familial breast cancer. No studies of ovarian cancer have been reported to date.</p> <p>Methods</p> <p>Two clinic-based case-control studies at the Mayo Clinic were assessed including 798 breast cancer cases, 843 breast cancer controls, 391 ovarian cancer cases, and 458 ovarian cancer controls. Genotyping at <it>TCF7L2 </it>rs12255372 used a 5' endonuclease assay, and statistical analysis used logistic regression among participants as a whole and among <it>a priori</it>-defined subsets.</p> <p>Results</p> <p>No associations with risk of breast or ovarian cancer were observed (ordinal model, p = 0.62 and p = 0.75, respectively). In addition, no associations were observed among sub-groups defined by age, BMI, family history, stage, grade, histology, or tumor behavior.</p> <p>Conclusion</p> <p>Although the biology of the Wnt/β-catenin signaling pathway and prior association between rs12255372 and numerous phenotypes warranted examination of this <it>TCF7L2 </it>SNP, no compelling evidence for association with breast or ovarian cancer was observed.</p