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Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer.

ABSTRACT: BACKGROUND:While numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, few associations have been reported with overall survival. In the absence of common prognostic genetic markers, we hypothesize that rare coding variants may be associated with overall EOC survival and assessed their contribution in two exome-based genotyping projects of the Ovarian Cancer Association Consortium (OCAC). METHODS:The primary patient set (Set 1) included 14 independent EOC studies (4,293 patients) and 227,892 variants, and a secondary patient set (Set 2) included six additional EOC studies (1,744 patients) and 114,620 variants. Because power to detect rare variants individually is reduced, gene-level tests were conducted. Sets were analyzed separately at individual variants and by gene, and then combined with meta-analyses (73,203 variants and 13,163 genes overlapped). RESULTS:No individual variant reached genome-wide statistical significance. A SNP previously implicated to be associated with EOC risk and, to a lesser extent, survival, rs8170, showed the strongest evidence of association with survival and similar effect size estimates across sets (Pmeta = 1.1E-6, HRSet1 = 1.17, HRSet2 = 1.14). Rare variants in ATG2B, an autophagy gene important for apoptosis, were significantly associated with survival after multiple testing correction (Pmeta = 1.1E-6; Pcorrected = 0.01). CONCLUSIONS:Common variant rs8170 and rare variants in ATG2B may be associated with EOC overall survival, although further study is needed. IMPACT:This study represents the first exome-wide association study of EOC survival to include rare variant analyses, and suggests that complementary single variant and gene-level analyses in large studies are needed to identify rare variants that warrant follow-up study. Cancer Epidemiol Biomarkers Prev; 25(3); 446-54. ©2016 AACR.

SUBMITTER: Winham SJ

PROVIDER: S-EPMC4779669 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer.

Winham Stacey J SJ Pirie Ailith A Chen Yian Ann YA Larson Melissa C MC Fogarty Zachary C ZC Earp Madalene A MA Anton-Culver Hoda H Bandera Elisa V EV Cramer Daniel D Doherty Jennifer A JA Goodman Marc T MT Gronwald Jacek J Karlan Beth Y BY Kjaer Susanne K SK Levine Douglas A DA Menon Usha U Ness Roberta B RB Pearce Celeste L CL Pejovic Tanja T Rossing Mary Anne MA Wentzensen Nicolas N Bean Yukie T YT Bisogna Maria M Brinton Louise A LA Carney Michael E ME Cunningham Julie M JM Cybulski Cezary C deFazio Anna A Dicks Ed M EM Edwards Robert P RP Gayther Simon A SA Gentry-Maharaj Aleksandra A Gore Martin M Iversen Edwin S ES Jensen Allan A Johnatty Sharon E SE Lester Jenny J Lin Hui-Yi HY Lissowska Jolanta J Lubinski Jan J Menkiszak Janusz J Modugno Francesmary F Moysich Kirsten B KB Orlow Irene I Pike Malcolm C MC Ramus Susan J SJ Song Honglin H Terry Kathryn L KL Thompson Pamela J PJ Tyrer Jonathan P JP van den Berg David J DJ Vierkant Robert A RA Vitonis Allison F AF Walsh Christine C Wilkens Lynne R LR Wu Anna H AH Yang Hannah H Ziogas Argyrios A Berchuck Andrew A Chenevix-Trench Georgia G Schildkraut Joellen M JM Permuth-Wey Jennifer J Phelan Catherine M CM Pharoah Paul D P PD Fridley Brooke L BL Sellers Thomas A TA Goode Ellen L EL

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20160108 3

<h4>Background</h4>While numerous susceptibility loci for epithelial ovarian cancer (EOC) have been identified, few associations have been reported with overall survival. In the absence of common prognostic genetic markers, we hypothesize that rare coding variants may be associated with overall EOC survival and assessed their contribution in two exome-based genotyping projects of the Ovarian Cancer Association Consortium (OCAC).<h4>Methods</h4>The primary patient set (Set 1) included 14 independ ...[more]

PMID: 26747452

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Project description:Ovarian cancer (OC), the eighth-leading cause of cancer-related death among females worldwide, is mainly represented by epithelial OC (EOC) that can be further subdivided into four subtypes: serous (75%), endometrioid (10%), clear cell (10%), and mucinous (3%). Major reasons for high mortality are the poor biological understanding of the OC mechanisms and a lack of reliable markers defining each EOC subtype. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression primarily by targeting messenger RNA (mRNA) transcripts. Their aberrant expression patterns have been associated with cancer development, including OC. However, the role of miRNAs in tumorigenesis is still to be determined, mainly due to the lack of consensus regarding optimal methodologies for identification and validation of miRNAs and their targets. Several tools for computational target prediction exist, but false interpretations remain a problem. The experimental validation of every potential miRNA-mRNA pair is not feasible, as it is laborious and expensive. In this study, we analyzed the correlation between global miRNA and mRNA expression patterns derived from microarray profiling of 197 EOC patients to identify the signatures of miRNA-mRNA interactions associated with overall survival (OS). The aim was to investigate whether these miRNA-mRNA signatures might have a prognostic value for OS in different subtypes of EOC. The content of our cohort (162 serous carcinomas, 15 endometrioid carcinomas, 11 mucinous carcinomas, and 9 clear cell carcinomas) reflects a real-world scenario of EOC. Several interaction pairs between 6 miRNAs (hsa-miR-126-3p, hsa-miR-223-3p, hsa-miR-23a-5p, hsa-miR-27a-5p, hsa-miR-486-5p, and hsa-miR-506-3p) and 8 mRNAs (ATF3, CH25H, EMP1, HBB, HBEGF, NAMPT, POSTN, and PROCR) were identified and the findings appear to be well supported by the literature. This indicates that our study has a potential to reveal miRNA-mRNA signatures relevant for EOC. Thus, the evaluation on independent cohorts will further evaluate the performance of such findings.

Project description:IntroductionGermline BRCA1/2-associated epithelial ovarian cancer has been associated with better progression-free survival and overall survival than sporadic epithelial ovarian cancer, but conclusive data are lacking.MethodsWe matched 389 BRCA1-associated and 123 BRCA2-associated epithelial ovarian cancer patients 1:1 to sporadic epithelial ovarian cancer patients on year of birth, year of diagnosis, and FIGO stage (< = IIA/> = IIB). Germline DNA test was performed before or after epithelial ovarian cancer diagnosis. All patients received chemotherapy. We used Cox proportional hazards models to estimate the associations between mutation status (BRCA1 or BRCA2 versus sporadic) and progression-free survival and overall survival. To investigate whether DNA testing after epithelial ovarian cancer diagnosis resulted in survival bias, we performed additional analyses limited to BRCA1/2-associated epithelial ovarian cancer patients with a DNA test result before cancer diagnosis (n = 73 BRCA1; n = 9 BRCA2) and their matched sporadic controls.ResultsThe median follow-up was 4.4 years (range 0.1-30.1). During the first three years after epithelial ovarian cancer diagnosis, progression-free survival was better for BRCA1 (HR 0.88, 95% CI 0.74-1.04) and BRCA2 (HR 0.58, 95% CI 0.41-0.81) patients than for sporadic patients. Overall survival was better during the first six years after epithelial ovarian cancer for BRCA1 (HR 0.7, 95% CI 0.58-0.84) and BRCA2 (HR 0.41, 95% CI 0.29-0.59) patients. After surviving these years, survival benefits disappeared or were in favor of the sporadic patients.ConclusionFor epithelial ovarian cancer patients who received chemotherapy, we confirmed survival benefit for BRCA1 and BRCA2 germline pathogenic variant carriers. This may indicate higher sensitivity to chemotherapy, both in first line treatment and in the recurrent setting. The observed benefit appears to be limited to a relatively short period after epithelial ovarian cancer diagnosis.

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Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer.

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Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer.

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