Analysis of Over 10,000 Cases Finds No Association between Previously Reported Candidate Polymorphisms and Ovarian Cancer Outcome

White, Kristin L.; Vierkant, Robert A.; Fogarty, Zachary C.; Charbonneau, Bridget; Block, Matthew S.; Pharoah, Paul D.P.; Chenevix-Trench, Georgia; Rossing, Mary Anne; Cramer, Daniel W.; Pearce, Celeste Leigh; Schildkraut, Joellen M.; Menon, Usha; Kjær, Susanne K.; Levine, Douglas A.; Gronwald, Jacek; Culver, Hoda Anton; Whittemore, Alice S.; Karlan, Beth Y.; Lambrechts, Diether; Wentzensen, Nicolas; Kupryjańczyk, Jolanta; Chang‐Claude, Jenny; Bandera, Elisa V.; Høgdall, Estrid; Heitz, Florian; Kaye, Stanley B.; Fasching, Peter A.; Campbell, Ian; Goodman, Marc T.; Pejović, Tanja; Bean, Yukie T.; Lurie, Galina; Eccles, Diana; Hein, Alexander; Beckmann, Matthias W.; Ekici, Arif B.; Paul, James; Brown, Robert E.; Flanagan, James M.; Harter, Philipp; Bois, Andreas du; Schwaab, Ira; Høgdall, Claus; Lundvall, Lene; Orlow, Irene; Paddock, Lisa E.; Rudolph, Anja; Eilber, Ursula; Dansonka-Mieszkowska, Agnieszka; Rzepecka, Iwona K.; Ziółkowska-Seta, Izabela; Brinton, Louise A.; Yang, Hannah; Despierre, Evelyn; Lambrechts, Sandrina; Vergote, Ignace; Walsh, Christine; Lester, Jenny; Sieh, Weiva; McGuire, Valerie; Rothstein, Joseph H.; Ziogas, Argyrios; Lubiński, Jan; Cybulski, Cezary; Menkiszak, Janusz; Jensen, Allan; Gayther, Simon A.; Ramus, Susan J.; Gentry‐Maharaj, Aleksandra; Berchuck, Andrew; Wu, Anna H.; Pike, Malcolm C.; DenBerg, David Van; Terry, Kathryn L.; Vitonis, Allison F.; Doherty, Jennifer A.; Johnatty, Sharon E.; deFazio, Anna; Song, Honglin; Tyrer, Jonathan P.; Sellers, Thomas A.; Phelan, Catherine M.; Kalli, Kimberly R.; Cunningham, Julie M.; Fridley, Brooke L.; Goode, Ellen L.

doi:10.1158/1055-9965.epi-13-0028

Cited by 20 publications

(16 citation statements)

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“…chemotherapy) could not be included as covariates or stratification factors due to a large amount of missing data; both should be examined in future genetic studies to assess their impact on survival outcomes. Finally, it should be noted that some of the data analyzed here were not independent from previous OCAC EOC overall survival reports (5, 10, 38); specifically, some variants on the exome arrays were also on GWAS or candidate gene arrays which had previously been used on a subset of the current patients. However, the vast majority of the current array content was largely used to test the novel rare variant hypothesis.…”

Section: Discussionmentioning

confidence: 92%

“…Most women are diagnosed with advanced stage disease, when five-year survival rates are low (2, 3). Several clinical and demographic factors are associated with survival, such as stage, grade and histological subtype (4), but few germline prognostic variants have been identified (5). The strongest known genetic risk factors for EOC are rare BRCA1 and BRCA2 mutations (6), which also confer differences in clinical characteristics including improved five-year, but not ten-year, survival (7–9).…”

Section: Introductionmentioning

confidence: 99%

“…The strongest known genetic risk factors for EOC are rare BRCA1 and BRCA2 mutations (6), which also confer differences in clinical characteristics including improved five-year, but not ten-year, survival (7–9). Although genome-wide association studies (GWAS) to identify common risk loci have been fruitful (10–15), studies of survival have been less so (5). For example, variant rs8170 at the 19p13 locus—a region associated with ovarian and breast cancer risk phenotypes and known to interact with BRCA1 (10, 16)— was associated with EOC survival in an initial phase of a GWAS (HR=1.35, P=2.4E-4) conducted by the Ovarian Cancer Association Consortium (OCAC), but not replicated in an independent dataset (HR=1.01, P=0.85) (10).…”

Section: Introductionmentioning

confidence: 99%

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Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer

Investigators

2016

Cancer Epidemiology, Biomarkers &Amp; Prevention

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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 (4293 patients) and 227,892 variants, and a secondary patient set (Set 2) included six additional EOC studies (1744 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.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer

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2016

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…The search for inherited variants associated with EOC outcome has proven challenging, with no published variants reaching genome-wide significance to date (15, 26). Here, by testing a candidate pathway within a consortium, we identified two SNPs from NF-κB-related genes that associated with survival in patients with distinct histologic subtypes of EOC using a pathway-wide statistical significance threshold.…”

Section: Discussionmentioning

confidence: 99%

“…A total of 10,084 women with invasive EOC (37,171 person-years follow-up) and greater than 90% estimated European ancestry were analyzed as described previously (15, 16). Participants were from 28 OCAC studies (Supplemental Table 1) based in Europe, North America, and Australia which conducted follow-up for vital status, including 12 studies (AUS, BAV, HAW, HSK, LAX, MAL, MAY, NCO, NEC, ORE, PVD, and SRO) followed for disease recurrence or progression.…”

Section: Methodsmentioning

confidence: 99%

Variation in NF-κB Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer

Block¹,

Charbonneau²,

Vierkant³

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that impact prognosis are not known. The nuclear factor-kappa B (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance—p < 2.5×10−5). Results were statistically significant when assessed for patients of a single histology. Key associations were with CARD11 (caspase recruitment domain family, member 11) rs41324349 in patients with mucinous EOC (HR 1.82, 95% CI 1.41-2.35, p=4.13×10−6) and TNFRSF13B (tumor necrosis factor receptor superfamily, member 13B) rs7501462 in patients with endometrioid EOC (HR 0.68, 95% CI 0.56-0.82, p=2.33×10−5). Other associations of note included TRAF2 (TNF receptor-associated factor 2) rs17250239 in patients with high-grade serous EOC (HR 0.84, 95% CI 0.77-0.92, p=6.49×10−5) and PLCG1 (phospholipase C, gamma 1) rs11696662 in patients with clear cell EOC (HR 0.43, 95% CI 0.26-0.73, p=4.56×10−4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies.

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Genetic Polymorphisms of P-glycoprotein: Echoes of Silence

Fung

Hunt

Kimchi-Sarfaty

et al. 2015

ABC Transporters - 40 Years On

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Analysis of Over 10,000 Cases Finds No Association between Previously Reported Candidate Polymorphisms and Ovarian Cancer Outcome

Cited by 20 publications

References 7 publications

Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer

Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer

Variation in NF-κB Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer

Genetic Polymorphisms of P-glycoprotein: Echoes of Silence

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