Clinical parameters affecting survival outcomes in patients with low-grade serous ovarian carcinoma: an international multicentre analysis.

BACKGROUND: Women with low-grade ovarian serous carcinoma (LGSC) benefit from surgical treatment; however, the role of chemotherapy is controversial. We examined an international database through the Ovarian Cancer Association Consortium to identify factors that affect survival in LGSC. METHODS: We performed a retrospective cohort analysis of patients with LGSC who had had primary surgery and had overall survival data available. We performed univariate and multivariate analyses of progression-free survival and overall survival, and generated Kaplan-Meier survival curves. RESULTS: Of the 707 patients with LGSC, 680 (96.2%) had available overall survival data. The patients' median age overall was 54 years. Of the 659 patients with International Federation of Obstetrics and Gynecology stage data, 156 (23.7%) had stage I disease, 64 (9.7%) had stage II, 395 (59.9%) had stage III, and 44 (6.7%) had stage IV. Of the 377 patients with surgical data, 200 (53.0%) had no visible residual disease. Of the 361 patients with chemotherapy data, 330 (91.4%) received first-line platinum-based chemotherapy. The median follow-up duration was 5.0 years. The median progression-free survival and overall survival were 43.2 months and 110.4 months, respectively. Multivariate analysis indicated a statistically significant impact of stage and residual disease on progression-free survival and overall survival. Platinum-based chemotherapy was not associated with a survival advantage. CONCLUSION: This multicentre analysis indicates that complete surgical cytoreduction to no visible residual disease has the most impact on improved survival in LGSC. This finding could immediately inform and change practice.

CA-125 Levels Are Predictive of Survival in Low-Grade Serous Ovarian Cancer-A Multicenter Analysis.

OBJECTIVE: Studies on low-grade serous ovarian cancer (LGSC) are limited by a low number of cases. The aim of this study was to define the prognostic significance of age, stage, and CA-125 levels on survival in a multi-institutional cohort of women with pathologically confirmed LGSC. METHODS: Women with LGSC were identified from the collaborative Ovarian Cancer Association Consortium (OCAC). Cases of newly diagnosed primary LGSC were included if peri-operative CA-125 levels were available. Age at diagnosis, FIGO stage, pre- and post-treatment CA-125 levels, residual disease, adjuvant chemotherapy, disease recurrence, and vital status were collected by the participating institutions. Progression-free (PFS) and overall survival (OS) were calculated. Multivariable (MVA) Cox proportional hazard models were used and hazard ratios (HR) calculated. RESULTS: A total of 176 women with LGSC were included in this study; 82% had stage III/IV disease. The median PFS was 2.3 years and the median OS was 6.4 years. Age at diagnosis was not significantly associated with worse PFS (p = 0.23) or OS (p = 0.3) (HR per year: 0.99; 95%CI, 0.96-1.01 and 0.98; 95%CI 0.95-1.01). FIGO stage III/IV was independently associated with PFS (HR 4.26, 95%CI 1.43-12.73) and OS (HR 1.69, 95%CI 0.56-5.05). Elevated CA-125 (≥35 U/mL) at diagnosis was not significantly associated with worse PFS (p = 0.87) or OS (p = 0.78) in MVA. Elevated CA-125 (≥35 U/mL) after completion of primary treatment was independently associated with worse PFS (HR 2.81, 95%CI 1.36-5.81) and OS (HR 6.62, 95%CI 2.45-17.92). In the MVA, residual disease was independently associated with PFS (0.022), but not OS (0.85). CONCLUSION: Advanced LGSC was associated with poor long-term prognosis. FIGO stage and abnormal post-treatment CA-125 level are key prognostic factors inversely associated with PFS and OS. HIGHLIGHTS: 1. Through a multi-center collaborative effort, data from 176 women with low-grade serous ovarian cancer were analyzed. 2. Although low-grade serous ovarian cancer is often considered indolent, the progression-free and overall survival are poor. 3. Elevated post-treatment CA-125 levels are independently associated with poor survival.

Case-case analysis addressing ascertainment bias for multigene panel testing implicates BRCA1 and PALB2 in endometrial cancer.

Hereditary endometrial cancer (EC) is most commonly attributed to pathogenic variants in mismatch repair genes. Evidence supports the existence of additional genetic risk factors in the context of multiple cancer diagnoses and/or family history of EC. EC patients (n = 5292) referred for diagnostic multigene cancer panel testing were annotated for presence of a pathogenic gene variant; personal history of prior, concurrent, or subsequent cancer of another type; reported family history of Lynch syndrome or EC. The Pearson χ2 test was used to assess differences in gene variant prevalence between case sub-groups defined by personal and/or family history of cancer/s, using cases with no family history of Lynch/EC as reference. Another cancer diagnosis was reported for 55% of EC cases. EC cases with a prior and reported family history of Lynch cancer were enriched for variants in MLH1 (p = 3.5 × 10-7 ), MSH2 (p = 3.1 × 10-7 ), and PMS2 (p = .02). Consistent with expectations for a breast cancer gene also predisposing to EC, the variant frequency was increased in EC patients with prior BC and family history of EC for BRCA1 (p = 1.7 × 10-5 ) and PALB2 (p = .0002). Strategic case-case analyses to address cohort ascertainment bias have provided a rationale to direct future studies of candidate hereditary EC genes.

Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer.

BACKGROUND: Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance. METHODS: We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy. RESULTS: We found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10-8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15-1.34; P = 1.47 × 10-8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro. CONCLUSIONS: The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association. IMPACT: This finding provides insight into genetic markers associated with EOC outcome and potential treatment options.See related commentary by Peres and Monteiro, p. 1604.

Menopausal hormone therapy prior to the diagnosis of ovarian cancer is associated with improved survival.

PURPOSE: Prior studies of menopausal hormone therapy (MHT) and ovarian cancer survival have been limited by lack of hormone regimen detail and insufficient sample sizes. To address these limitations, a comprehensive analysis of 6419 post-menopausal women with pathologically confirmed ovarian carcinoma was conducted to examine the association between MHT use prior to diagnosis and survival. METHODS: Data from 15 studies in the Ovarian Cancer Association Consortium were included. MHT use was examined by type (estrogen-only (ET) or estrogen+progestin (EPT)), duration, and recency of use relative to diagnosis. Cox proportional hazards models were used to estimate the association between hormone therapy use and survival. Logistic regression and mediation analysis was used to explore the relationship between MHT use and residual disease following debulking surgery. RESULTS: Use of ET or EPT for at least five years prior to diagnosis was associated with better ovarian cancer survival (hazard ratio, 0.80; 95% CI, 0.74 to 0.87). Among women with advanced stage, high-grade serous carcinoma, those who used MHT were less likely to have any macroscopic residual disease at the time of primary debulking surgery (p for trend <0.01 for duration of MHT use). Residual disease mediated some (17%) of the relationship between MHT and survival. CONCLUSIONS: Pre-diagnosis MHT use for 5+ years was a favorable prognostic factor for women with ovarian cancer. This large study is consistent with prior smaller studies, and further work is needed to understand the underlying mechanism.

Generating high-quality data abstractions from scanned clinical records: text-mining-assisted extraction of endometrial carcinoma pathology features as proof of principle.

OBJECTIVE: Medical research studies often rely on the manual collection of data from scanned typewritten clinical records, which can be laborious, time consuming and error prone because of the need to review individual clinical records. We aimed to use text mining to assist with the extraction of clinical features from complex text-based scanned pathology records for medical research studies. DESIGN: Text mining performance was measured by extracting and annotating three distinct pathological features from scanned photocopies of endometrial carcinoma clinical pathology reports, and comparing results to manually abstracted terms. Inclusion and exclusion keyword trigger terms to capture leiomyomas, endometriosis and adenomyosis were provided based on expert knowledge. Terms were expanded with character variations based on common optical character recognition (OCR) error patterns as well as negation phrases found in sample reports. The approach was evaluated on an unseen test set of 1293 scanned pathology reports originating from laboratories across Australia. SETTING: Scanned typewritten pathology reports for women aged 18-79 years with newly diagnosed endometrial cancer (2005-2007) in Australia. RESULTS: High concordance with final abstracted codes was observed for identifying the presence of three pathology features (94%-98% F-measure). The approach was more consistent and reliable than manual abstractions, identifying 3%-14% additional feature instances. CONCLUSION: Keyword trigger-based automation with OCR error correction and negation handling proved not only to be rapid and convenient, but also providing consistent and reliable data abstractions from scanned clinical records. In conjunction with manual review, it can assist in the generation of high-quality data abstractions for medical research studies.

Co-existence of leiomyomas, adenomyosis and endometriosis in women with endometrial cancer.

Leiomyomas, adenomyosis, and endometriosis are reported to be risk factors for endometrial carcinoma (EC), and adenomyosis and endometriosis also for ovarian carcinoma (OC). We aimed to describe the prevalence of these conditions in EC patients with or without an OC diagnosis, and to investigate their relationship with EC risk and prognostic factors in these patients. We evaluated the co-existence of these three conditions in 1399 EC patients, and compared the prevalence of epidemiological risk factors and tumor prognostic features in patients with each condition versus not. Prevalence of conditions was also assessed in the subset of patients with prior/concurrent OC. The observed coexistence of leiomyomas, adenomyosis and endometriosis significantly deviated from that expected (P = 1.2 × 10-8). Patients were more likely to: report a younger age at menarche (PTrend = 0.004) if they had leiomyomas; have used oral contraceptives (P = 6.6 × 10-5) or had ≥2 full-term pregnancies (PTrend = 2.0 × 10-9) if they had adenomyosis; be diagnosed with EC at younger age (P = 5.0 × 10-11) if they had endometriosis. Patients with prior/concurrent OC were more likely to be diagnosed at younger age (P = 5.0 × 10-5), have endometriosis (P = 9.9 × 10-7), and present with higher stage EC (PTrend = 6.6 × 10-5). These findings justify further consideration of these gynecologic conditions as independent risk and prognostic factors for EC.

Risk and prognostic factors for endometrial carcinoma after diagnosis of breast or Lynch-associated cancers-A population-based analysis.

We hypothesized that endometrial carcinoma (EC) patients with a prior cancer diagnosis, after accounting for EC arising after tamoxifen-treated prior breast carcinoma, are more likely to have an underlying genetic basis. We used information from a population-based study to compare measured risk factors, tumor characteristics, survival, and known mismatch repair (MMR) pathogenic variant status for EC subgroups according to prior diagnosis of cancer (none, breast cancer tamoxifen-treated or not, Lynch Syndrome (LS)-associated cancer). Family history of any cancer was increased for EC cases with prior breast cancer, both tamoxifen treated (P = 0.005) and untreated (P = 0.01). EC cases with prior LS-associated cancer more often reported family history of LS-associated cancer (P = 0.04) and breast cancer (P = 0.05). EC patients with a germline pathogenic MMR gene variant were more likely to report a prior cancer than cases with a MMR proficient tumor (P = 0.0001), but more than half (54.5%) of MMR carriers reported no prior cancer. Women developing EC after tamoxifen treatment for breast cancer were significantly more likely to develop EC of malignant mixed mullerian tumor subtype (13.2% vs 2.6%, P = 1.3 × 10-6 ), present with stage IV disease (8.8% vs 1.2%, P = 1.6 × 10-6 ), and have poorer survival (HRadj 1.96; P = 0.001). While report of prior cancer is an indicator of MMR pathogenic variant status, molecular analysis of all ECs at diagnosis is warranted to detect all patients with LS. Results also indicate the importance of longer-term monitoring of women treated with tamoxifen for symptoms of EC, and the need for studies assessing the biological mechanism underlying the poorer prognosis of this subset of EC patients.

MyD88 and TLR4 Expression in Epithelial Ovarian Cancer.

OBJECTIVE: To evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival. PATIENTS AND METHODS: We conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong). RESULTS: Expression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P<.001 for both). In HGSOC, strong MyD88 expression was modestly associated with shortened overall survival (hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P=.04) but was also associated with advanced stage (P<.001). The expression of TLR4 was not associated with survival. In low-grade serous ovarian cancer (LGSOC), strong expression of both MyD88 and TLR4 was associated with favorable survival (HR [95% CI], 0.49 [0.29-0.84] and 0.44 [0.21-0.89], respectively; P=.009 and P=.02, respectively). CONCLUSION: Results are consistent with an association between strong MyD88 staining and advanced stage and poorer survival in HGSOC and demonstrate correlation between strong MyD88 and TLR4 staining and improved survival in LGSOC, highlighting the biological differences between the 2 serous histotypes.

Genome-wide association study of paclitaxel and carboplatin disposition in women with epithelial ovarian cancer.

Identifying single nucleotide polymorphisms (SNPs) that influence chemotherapy disposition may help to personalize cancer treatment and limit toxicity. Genome-wide approaches are unbiased, compared with candidate gene studies, but usually require large cohorts. As most chemotherapy is given cyclically multiple blood sampling is required to adequately define drug disposition, limiting patient recruitment. We found that carboplatin and paclitaxel disposition are stable phenotypes in ovarian cancer patients and tested a genome-wide association study (GWAS) design to identify SNPs associated with chemotherapy disposition. We found highly significant SNPs in ABCC2, a known carboplatin transporter, associated with carboplatin clearance (asymptotic P = 5.2 × 106, empirical P = 1.4 × 10-5), indicating biological plausibility. We also identified novel SNPs associated with paclitaxel disposition, including rs17130142 with genome-wide significance (asymptotic P = 2.0 × 10-9, empirical P = 1.3 × 10-7). Although requiring further validation, our work demonstrated that GWAS of chemotherapeutic drug disposition can be effective, even in relatively small cohorts, and can be adopted in drug development and treatment programs.

Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci.

We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D and ZNF100 are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the ZNF100 promoter region correlated with candidate outcome variants. At 1q22, putative regulatory elements enhanced MEF2D promoter activity and haplotypes containing candidate outcome variants modulated these effects. In a public dataset, MEF2D and ZNF100 expression were both associated with ovarian cancer progression-free or overall survival time. In an extended set of 6,162 epithelial ovarian cancer patients, we found that functional candidates at the 1q22 and 19p12 loci, as well as other regional variants, were nominally associated with patient outcome; however, no associations reached our threshold for statistical significance (p<1×10-5). Larger patient numbers will be needed to convincingly identify any true associations at these loci.

Family history of cancer predicts endometrial cancer risk independently of Lynch Syndrome: Implications for genetic counselling.

OBJECTIVE: To determine endometrial cancer (EC) risk according to family cancer history, including assessment by degree of relatedness, type of and age at cancer diagnosis of relatives. METHODS: Self-reported family cancer history was available for 1353 EC patients and 628 controls. Logistic regression was used to quantify the association between EC and cancer diagnosis in ≥1 first or second degree relative, and to assess whether level of risk differed by degree of relationship and/or relative's age at diagnosis. Risk was also evaluated for family history of up to three cancers from known familial syndromes (Lynch, Cowden, hereditary breast and ovarian cancer) overall, by histological subtype and, for a subset of 678 patients, by EC tumor mismatch repair (MMR) gene expression. RESULTS: Report of EC in ≥1 first- or second-degree relative was associated with significantly increased risk of EC (P=3.8×10-7), independent of lifestyle risk factors. There was a trend in increasing EC risk with closer relatedness and younger age at EC diagnosis in relatives (PTrend=4.43×10-6), and with increasing numbers of Lynch cancers in relatives (PTrend≤0.0001). EC risk associated with family history did not differ by proband tumor MMR status, or histological subtype. Reported EC in first- or second-degree relatives remained associated with EC risk after conservative correction for potential misreported family history (OR 2.0; 95% CI, 1.24-3.37, P=0.004). CONCLUSION: The strongest predictor of EC risk was closer relatedness and younger EC diagnosis age in ≥1 relative. Associations remained significant irrespective of proband MMR status, and after excluding MMR pathogenic variant carriers, indicating that Lynch syndrome genes do not fully explain familial EC risk.

Breastfeeding and Endometrial Cancer Risk: An Analysis From the Epidemiology of Endometrial Cancer Consortium.

OBJECTIVE: To investigate the association between breastfeeding and endometrial cancer risk using pooled data from 17 studies participating in the Epidemiology of Endometrial Cancer Consortium. METHODS: We conducted a meta-analysis with individual-level data from three cohort and 14 case-control studies. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for the association between breastfeeding and risk of endometrial cancer using multivariable logistic regression and pooled using random-effects meta-analysis. We investigated between-study heterogeneity with I  and Q statistics and metaregression. RESULTS: After excluding nulliparous women, the analyses included 8,981 women with endometrial cancer and 17,241 women in a control group. Ever breastfeeding was associated with an 11% reduction in risk of endometrial cancer (pooled OR 0.89, 95% CI 0.81-0.98). Longer average duration of breastfeeding per child was associated with lower risk of endometrial cancer, although there appeared to be some leveling of this effect beyond 6-9 months. The association with ever breastfeeding was not explained by greater parity and did not vary notably by body mass index or histologic subtype (grouped as endometrioid and mucinous compared with serous and clear cell). CONCLUSION: Our findings suggest that reducing endometrial cancer risk can be added to the list of maternal benefits associated with breastfeeding. Ongoing promotion, support, and facilitation of this safe and beneficial behavior might therefore contribute to the prevention of this increasingly common cancer.

Predictors of pretreatment CA125 at ovarian cancer diagnosis: a pooled analysis in the Ovarian Cancer Association Consortium.

PURPOSE: Cancer antigen 125 (CA125) is a glycoprotein expressed by epithelial cells of several normal tissue types and overexpressed by several epithelial cancers. Serum CA125 levels are mostly used as an aid in the diagnosis of ovarian cancer patients, to monitor response to treatment and detect cancer recurrence. Besides tumor characteristics, CA125 levels are also influenced by several epidemiologic factors, such as age, parity, and oral contraceptive use. Identifying factors that influence CA125 levels in ovarian cancer patients could aid in the interpretation of CA125 values for individuals. METHODS: We evaluated predictors of pretreatment CA125 in 13 studies participating in the Ovarian Cancer Association Consortium. This analysis included a total of 5,091 women with invasive epithelial ovarian cancer with pretreatment CA125 measurements. We used probit scores to account for variability in CA125 between studies and linear regression to estimate the association between epidemiologic factors and tumor characteristics and pretreatment CA125 levels. RESULTS: In age-adjusted models, older age, history of pregnancy, history of tubal ligation, family history of breast cancer, and family history of ovarian cancer were associated with higher CA125 levels while endometriosis was associated with lower CA125 levels. After adjusting for tumor-related characteristics (stage, histology, grade), body mass index (BMI) higher than 30 kg/m2 was associated with 10% (95% CI 2, 19%) higher CA125 levels, while race (non-white vs. white) was associated with 15% (95% CI 4, 27%) higher CA125 levels. CONCLUSION: Our results suggest that high BMI and race may influence CA125 levels independent of tumor characteristics. Validation is needed in studies that use a single assay for CA125 measurement and have a diverse study population.

No Evidence That Genetic Variation in the Myeloid-Derived Suppressor Cell Pathway Influences Ovarian Cancer Survival.

Background: The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immunosuppressive/protumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be a prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses.Methods: We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association Study and the admixture likelihood method were used to test gene and pathway associations with survival.Results: We did not identify individual SNPs that were significantly associated with survival after correction for multiple testing (P < 3.5 × 10-5), nor did we identify significant associations between the MDSC pathway overall, or the 24 individual genes and EOC survival.Conclusions: In this well-powered analysis, we observed no evidence that inherited variations in MDSC-associated SNPs, individual genes, or the collective genetic pathway contributed to EOC survival outcomes.Impact: Common inherited variation in genes relevant to MDSCs was not associated with survival in women diagnosed with invasive EOC. Cancer Epidemiol Biomarkers Prev; 26(3); 420-4. ©2016 AACR.

Assessment of Multifactor Gene-Environment Interactions and Ovarian Cancer Risk: Candidate Genes, Obesity, and Hormone-Related Risk Factors.

BACKGROUND: Many epithelial ovarian cancer (EOC) risk factors relate to hormone exposure and elevated estrogen levels are associated with obesity in postmenopausal women. Therefore, we hypothesized that gene-environment interactions related to hormone-related risk factors could differ between obese and non-obese women. METHODS: We considered interactions between 11,441 SNPs within 80 candidate genes related to hormone biosynthesis and metabolism and insulin-like growth factors with six hormone-related factors (oral contraceptive use, parity, endometriosis, tubal ligation, hormone replacement therapy, and estrogen use) and assessed whether these interactions differed between obese and non-obese women. Interactions were assessed using logistic regression models and data from 14 case-control studies (6,247 cases; 10,379 controls). Histotype-specific analyses were also completed. RESULTS: SNPs in the following candidate genes showed notable interaction: IGF1R (rs41497346, estrogen plus progesterone hormone therapy, histology = all, P = 4.9 × 10(-6)) and ESR1 (rs12661437, endometriosis, histology = all, P = 1.5 × 10(-5)). The most notable obesity-gene-hormone risk factor interaction was within INSR (rs113759408, parity, histology = endometrioid, P = 8.8 × 10(-6)). CONCLUSIONS: We have demonstrated the feasibility of assessing multifactor interactions in large genetic epidemiology studies. Follow-up studies are necessary to assess the robustness of our findings for ESR1, CYP11A1, IGF1R, CYP11B1, INSR, and IGFBP2 Future work is needed to develop powerful statistical methods able to detect these complex interactions. IMPACT: Assessment of multifactor interaction is feasible, and, here, suggests that the relationship between genetic variants within candidate genes and hormone-related risk factors may vary EOC susceptibility. Cancer Epidemiol Biomarkers Prev; 25(5); 780-90. ©2016 AACR.

Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer.

Women with epithelial ovarian cancer (EOC) are usually treated with platinum/taxane therapy after cytoreductive surgery but there is considerable inter-individual variation in response. To identify germline single-nucleotide polymorphisms (SNPs) that contribute to variations in individual responses to chemotherapy, we carried out a multi-phase genome-wide association study (GWAS) in 1,244 women diagnosed with serous EOC who were treated with the same first-line chemotherapy, carboplatin and paclitaxel. We identified two SNPs (rs7874043 and rs72700653) in TTC39B (best P=7x10-5, HR=1.90, for rs7874043) associated with progression-free survival (PFS). Functional analyses show that both SNPs lie in a putative regulatory element (PRE) that physically interacts with the promoters of PSIP1, CCDC171 and an alternative promoter of TTC39B. The C allele of rs7874043 is associated with poor PFS and showed increased binding of the Sp1 transcription factor, which is critical for chromatin interactions with PSIP1. Silencing of PSIP1 significantly impaired DNA damage-induced Rad51 nuclear foci and reduced cell viability in ovarian cancer lines. PSIP1 (PC4 and SFRS1 Interacting Protein 1) is known to protect cells from stress-induced apoptosis, and high expression is associated with poor PFS in EOC patients. We therefore suggest that the minor allele of rs7874043 confers poor PFS by increasing PSIP1 expression.

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

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.

No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer.

OBJECTIVE: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. METHODS: Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). RESULTS: We found no association with risk of ovarian cancer (OR=0.99, 95% CI 0.94-1.04, p=0.74) or breast cancer (OR=0.98, 95% CI 0.94-1.01, p=0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR=1.09, 95% CI 0.97-1.23, p=0.14, breast cancer HR=1.04, 95% CI 0.97-1.12, p=0.27; BRCA2, ovarian cancer HR=0.89, 95% CI 0.71-1.13, p=0.34, breast cancer HR=1.06, 95% CI 0.94-1.19, p=0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR=0.94, 95% CI 0.83-1.07, p=0.38), breast cancer (HR=0.96, 95% CI 0.87-1.06, p=0.38), and all other previously-reported associations. CONCLUSIONS: rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.