Genome-wide analysis to assess if heavy alcohol consumption modifies the association between SNPs and pancreatic cancer risk.

BACKGROUND: Pancreatic cancer is a leading cause of cancer-related death globally. Risk factors for pancreatic cancer include common genetic variants and potentially heavy alcohol consumption. We assessed if genetic variants modify the association between heavy alcohol consumption and pancreatic cancer risk. METHODS: We conducted a genome-wide interaction analysis of single nucleotide polymorphisms (SNP) by heavy alcohol consumption (more than 3 drinks per day) for pancreatic cancer in European ancestry populations from genome-wide association studies (GWAS). Our analysis included 3,707 cases and 4,167 controls from case-control studies and 1,098 cases and 1,162 controls from cohort studies. Fixed effect meta-analyses were conducted. RESULTS: A potential novel region of association on 10p11.22, lead SNP rs7898449 (Pinteraction = 5.1 x 10-8 in the meta-analysis, Pinteraction = 2.1x10-9 in the case-control studies, Pinteraction = 0.91 cohort studies) was identified. A SNP correlated with this lead SNP is an eQTL for the NRP1 gene. Of the 17 genomic regions with genome-wide significant evidence of association with pancreatic cancer in prior studies, we observed suggestive evidence that heavy alcohol consumption modified the association for one SNP near LINC00673, rs11655237 on 17q25.1 (Pinteraction = 0.004). CONCLUSIONS: We identified a novel genomic region that may be associated with pancreatic cancer risk in conjunction with heavy alcohol consumption located near an eQTL for the NRP1, a protein that plays an important role in the development and progression of pancreatic cancer Impact: This work can provide insight into the etiology of pancreatic cancer particularly in heavy drinkers.

Racial and ethnic differences in epithelial ovarian cancer risk: an analysis from the Ovarian Cancer Association Consortium.

BACKGROUND: Limited estimates exist on risk factors for epithelial ovarian cancer (EOC) in Asian, Hispanic, and Native Hawaiian/Pacific Islander (NHPI) women. METHODS: Participants included 1734 Asian (785 cases, 949 controls), 266 NHPI (99 cases, 167 controls), 1149 Hispanic (505 cases, 644 controls), and 24,189 White (9,981 cases, 14,208 controls) women from 11 studies in the Ovarian Cancer Association Consortium. Logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) for risk associations by race and ethnicity. RESULTS: Heterogeneity in EOC risk associations by race and ethnicity (p ≤ 0.02) was observed for oral contraceptive (OC) use, parity, tubal ligation and smoking. We observed inverse associations with EOC risk for OC use and parity across all groups; associations were strongest in NHPI and Asian women. The inverse association for tubal ligation with risk was most pronounced for NHPI participants (OR=0.25, 95% CI 0.13-0.48), versus Asian and White participants, respectively (OR=0.68, 95% CI 0.51-0.90; OR=0.78, 95% CI 0.73-0.85). CONCLUSIONS: Differences in EOC risk factor associations were observed across racial and ethnic groups, which could in part be due to varying prevalence of EOC histotypes. Inclusion of greater diversity in future studies is essential to inform prevention strategies.

Hypertension and Risk of Endometrial Cancer: A Pooled Analysis in the Epidemiology of Endometrial Cancer Consortium (E2C2).

BACKGROUND: The incidence rates of endometrial cancer are increasing, which may partly be explained by the rising prevalence of obesity, an established risk factor for endometrial cancer. Hypertension, another component of metabolic syndrome, is also increasing in prevalence, and emerging evidence suggests that it may be associated with the development of certain cancers. The role of hypertension independent of other components of metabolic syndrome in the etiology of endometrial cancer remains unclear. In this study, we evaluated hypertension as an independent risk factor for endometrial cancer and whether this association is modified by other established risk factors. METHODS: We included 15,631 endometrial cancer cases and 42,239 controls matched on age, race, and study-specific factors from 29 studies in the Epidemiology of Endometrial Cancer Consortium. We used multivariable unconditional logistic regression models to estimate ORs and 95% confidence intervals (CI) to evaluate the association between hypertension and endometrial cancer and whether this association differed by study design, race/ethnicity, body mass index, diabetes status, smoking status, or reproductive factors. RESULTS: Hypertension was associated with an increased risk of endometrial cancer (OR, 1.14; 95% CI, 1.09-1.19). There was significant heterogeneity by study design (Phet < 0.01), with a stronger magnitude of association observed among case-control versus cohort studies. Stronger associations were also noted for pre-/perimenopausal women and never users of postmenopausal hormone therapy. CONCLUSIONS: Hypertension is associated with endometrial cancer risk independently from known risk factors. Future research should focus on biologic mechanisms underlying this association. IMPACT: This study provides evidence that hypertension may be an independent risk factor for endometrial cancer.

Impact of Pre-Diagnostic Risk Factors on Short- and Long-Term Ovarian Cancer Survival Trajectories: A Longitudinal Observational Study.

Tumor- and treatment-related factors are established predictors of ovarian cancer survival. New studies suggest a differential impact of exposures on ovarian cancer survival trajectories (i.e., rapidly fatal to long-term disease). This study examined the impact of pre-diagnostic risk factors on short- and long-term ovarian cancer survival trajectories in the Canadian context. This population-based longitudinal observational study included women diagnosed with invasive epithelial ovarian cancer from 1995 to 2004 in Ontario. Data were obtained from medical records, interviews, and the provincial cancer registry. Extended Cox proportional hazard models estimated the association between risk factors and all-cause and ovarian cancer-specific mortality by survival time intervals (<3 years (i.e., short-term survival), 3 to <6 years, 6 to <10 years, and ≥10 years (i.e., long-term survival)). Among 1421 women, histology, stage, and residual disease were the most important predictors of all-cause mortality in all survival trajectories, particularly for short-term survival. Reproductive and lifestyle factors did not strongly impact short-term overall survival but were associated with long-term overall survival. As such, among long-term survivors, history of breastfeeding significantly decreased the risk of all-cause mortality (HR 0.65; 95% CI 0.46, 0.93; p < 0.05), whereas smoking history (HR 1.75; 95% CI 1.27, 2.40; p < 0.05) and obesity (HR 1.81; 95% CI 1.24, 2.65; p < 0.05) significantly increased the risk of all-cause mortality. The findings were consistent with ovarian cancer-specific mortality. These findings suggest that pre-diagnostic exposures differentially influence survival time following a diagnosis of ovarian cancer.

Detection of hepatocellular carcinoma methylation markers in salivary DNA.

BACKGROUND: Alterations to DNA methylation have been identified in both hepatocellular carcinoma (HCC) tumor and circulating DNA from affected individuals. These markers have potential utility in HCC screening. Adherence to HCC screening is poor and acceptable HCC screening tests are needed. METHODS: A feasibility study was performed on a subset of case patients and control subjects from a prior study of risk factors for HCC. Case patients (n=12) included adults aged 47-85 years with a first diagnosis of HCC between 2011 and 2016 and without viral hepatitis. Control subjects (n=12) were matched on age, sex, and state of residence. Participants provided saliva samples for DNA genotyping. Log fold change in salivary DNA methylation at 1359 CpG sites representing 25 candidate genes previously associated with HCC was compared across case patients and control subjects. RESULTS: The quantity of DNA ranged from 9.65 to 257.79 µg. The purity of DNA isolates was good, with mean OD260/280 ratio of 1.78 (SD: 0.14). Of 25 candidate genes, 16 had at ≥1 CpG site with detectable differences in methylation across HCC case patients and control subjects. Sites differentially methylated in HCC case patients included genes encoding tumor suppressors (PRDM2, RUNX3, p15/16, and RASSF1/5), regulators of cell cycle progression (DAPK1 and TP73), and DNA repair (MGMT and GSTP1). No associations met the significance threshold 3.7 × 10-5 required for multiple comparisons. CONCLUSIONS: Salivary DNA may be a feasible alternative to blood samples in the era of novel DNA-based screening tests for HCC. The ease of saliva-based testing supports further investigation of its potential.

Machine learning-based cluster analysis of immune cell subtypes and breast cancer survival.

Host immunity involves various immune cells working in concert to achieve balanced immune response. Host immunity interacts with tumorigenic process impacting disease outcome. Clusters of different immune cells may reveal unique host immunity in relation to breast cancer progression. CIBERSORT algorithm was used to estimate relative abundances of 22 immune cell types in 3 datasets, METABRIC, TCGA, and our study. The cell type data in METABRIC were analyzed for cluster using unsupervised hierarchical clustering (UHC). The UHC results were employed to train machine learning models. Kaplan-Meier and Cox regression survival analyses were performed to assess cell clusters in association with relapse-free and overall survival. Differentially expressed genes by clusters were interrogated with IPA for molecular signatures. UHC analysis identified two distinct immune cell clusters, clusters A (83.2%) and B (16.8%). Memory B cells, plasma cells, CD8 positive T cells, resting memory CD4 T cells, activated NK cells, monocytes, M1 macrophages, and resting mast cells were more abundant in clusters A than B, whereas regulatory T cells and M0 and M2 macrophages were more in clusters B than A. Patients in cluster A had favorable survival. Similar survival associations were also observed in other independent studies. IPA analysis showed that pathogen-induced cytokine storm signaling pathway, phagosome formation, and T cell receptor signaling were related to the cell type clusters. Our finding suggests that different immune cell clusters may indicate distinct immune responses to tumor growth, suggesting their potential for disease management.

Night shift work, sleep duration and endometrial cancer risk: A pooled analysis from the Epidemiology of Endometrial Cancer Consortium (E2C2).

Data on the role of circadian related factors in the etiology of endometrial cancer are scarce. We collected individual data on night shift work or daily sleep duration from 7,207 cases and 22,027 controls participating in 11 studies from the Epidemiology of Endometrial Cancer Consortium (E2C2). Main analyses were performed among postmenopausal women: 6,335 endometrial cancer cases and 18,453 controls. Using individual data, study-specific odd ratios (ORs) and their corresponding 95% confidence intervals (CIs) were estimated with logistic regression and pooled analyses were conducted using random-effects meta-analyses. A non-significant inverse association was observed between endometrial cancer and night shift work (OR=0.89, 95%CI=0.72-1.09; I2=0.0%, Pheterogeneity=0.676). Associations did not vary by shift type (permanent or rotating), or duration of night work. Categorizations of short (<7h) or long (≥9h) sleep duration were not associated with endometrial cancer risk (ORshort=1.02, 95%CI=0.95-1.10; I2=55.3%, Pheterogeneity=0.022; ORlong=0.93, 95%CI=0.81-1.06; I2=11.5%, Pheterogeneity=0.339). No associations were observed per 1-h increment of sleep (OR=0.98, 95%CI=0.95-1.01; I2=46.1%, Pheterogeneity=0.063), but an inverse association was identified among obese women (OR=0.93, 95%CI=0.89-0.98 per 1-h increment; I2=12.7%, Pheterogeneity=0.329). Overall, these pooled analyses provide evidence that night shift work and sleep duration are not strong risk factors for endometrial cancer in postmenopausal women.

Randomized trial of exercise on cancer-related blood biomarkers and survival in women with ovarian cancer.

BACKGROUND: In randomized trials in women with breast cancer, exercise has been shown to have beneficial effects on cancer-related circulating biomarkers that may impact survival. Such studies are lacking for ovarian cancer. METHODS: This secondary analysis of a published randomized controlled trial examined the impact of a 6-month exercise intervention versus attention-control on change in prespecified circulating biomarkers (cancer antigen 125 (CA-125), C-reactive protein (CRP), insulin-like growth factor-1(IGF-1), insulin and leptin) in a subset of participants who provided a fasting blood draw (N = 104/144) at enrollment and at 6 months. Change in biomarkers between study arms was compared using a linear mixed effects model analysis. An exploratory analysis of the exercise intervention versus attention-control on all-cause mortality included all (N = 144) participants. All statistical tests were two-sided. RESULTS: Participants included in the biomarker analysis were 57.0 ± 8.8 (mean ± SD) years old and 1.6 ± 0.9 years post-diagnosis. Adherence to the exercise intervention was 176.4 ± 63.5 min/week. Post intervention IGF-1 (group difference in change: -14.2 (-26.1 to -2.3) ng/mL (least squared means (95% CI))) and leptin (-8.9 (-16.5 to -1.4) ng/mL) were significantly reduced in the exercise group (N = 53) compared to those in attention-control (N = 51). No group difference in change was seen for CA-125 (p = 0.54), CRP (p = 0.95), or insulin (p = 0.37). With median follow-up of 70 months [range 6.6-105.4 months], 50/144 (34.7%) (exercise group; 24/74 (32.4%) versus attention-control group; 26/70 (37.1%)) participants died with no between group difference in overall survival (p = 0.99). CONCLUSIONS: Further studies are needed to determine the clinical significance of exercise-induced changes in cancer-related circulating biomarkers in women with ovarian cancer.

Relationship between ABO Blood Group Alleles and Pancreatic Cancer Is Modulated by Secretor (FUT2) Genotype, but Not Lewis Antigen (FUT3) Genotype.

BACKGROUND: In Western populations, pancreatic ductal adenocarcinoma (PDAC) risk has been found to be greater among individuals with non-O blood types than those with O blood type. However, the association has not been fully evaluated with respect to FUT2 (determining secretor status) and FUT3 (determining Lewis antigens) status, two biologically important genes in the expression of ABO blood groups with PDAC. METHODS: We examined interactions in data from 8,027 cases and 11,362 controls in large pancreatic cancer consortia (PanScan I-III and PanC4) by using genetic variants to predict ABO blood groups (rs505922 and rs8176746), secretor status (rs601338), and Lewis antigens (rs812936, rs28362459, and rs3894326). Multivariable logistic regression was used to estimate ORs and 95% confidence intervals (CI) of the risk of PDAC adjusted for age and sex. We examined multiplicative interactions of ABO with secretor status and Lewis antigens by considering each product term between ABO and secretor and between ABO and Lewis antigens individually. RESULTS: We found that the increased risk associated with non-O blood groups was somewhat stronger among secretors than nonsecretors [ORs, 1.28 (95% CI, 1.15-1.42) and 1.17 (95% CI, 1.03-1.32) respectively; Pinteraction = 0.002]. We did not find any interactions between ABO and Lewis antigens. CONCLUSIONS: Our large consortia data provide evidence of effect modification in the association between non-O blood type and pancreatic cancer risk by secretor status. IMPACT: Our results indicate that the association between ABO blood type and PDAC risk may vary by secretor status, but not by Lewis antigens.

Folate Intake and Ovarian Cancer Risk among Women with Endometriosis: A Case-Control Study from the Ovarian Cancer Association Consortium.

BACKGROUND: Although folate intake has not been associated with an increased risk of ovarian cancer overall, studies of other cancer types have suggested that high folate intake may promote carcinogenesis in precancerous lesions. Women with endometriosis (a potential precancerous lesion) have an increased risk of developing ovarian cancer; however, whether high folate intake increases risk in this group is unknown. METHODS: We conducted a pooled analysis of six case-control studies from the Ovarian Cancer Association Consortium to investigate the association between folate intake and risk of ovarian cancer among women with and without self-reported endometriosis. We included 570 cases/558 controls with and 5,171/7,559 without endometriosis. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals for the association between folate intake (dietary, supplemental, and total) and ovarian cancer risk. Finally, we used Mendelian randomization (MR) to evaluate our results using genetic markers as a proxy for folate status. RESULTS: Higher dietary folate intake was associated with an increased risk of ovarian cancer for women with endometriosis [OR, 1.37 (1.01-1.86)] but not for women without endometriosis. There was no association between supplemental folate intake and ovarian cancer risk for women with or without endometriosis. A similar pattern was seen using MR. CONCLUSIONS: High dietary folate intake may be associated with an increased risk of ovarian cancer among women with endometriosis. IMPACT: Women with endometriosis with high folate diets may be at increased risk of ovarian cancer. Further research is needed on the potential cancer-promoting effects of folate in this group.

Dynamic changes of circulating soluble PD-1/PD-L1 and its association with patient survival in immune checkpoint blockade-treated melanoma.

Immune checkpoint PD-1 and its ligand PD-L1 lead to T cell exhaustion, and a high level of circulating soluble PD-L1 at baseline indicates a poor prognosis in melanoma and other solid tumor types. Here we show that the dynamic changes of circulating soluble PD-1 and PD-L1 across the course of immune checkpoint blockades (ICBs) and their changes associate with patient survival in melanoma in a retrospective study. A high change of soluble PD-L1 level at a time-point but not PD-1 significantly increased the mortality, whereas a high change of soluble PD-1/PD-L1 ratio significantly reduced the mortality. After the initial immunotherapy, both soluble PD-1 and PD-L1 increased. However, the change pattern of soluble PD-L1 level was particularly dependent on patients' survival status. These findings indicate that the magnitudes of circulating soluble PD-L1 and PD-1/PD-L1 ratio changes over the time may reflect the patients' response to ICBs or the progression of the disease and predict the survival in melanoma patients treated with ICBs.

Dietary omega-3 fatty acids and endometrial cancer risk in the Epidemiology of Endometrial Cancer Consortium: An individual-participant meta-analysis.

BACKGROUND: Limited data from prospective studies suggest that higher dietary intake of long-chain omega-3 polyunsaturated fatty acids (LCn3PUFA), which hold anti-inflammatory properties, may reduce endometrial cancer risk; particularly among certain subgroups characterized by body mass and tumor pathology. MATERIALS AND METHODS: Data from 12 prospective cohort studies participating in the Epidemiology of Endometrial Cancer Consortium were harmonized as nested case-control studies, including 7268 endometrial cancer cases and 26,133 controls. Habitual diet was assessed by food frequency questionnaire, from which fatty acid intakes were estimated. Two-stage individual-participant data mixed effects meta-analysis estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) through logistic regression for associations between study-specific energy-adjusted quartiles of LCn3PUFA and endometrial cancer risk. RESULTS: Women with the highest versus lowest estimated dietary intakes of docosahexaenoic acid, the most abundant LCn3PUFA in diet, had a 9% increased endometrial cancer risk (Quartile 4 vs. Quartile 1: OR 1.09, 95% CI: 1.01-1.19; P trend = 0.04). Similar elevated risks were observed for the summary measure of total LCn3PUFA (OR 1.07, 95% CI: 0.99-1.16; P trend = 0.06). Stratified by body mass index, higher intakes of LCn3PUFA were associated with 12-19% increased endometrial cancer risk among overweight/obese women and no increased risk among normal-weight women. Higher associations appeared restricted to White women. The results did not differ by cancer grade. CONCLUSION: Higher dietary intakes of LCn3PUFA are unlikely to reduce endometrial cancer incidence; rather, they may be associated with small to moderate increases in risk in some subgroups of women, particularly overweight/obese women.

Risk prediction models for endometrial cancer: development and validation in an international consortium.

BACKGROUND: Endometrial cancer risk stratification may help target interventions, screening, or prophylactic hysterectomy to mitigate the rising burden of this cancer. However, existing prediction models have been developed in select cohorts and have not considered genetic factors. METHODS: We developed endometrial cancer risk prediction models using data on postmenopausal White women aged 45-85 years from 19 case-control studies in the Epidemiology of Endometrial Cancer Consortium (E2C2). Relative risk estimates for predictors were combined with age-specific endometrial cancer incidence rates and estimates for the underlying risk factor distribution. We externally validated the models in 3 cohorts: Nurses' Health Study (NHS), NHS II, and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. RESULTS: Area under the receiver operating characteristic curves for the epidemiologic model ranged from 0.64 (95% confidence interval [CI] = 0.62 to 0.67) to 0.69 (95% CI = 0.66 to 0.72). Improvements in discrimination from the addition of genetic factors were modest (no change in area under the receiver operating characteristic curves in NHS; PLCO = 0.64 to 0.66). The epidemiologic model was well calibrated in NHS II (overall expected-to-observed ratio [E/O] = 1.09, 95% CI = 0.98 to 1.22) and PLCO (overall E/O = 1.04, 95% CI = 0.95 to 1.13) but poorly calibrated in NHS (overall E/O = 0.55, 95% CI = 0.51 to 0.59). CONCLUSIONS: Using data from the largest, most heterogeneous study population to date (to our knowledge), prediction models based on epidemiologic factors alone successfully identified women at high risk of endometrial cancer. Genetic factors offered limited improvements in discrimination. Further work is needed to refine this tool for clinical or public health practice and expand these models to multiethnic populations.

Effects of risk factors for ovarian cancer in women with and without endometriosis.

OBJECTIVE: To evaluate the associations between 10 well-established ovarian cancer risk factors and risk of ovarian cancer among women with vs. without endometriosis. DESIGN: Pooled analysis of 9 case-control studies in the Ovarian Cancer Association Consortium. SETTING: Population-based. PATIENT(S): We included 8,500 women with ovarian cancer, 13,592 control women. INTERVENTION(S): Ten well-established ovarian cancer risk factors. MAIN OUTCOME MEASURE(S): Risk of ovarian cancer for women with and without endometriosis. RESULT(S): Most risk factor-ovarian cancer associations were similar when comparing women with and without endometriosis, and no interactions were statistically significant. However, body mass index (BMI) 25-<30 kg/m2 was associated with increased ovarian cancer risk among women with endometriosis (odds ratio [OR] = 1.27, 95% confidence interval [CI] 1.00-1.60), but not associated with the risk among women without endometriosis (OR = 0.97; 95% CI, 0.91-1.05) when compared with BMI 18.5-<25 kg/m2; an increased risk was observed for a BMI ≥30 kg/m2, although there was little difference comparing women with endometriosis (OR = 1.21; 95% CI, 0.94-1.57) to women without (OR = 1.13; 95% CI, 1.04-1.22) (P-interaction = .51). Genital talcum powder use and long-term menopausal estrogen-only therapy use showed increased ovarian cancer risk, but risk appeared greater for those with endometriosis vs. those without (genital talcum powder: OR = 1.38; 95% CI, 1.04-1.84 vs. OR = 1.12; 95% CI, 1.01-1.25, respectively; ≥10 years of estrogen-only therapy: OR = 1.88; 95% CI, 1.09-3.24 vs. OR = 1.42; 95% CI, 1.14-1.76, respectively); neither of these interactions were statistically significant (P-interaction = .65 and P-interaction = .96, respectively). CONCLUSION(S): The associations between ovarian cancer and most risk factors were similar among women with and without endometriosis. However, there was some suggestion of differences by endometriosis status for BMI, menopausal hormone therapy use, and genital talcum powder use, highlighting the complexity of ovarian cancer etiology.

eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma.

BACKGROUND: Over 20 susceptibility single-nucleotide polymorphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability. METHODS: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression. RESULTS: Although the standard approach did not identify significant signals, the eQTL set-based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1). CONCLUSIONS: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set-based genetic association approach. IMPACT: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set-based genetic association approach as an alternative method for TWAS analysis.

Impact of germline mutations in cancer-predisposing genes on long-term survival in patients with epithelial ovarian cancer.

BACKGROUND: Several clinical and tumour factors impact on ovarian cancer survival. It is important to evaluate if germline mutations impact long-term outcomes among patients with epithelial ovarian cancer. METHODS: We followed 1422 Ontario women with ovarian cancer. Clinical information was obtained from medical records and vital status was determined by registry linkage. Germline genetic testing was performed for 12 susceptibility genes. We estimated 20-year cancer-specific survival according to various factors. RESULTS: Twenty-year survival was inferior for women with serous cancers vs. other types (22.3% vs. 68.6%; P < 0.0001). Of the 1422 patients, 248 (17.4%) carried a germline mutation; 119 BRCA1; 75 BRCA2; 7 in a mismatch repair (MMR) gene and 47 in one of seven other genes. Among serous patients, 20-year survival was 28.9% for similar for women with a BRCA1 (28.9%), BRCA2 (21.2%) or no mutation (21.6%). Among endometrioid patients, 20-year survival was poor for women with a BRCA vs. no mutation (47.3% vs. 70.4%; P = 0.004). Six of the seven MMR mutation carriers are currently alive, while all three PALB2 mutation carriers died within 3 years of diagnosis. Among women with Stage III/IV serous cancers, 20-year survival was 9.4% for those with vs. 46.5% for those with no residual disease (HR = 2.91; 95% CI 2.12-4.09, P < 0.0001). CONCLUSIONS: The most important predictor of long-term survival was no residual disease post surgery. BRCA mutation status was not predictive of long-term survival while those with MMR mutations had excellent survival. Larger studies on PALB2 carriers are needed.

Reproductive Factors Do Not Influence Survival with Ovarian Cancer.

BACKGROUND: Previous studies on the association between reproductive factors and ovarian cancer survival are equivocal, possibly due to small sample sizes. METHODS: Using data on 11,175 people diagnosed with primary invasive epithelial ovarian, fallopian tube, or primary peritoneal cancer (ovarian cancer) from 16 studies in the Ovarian Cancer Association Consortium (OCAC), we examined the associations between survival and age at menarche, combined oral contraceptive use, parity, breastfeeding, age at last pregnancy, and menopausal status using Cox proportional hazard models. The models were adjusted for age at diagnosis, race/ethnicity, education level, and OCAC study and stratified on stage and histotype. RESULTS: During the mean follow-up of 6.34 years (SD = 4.80), 6,418 patients passed away (57.4%). There was no evidence of associations between the reproductive factors and survival among patients with ovarian cancer overall or by histotype. CONCLUSIONS: This study found no association between reproductive factors and survival after an ovarian cancer diagnosis. IMPACT: Reproductive factors are well-established risk factors for ovarian cancer, but they are not associated with survival after a diagnosis of ovarian cancer.

Oral Cyanobacteria and Hepatocellular Carcinoma.

BACKGROUND: Gut microbial alterations have been linked to chronic liver disease and hepatocellular carcinoma (HCC). The role of the oral microbiome in liver cancer development has not been widely investigated. METHODS: Bacterial 16S rRNA sequences were evaluated in oral samples from 90 HCC cases and 90 controls who were a part of a larger U.S. case-control study of HCC among patients diagnosed from 2011 to 2016. RESULTS: The oral microbiome of HCC cases showed significantly reduced alpha diversity compared with controls (Shannon P = 0.002; Simpson P = 0.049), and beta diversity significantly differed (weighted Unifrac P = 0.004). The relative abundance of 30 taxa significantly varied including Cyanobacteria, which was enriched in cases compared with controls (P = 0.018). Cyanobacteria was positively associated with HCC [OR, 8.71; 95% confidence interval (CI), 1.22-62.00; P = 0.031] after adjustment for age, race, birthplace, education, smoking, alcohol, obesity, type 2 diabetes, Hepatitis C virus (HCV), Hepatitis B virus (HBV), fatty liver disease, aspirin use, other NSAID use, laboratory batch, and other significant taxa. When stratified by HCC risk factors, significant associations of Cyanobacteria with HCC were exclusively observed among individuals with negative histories of established risk factors as well as females and college graduates. Cyanobacterial genes positively associated with HCC were specific to taxa producing microcystin, the hepatotoxic tumor promotor, and other genes known to be upregulated with microcystin exposure. CONCLUSIONS: Our study provides novel evidence that oral Cyanobacteria may be an independent risk factor for HCC. IMPACT: These findings support future studies to further examine the causal relationship between oral Cyanobacteria and HCC risk.

High Prediagnosis Inflammation-Related Risk Score Associated with Decreased Ovarian Cancer Survival.

BACKGROUND: There is suggestive evidence that inflammation is related to ovarian cancer survival. However, more research is needed to identify inflammation-related factors that are associated with ovarian cancer survival and to determine their combined effects. METHODS: This analysis used pooled data on 8,147 women with invasive epithelial ovarian cancer from the Ovarian Cancer Association Consortium. The prediagnosis inflammation-related exposures of interest included alcohol use; aspirin use; other nonsteroidal anti-inflammatory drug use; body mass index; environmental tobacco smoke exposure; history of pelvic inflammatory disease, polycystic ovarian syndrome, and endometriosis; menopausal hormone therapy use; physical inactivity; smoking status; and talc use. Using Cox proportional hazards models, the relationship between each exposure and survival was assessed in 50% of the data. A weighted inflammation-related risk score (IRRS) was developed, and its association with survival was assessed using Cox proportional hazards models in the remaining 50% of the data. RESULTS: There was a statistically significant trend of increasing risk of death per quartile of the IRRS [HR = 1.09; 95% confidence interval (CI), 1.03-1.14]. Women in the upper quartile of the IRRS had a 31% higher death rate compared with the lowest quartile (95% CI, 1.11-1.54). CONCLUSIONS: A higher prediagnosis IRRS was associated with an increased mortality risk after an ovarian cancer diagnosis. Further investigation is warranted to evaluate whether postdiagnosis exposures are also associated with survival. IMPACT: Given that pre- and postdiagnosis exposures are often correlated and many are modifiable, our study results can ultimately motivate the development of behavioral recommendations to enhance survival among patients with ovarian cancer.

Prediction of Pancreatic Cancer in Diabetes Patients with Worsening Glycemic Control.

BACKGROUND: Worsening glycemic control indicates elevated risk of pancreatic ductal adenocarcinoma (PDAC). We developed prediction models for PDAC among those with worsening glycemic control after diabetes diagnosis. METHODS: In 2000-2016 records within the Veterans Affairs Health System (VA), we identified three cohorts with progression of diabetes: (i) insulin initiation (n = 449,685), (ii) initiation of combination oral hypoglycemic medication (n = 414,460), and (iii) hemoglobin A1c (HbA1c) ≥8% with ≥Δ1% within 15 months (n = 593,401). We computed 12-, 36-, and 60-month incidence of PDAC and developed prediction models separately for males and females, with consideration of >30 demographic, behavioral, clinical, and laboratory variables. Models were selected to optimize Akaike's Information Criterion, and performance for predicting 12-, 36-, and 60-month incident PDAC was evaluated by bootstrap. RESULTS: Incidence of PDAC was highest for insulin initiators and greater in males than in females. Optimism-corrected c-indices of the models for predicting 36-month incidence of PDAC in the male population were: (i) 0.72, (ii) 0.70, and (iii) 0.71, respectively. Models performed better for predicting 12-month incident PDAC [c-index (i) 0.78, (ii) 0.73, (iii) 0.76 for males], and worse for predicting 60-month incident PDAC [c-index (i) 0.69, (ii) 0.67, (iii) 0.68 for males]. Model performance was lower among females. For subjects whose model-predicted 36-month PDAC risks were ≥1%, the observed incidences were (i) 1.9%, (ii) 2.2%, and (iii) 1.8%. CONCLUSIONS: Sex-specific models for PDAC can estimate risk of PDAC at the time of progression of diabetes. IMPACT: Our models can identify diabetes patients who would benefit from PDAC screening.