Kirsten B. Moysich

Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population

PURPOSE The aim of this study was to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to invasive epithelial ovarian cancer (EOC) in the population and in a screening trial of individuals at high risk of ovarian cancer. PATIENTS AND METHODS The coding sequence and splice site boundaries of the three RAD51 genes were sequenced and analyzed in germline DNA from a case-control study of 3,429 patients with invasive EOC and 2,772 controls as well as in 2,000 unaffected women who were BRCA1/BRCA2 negative from the United Kingdom Familial Ovarian Cancer Screening Study (UK_FOCSS) after quality-control analysis. RESULTS In the case-control study, we identified predicted deleterious mutations in 28 EOC cases (0.82%) compared with three controls (0.11%; P < .001). Mutations in EOC cases were more frequent in RAD51C (14 occurrences, 0.41%) and RAD51D (12 occurrences, 0.35%) than in RAD51B (two occurrences, 0.06%). RAD51C mutations were associated with an odds ratio of 5.2 (95% CI, 1.1 to 24; P = .035), and RAD51D mutations conferred an odds ratio of 12 (95% CI, 1.5 to 90; P = .019). We identified 13 RAD51 mutations (0.65%) in unaffected UK_FOCSS participants (RAD51C, n = 7; RAD51D, n = 5; and RAD51B, n = 1), which was a significantly greater rate than in controls (P < .001); furthermore, RAD51 mutation carriers were more likely than noncarriers to have a family history of ovarian cancer (P < .001). CONCLUSION These results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of EOC that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing.

Tagging Single Nucleotide Polymorphisms in Cell Cycle Control Genes and Susceptibility to Invasive Epithelial Ovarian Cancer

High-risk susceptibility genes explain <40% of the excess risk of familial ovarian cancer. Therefore, other ovarian cancer susceptibility genes are likely to exist. We have used a single nucleotide polymorphism (SNP)-tagging approach to evaluate common variants in 13 genes involved in cell cycle control-CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, and CDKN2D-and risk of invasive epithelial ovarian cancer. We used a two-stage, multicenter, case-control study. In stage 1, 88 SNPs that tag common variation in these genes were genotyped in three studies from the United Kingdom, United States, and Denmark ( approximately 1,500 cases and 2,500 controls). Genotype frequencies in cases and controls were compared using logistic regression. In stage 2, eight other studies from Australia, Poland, and the United States ( approximately 2,000 cases and approximately 3,200 controls) were genotyped for the five most significant SNPs from stage 1. No SNP was significant in the stage 2 data alone. Using the combined stages 1 and 2 data set, CDKN2A rs3731257 and CDKN1B rs2066827 were associated with disease risk (unadjusted P trend = 0.008 and 0.036, respectively), but these were not significant after adjusting for multiple testing. Carrying the minor allele of these SNPs was found to be associated with reduced risk [OR, 0.91 (0.85-0.98) for rs3731257; and OR, 0.93 (0.87-0.995) for rs2066827]. In conclusion, we have found evidence that a single tagged SNP in both the CDKN2A and CDKN1B genes may be associated with reduced ovarian cancer risk. This study highlights the need for multicenter collaborations for genetic association studies.

Wood dust exposure and the risk of upper aero-digestive and respiratory cancers in males.

Background: Wood dust (WD) has been designated a human carcinogen that can cause sino-nasal cancers. However, evidence of its association with other upper aero-digestive tract and respiratory (UADR) cancers is inconsistent. Objective: To examine the relationship between WD exposure and the risk of different histological subtypes of UADR cancers. Methods: In a hospital-based case-control study conducted at Roswell Park Cancer Institute, Buffalo, NY, USA, an examination was carried out to determine the effect of self-reported WD exposure on 1522 male UADR cancer cases (241 oral and oropharyngeal, 90 nasal cavity, nasopharyngeal and hypopharyngeal, 124 laryngeal, 809 lung and tracheal and 258 oesophagus and gastric cardia) and 1522 male controls, frequency matched on age and smoking history. Odds ratios (OR) were calculated after adjusting for relevant risk factors including tobacco smoking. Results: The results show that regular WD exposure was associated with a statistically significant increased risk of 32% for all UADR cancers (OR 1.32; 95% CI 1.01 to 1.77; p-trend = 0.05) and 69% for lung cancer alone (OR 1.69; 95% CI 1.20 to 2.36; p-trend = 0.007). WD was associated with an 82–93% increased risk of squamous cell, small cell and adenocarcinoma of the lung and more than twice the risk of developing squamous cell carcinoma of the nasal cavity, nasopharynx and hypopharynx, with a significant dose–response relationship. Oral and oropharyngeal cancers showed a non-significant increase in risk. A significant increase in risk of laryngeal and lung cancers was noted for subjects regularly exposed to WD for >20 years. Cancers of the oesophagus and gastric cardia did not show any risk associated with WD. WD was associated with a significantly greater risk of UADR cancers among people who had ever smoked than never smokers. Conclusion: WD exposure is a potential risk factor for UADR cancers, especially for cancers of the nasal cavity, nasopharynx, larynx and lung.

Diabetes mellitus and gastric carcinoma: Is there an association?

Diabetes mellitus (DM) has been associated with the risk of several gastrointestinal cancers including liver, pancreas, colon and rectum. However, the evidence is inconclusive for gastric adenocarcinoma (GC). In the current review, we summarize 20 population-based cohort studies that compared GC incidence and mortality between diabetic and non-diabetic population. We discuss the shared risk factors and provide qualitative and quantitative (meta-analytic) summary of the current evidence evaluating the association by high-risk subgroups. The overall risk-estimate based on all studies did not show an increased risk of GC in diabetics. However, 2 cohort studies conducted in East Asian countries, where Helicobacter pylori infection and GC rates are higher, showed a higher risk of GC in diabetics. Additionally, high plasma glucose levels in the presence of Helicobacter pylori infection increased the risk of GC by over four times, suggesting a multiplicative effect. Results from the meta-analysis show that, the risk of GC was also higher in populations with greater prevalence of type 1 DM (relative risk = 1.60), suggesting an insulin-independent carcinogenic process in this subgroup. The risk of mortality due to GC was higher in diabetics compared to non-diabetics (relative risk = 1.62). Although the overall risk estimates do not show an association between DM and GC, complex interactions between infectious, molecular, demographic and host factors may convey a higher risk in certain subgroups. Future studies should be sufficiently powered for detailed subgroup analysis to elucidate the causative and mechanistic association between DM and GC.

The Chernobyl childhood leukemia study: background & lessons learned

Many challenges emerged during completion of a study to examine radiation dose and acute leukemia among children in areas of the former Soviet Union. In an era of globalization, our experiences might benefit others involved in multinational investigations.

History of hypertension, heart disease, and diabetes and ovarian cancer patient survival: evidence from the ovarian cancer association consortium

PurposeSurvival following ovarian cancer diagnosis is generally low; understanding factors related to prognosis could be important to optimize treatment. The role of previously diagnosed comorbidities and use of medications for those conditions in relation to prognosis for ovarian cancer patients has not been studied extensively, particularly according to histological subtype.MethodsUsing pooled data from fifteen studies participating in the Ovarian Cancer Association Consortium, we examined the associations between history of hypertension, heart disease, diabetes, and medications taken for these conditions and overall survival (OS) and progression-free survival (PFS) among patients diagnosed with invasive epithelial ovarian carcinoma. We used Cox proportional hazards regression models adjusted for age and stage to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) overall and within strata of histological subtypes.ResultsHistory of diabetes was associated with increased risk of mortality (n = 7,674; HR = 1.12; 95% CI = 1.01–1.25). No significant mortality associations were observed for hypertension (n = 6,482; HR = 0.95; 95% CI = 0.88–1.02) or heart disease (n = 4,252; HR = 1.05; 95% CI = 0.87–1.27). No association of these comorbidities was found with PFS in the overall study population. However, among patients with endometrioid tumors, hypertension was associated with lower risk of progression (n = 339, HR = 0.54; 95% CI = 0.35–0.84). Comorbidity was not associated with OS or PFS for any of the other histological subtypes. Ever use of beta blockers, oral antidiabetic medications, and insulin was associated with increased mortality, HR = 1.20; 95% CI = 1.03–1.40, HR = 1.28; 95% CI = 1.05–1.55, and HR = 1.63; 95% CI = 1.20–2.20, respectively. Ever use of diuretics was inversely associated with mortality, HR = 0.71; 95% CI = 0.53–0.94.ConclusionsHistories of hypertension, diabetes, and use of diuretics, beta blockers, insulin, and oral antidiabetic medications may influence the survival of ovarian cancer patients. Understanding mechanisms for these observations could provide insight regarding treatment.

Use of common analgesics is not associated with ovarian cancer survival

Background: Use of analgesics has been associated with lower risk of ovarian cancer, but, to date, very few studies have explored the association between analgesics and ovarian cancer survival. Methods: We examined the relationship between self-reported prediagnostic use of aspirin, ibuprofen, and acetaminophen and overall survival (OS), progression-free survival (PFS), ascites at the time of primary treatment, and persistence of disease after primary treatment among 699 women diagnosed with epithelial ovarian carcinoma. The associations between use of these medications and OS and PFS were estimated using Cox proportional hazards models. We utilized unconditional logistic regression models to estimate associations between medication use and presence of ascites and persistence of disease. Results: Prediagnostic intake of aspirin, both low-dose and regular-dose, ibuprofen, and acetaminophen was not associated with any of the outcomes of interest. Conclusions: Our results indicate a lack of association between prediagnostic intake of selected analgesics and OS, PFS, presence of ascites at the time of primary treatment, and persistence of disease after primary treatment. Impact: Prediagnostic intake of analgesics may not be associated with ovarian cancer outcomes. Cancer Epidemiol Biomarkers Prev; 24(8); 1291–4. ©2015 AACR.

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.

History of thyroid disease and survival of ovarian cancer patients: results from the Ovarian Cancer Association Consortium, a brief report

Background:Findings from in vitro studies suggest that increased exposure to thyroid hormones can influence progression of ovarian tumours. However, epidemiologic evidence on this topic is limited.Methods:We pooled data from 11 studies from the Ovarian Cancer Association Consortium. Using multivariate Cox proportional hazards models, we estimated associations between hyper- and hypothyroidism and medications prescribed for these conditions with 5-year all-cause survival among women diagnosed with invasive ovarian cancer.Results:Overall, there was a nonsignificant association with history of hyperthyroidism (n=160 cases) and mortality (HR=1.22; 95% CI=0.97–1.53). Furthermore, diagnosis of hyperthyroidism within the 5 years before ovarian cancer diagnosis was associated with an increased risk of death (HR=1.94; 95% CI=1.19–3.18). A more modest association was observed with history of hypothyroidism (n=624 cases) and mortality (HR=1.16; 95% CI=1.03–1.31). Neither duration of hypothyroidism nor use of thyroid medications was associated with survival.Conclusions:In this large study of women with ovarian cancer, we found that recent history of hyperthyroidism and overall history of hypothyroidism were associated with worse 5-year survival.

History of Comorbidities and Survival of Ovarian Cancer Patients, Results from the Ovarian Cancer Association Consortium.

Background: Comorbidities can affect survival of ovarian cancer patients by influencing treatment efficacy. However, little evidence exists on the association between individual concurrent comorbidities and prognosis in ovarian cancer patients. Methods: Among patients diagnosed with invasive ovarian carcinoma who participated in 23 studies included in the Ovarian Cancer Association Consortium, we explored associations between histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, and neurological diseases and overall and progression-free survival. Using Cox proportional hazards regression models adjusted for age at diagnosis, stage of disease, histology, and study site, we estimated pooled HRs and 95% confidence intervals to assess associations between each comorbidity and ovarian cancer outcomes. Results: None of the comorbidities were associated with ovarian cancer outcome in the overall sample nor in strata defined by histologic subtype, weight status, age at diagnosis, or stage of disease (local/regional vs. advanced). Conclusions: Histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, or neurologic diseases were not associated with ovarian cancer overall or progression-free survival. Impact: These previously diagnosed chronic diseases do not appear to affect ovarian cancer prognosis. Cancer Epidemiol Biomarkers Prev; 26(9); 1470–3. ©2017 AACR.