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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

Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations.Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls).Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network.Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development.Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574–84. ©2015 AACR.

Top independently associated SNPs from the TRICL lung cancer GWAS meta-analysis.

Purpose: Newfoundland has one of the highest rates of colorectal cancer in North America. The most common hereditary form of colorectal cancer is hereditary nonpolyposis colorectal cancer caused by mutations in genes involved in mismatch repair. Our purpose was to determine the proportion of hereditary colorectal cancer and to determine the genetic basis of disease in both population and clinically referred cohorts from Newfoundland.Experimental Design: Seventy-eight colorectal cancer patients were accrued over a 2-year period from the Avalon Peninsula of Newfoundland. We also examined 31 hereditary nonpolyposis colorectal cancer–like families, which had been referred to the Provincial Medical Genetics Program. Tumors from probands were tested by immunohistochemistry for deficiencies in MLH1, MSH2, and MSH6 proteins and tested for DNA microsatellite instability. Mutation analyses of MLH1, MSH2, and MSH6 were undertaken by direct sequencing and an assay to detect deletions, amplifications, and rearrangements in MSH2 and MLH1.Results: We identified eight population-based families that fulfill the Amsterdam I or II criteria, 4 (50%) of which seem to have hereditary cancer not attributable to the most commonly mutated mismatch repair genes. In addition, in 16 of 21 (76%) referred families fulfilling Amsterdam I or II criteria, no mutations were found in the three most commonly altered mismatch repair genes, and tumor analyses corroborated these findings.Conclusions: It seems that strong and novel genetic causes of hereditary colorectal cancer are responsible for a high proportion of colorectal cancer in this population. Conditions are suitable for the identification of these genes by linkage studies of large Newfoundland cancer families.

For individuals in the EAGLE study, all consisting of Italians, a pathway-level susceptibility effect was computed for each pathway in MSigDB as the sum of relevant SNP variant alleles weighted by their log odds ratios from the TRICL lung squamous cell carcinoma GWAS meta-analysis. Pathway values were also multiplied by cumulative smoking pack-years to produce pathway-smoking interactions. The pathways and pathway-smoking interactions that differ most between lung squamous cell carcinoma cases and healthy controls (t-test P < 0.05) in the EAGLE study are presented. Pearson correlation coefficients between these pathways and pathway-smoking interactions, and each of age, sex, and smoking pack-years are presented as well.

Supplementary Tables 1-3 from High Frequency of Hereditary Colorectal Cancer in Newfoundland Likely Involves Novel Susceptibility Genes

RLGS fragments and their corresponding chromosome loci

Supplementary Tables S1-6, Figures S1-2. Supplementary Table S1: Summary of serous EOC GWAS data sets; Supplementary Table S2: Genes in the six significant co-expression networks; Supplementary Table S3: GSEA results after LD-based clumping of SNPs; Supplementary Table S4: GSEA results for the replication data set (COGS); Supplementary Table S5: GSEA results for all networks with > 10 genes; Supplementary Table S6: Number of intragenic SNPs and genes covered by SNPs in the different analyses; Supplementary Figure S1: Q-Q plots of the minimum P-value among all SNPs in each gene with and without the modified Sidak correction; Supplementary Figure S2: Disease Association Protein-Protein Link Evaluator (DAPPLE) protein-protein interaction network

For individuals in the EAGLE study, all consisting of Italians, a pathway-level susceptibility effect was computed for each pathway in MSigDB as the sum of relevant SNP variant alleles weighted by their log odds ratios from the TRICL lung adenocarcinoma GWAS meta-analysis. Pathway values were also multiplied by cumulative smoking pack-years to produce pathway-smoking interactions. The pathways and pathway-smoking interactions that differ most between lung adenocarcinoma cases and healthy controls (t-test P < 0.05) in the EAGLE study are presented. Pearson correlation coefficients between these pathways and pathway-smoking interactions, and each of age, sex, and smoking pack-years are presented as well.

Background: Although genome-wide association studies (GWAS) have identified many genetic variants that are strongly associated with lung cancer, these variants have low penetrance and serve as poor predictors of lung cancer in individuals. We sought to increase the predictive value of germline variants by considering their cumulative effects in the context of biologic pathways.Methods: For individuals in the Environment and Genetics in Lung Cancer Etiology study (1,815 cases/1,971 controls), we computed pathway-level susceptibility effects as the sum of relevant SNP variant alleles weighted by their log-additive effects from a separate lung cancer GWAS meta-analysis (7,766 cases/37,482 controls). Logistic regression models based on age, sex, smoking, genetic variants, and principal components of pathway effects and pathway–smoking interactions were trained and optimized in cross-validation and further tested on an independent dataset (556 cases/830 controls). We assessed prediction performance using area under the receiver operating characteristic curve (AUC).Results: Compared with typical binomial prediction models that have epidemiologic predictors (AUC = 0.607) in addition to top GWAS variants (AUC = 0.617), our pathway-based smoking-interactive multinomial model significantly improved prediction performance in external validation (AUC = 0.656, P < 0.0001).Conclusions: Our biologically informed approach demonstrated a larger increase in AUC over nongenetic counterpart models relative to previous approaches that incorporate variants.Impact: This model is the first of its kind to evaluate lung cancer prediction using subtype-stratified genetic effects organized into pathways and interacted with smoking. We propose pathway–exposure interactions as a potentially powerful new contributor to risk inference. Cancer Epidemiol Biomarkers Prev; 25(8); 1208–15. ©2016 AACR.

Paradoxically epidemiological data illustrate a negative relationship between dietary folate intake and colorectal cancer (CRC) risk. The occurrence and progression of CRC may be influenced by variants in some key enzyme coding genes in the folate metabolic pathway. We investigated the correlation between genetic variants in methionine synthase reductase (This study used data collected from the Newfoundland Familial Colorectal Cancer Study. A total of 532 patients diagnosed with CRC for the first time from 1999 to 2003 were enrolled, and their mortality were tracked until April 2010. DNA samples were genotyped by Illumina's integrated quantum 1 million chip. Cox models were established to assess 33 tag single-nucleotide polymorphisms inThePolymorphic variants in

Vitamin D, Ca and dairy products are negatively associated with colorectal cancer (CRC) incidence, but little is known of their influence on CRC survival. To investigate prediagnostic intakes of vitamin D, Ca and dairy products for their relevance to CRC prognosis, we analysed 504 CRC patients enrolled in the Newfoundland Colorectal Cancer Registry Cohort Study who were diagnosed for the first time with CRC between 1999 and 2003. Follow-up for mortality and cancer recurrence was through April 2010. Data on diet and lifestyle factors were gathered via a validated, semi-quantitative FFQ and a Personal History Questionnaire. Multivariate Cox models estimated hazard ratios (HR) and 95 % CI for the relationship of prediagnostic intakes of vitamin D, Ca and dairy products with all-cause mortality (overall survival, OS) and disease-free survival (DFS) among CRC patients. We found that prediagnostic Ca intake from foods, but not total Ca intake, was negatively associated with all-cause mortality (HR for Q2 v. Q1, 0·44; 95 % CI, 0·26, 0·75). An inverse relationship was also seen in a dose–response fashion for prediagnostic cheese intake (HR for Q4 v. Q1, 0·57, 95 % CI, 0·34, 0·95, Ptrend = 0·029). No evidence for modification by sex, physical activity, alcohol drinking and cigarette smoking was observed. In summary, high prediagnostic intakes of cheese and Ca from foods may be associated with increased survival among CRC patients. By manipulating diet, this study may contribute to the development of novel therapies that add to the armamentarium against CRC. Replication studies are required before any nutritional interventions are made available.

We examined dietary fiber intake for its relevance to Colorectal cancer (CRC) survival in a cohort of CRC patients and a meta-analysis including results from four prospective cohort studies. We analyzed 504 CRC patients enrolled in the Newfoundland Familial Colorectal Cancer Study (NFCCS) who were newly diagnosed with CRC between 1999 and 2003. Follow-up for deaths was through April 2010. All participants completed a self-administered food frequency questionnaire to evaluate their dietary intakes one year before diagnosis. Multivariable Cox proportional hazard models were used to explore the associations of dietary fiber intake with all-cause mortality and CRC-specific mortality. In the meta-analysis, we identified prospective cohort studies published between January 1991 and December 2021 by searching PubMed, EMBASE, and Cochrane Library. Fixed-effects or random-effects models were used to combine the study-specific hazard ratio (HR) from our original analysis and three other cohorts. In the NFCCS, we found that CRC patients with the second quartile of dietary fiber intake had a 42% lower risk of all-cause mortality (HR: 0.58, 95% CI: 0.35–0.98) and 58% lower risk of CRC-specific mortality (HR: 0.42, 95% CI: 0.21–0.87) compared with those with the lowest quartile. In the meta-analysis, a similar inverse association between dietary fiber and total mortality was detected among CRC patients; each 10 g/day increase in dietary fiber intake was associated with a 16% decreased risk of total mortality. The dose–response meta-analysis showed a linear relationship between dietary fiber intake and all-cause mortality, with no sign of a plateau. For CRC-specific mortality, intriguingly, the benefit associated with increasing dietary fiber intake achieved its maximum at approximately 22 g/day, and no further reduction in CRC-specific mortality was observed beyond this intake level. Our results suggest that high dietary fiber intake may be associated with prolonged survival among CRC patients. Our findings add to the sparse literature on the role of dietary fiber in CRC survival.

Population‐level identification of children and youth with ASD is essential for surveillance and planning for required services. The objective of this study was to develop and validate an algorithm for the identification of children and youth with ASD using administrative health data. In this retrospective validation study, we linked an electronic medical record (EMR)‐based reference standard, consisting 10,000 individuals aged 1–24 years, including 112 confirmed ASD cases to Ontario administrative health data, for the testing of multiple case‐finding algorithms. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and corresponding 95% confidence intervals (CI) were calculated for each algorithm. The optimal algorithm was validated in three external cohorts representing family practice, education, and specialized clinical settings. The optimal algorithm included an ASD diagnostic code for a single hospital discharge or emergency department visit or outpatient surgery, or three ASD physician billing codes in 3 years. This algorithm's sensitivity was 50.0% (95%CI 40.7–88.7%), specificity 99.6% (99.4–99.7), PPV 56.6% (46.8–66.3), and NPV 99.4% (99.3–99.6). The results of this study illustrate limitations and need for cautious interpretation when using administrative health data alone for the identification of children and youth with ASD. Lay Summary We tested algorithms (set of rules) to identify young people with ASD using routinely collected administrative health data. Even the best algorithm misses more than half of those in Ontario with ASD. To understand this better, we tested how well the algorithm worked in different settings (family practice, education, and specialized clinics). The identification of individuals with ASD at a population level is essential for planning for support services and the allocation of resources. Autism Res 2021, 14: 1037–1045. © 2021 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals LLC.

Funder: Funding details are provided in the Supplementary Material, Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally-efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, ���select and shrink for summary statistics��� (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestry; 7,669 women of East Asian ancestry; 1,072 women of African ancestry, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestry. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38(95%CI:1.28���1.48,AUC:0.588) per unit standard deviation, in women of European ancestry; 1.14(95%CI:1.08���1.19,AUC:0.538) in women of East Asian ancestry; 1.38(95%CI:1.21-1.58,AUC:0.593) in women of African ancestry; hazard ratios of 1.37(95%CI:1.30���1.44,AUC:0.592) in BRCA1 pathogenic variant carriers and 1.51(95%CI:1.36-1.67,AUC:0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder requiring significant health and educational resources for affected individuals. A reference standard for ASD was generated from an existing population-based cohort of 10,000 children and youth aged 1-24 years who were randomly selected for chart abstraction from 29,256 patients from 119 family physicians. We developed and validated an algorithm to identify children and youth with ASD within an electronic medical record system (N = 80,237, aged 1-24 years) in order to examine the prevalence of comorbidities and quantify health system utilization within the cohort. We identified 1,062 children and youth with ASD representing a prevalence of 1.32%. Compared to individuals without ASD, those with ASD had a higher prevalence of asthma, were more likely to visit a specialist, undergo surgery, and be hospitalized for psychiatric reasons. Children and youth with ASD in Ontario have complex health system needs, illustrated through a significant burden of comorbidities and increased health system utilization. LAY SUMMARY: Our paper generates population-based estimates of health system use by children and youth with ASD, who have a higher burden of comorbidities than the general population. We developed a case-finding algorithm and applied it in electronic medical records to create a cohort of children and youth with ASD, thereby generating an important resource to further study the health care needs of individuals with ASD.

Background: Lung cancer remains the leading cause of cancer death worldwide, with 15% to 20% occurring in never smokers. To assess genetic determinants for prognosis among never smokers, we conducted a genome-wide investigation in the International Lung Cancer Consortium (ILCCO). Methods: Genomic and clinical data from 1,569 never-smoking patients with lung cancer of European ancestry from 10 ILCCO studies were included. HRs and 95% confidence intervals of overall survival were estimated. We assessed whether the associations were mediated through mRNA expression–based 1,553 normal lung tissues from the lung expression quantitative trait loci (eQTL) dataset and Genotype-Tissue Expression (GTEx). For cross-ethnicity generalization, we assessed the associations in a Japanese study (N = 887). Results: One locus at 13q22.2 was associated with lung adenocarcinoma survival at genome-wide level, with carriers of rs12875562-T allele exhibiting poor prognosis [HR = 1.71 (1.41–2.07), P = 3.60 × 10−8], and altered mRNA expression of LMO7DN in lung tissue (GTEx, P = 9.40 × 10−7; Lung eQTL dataset, P = 0.003). Furthermore, 2 of 11 independent loci that reached the suggestive significance level (P < 10−6) were significant eQTL affecting mRNA expression of nearby genes in lung tissues, including CAPZB at 1p36.13 and UBAC1 at 9q34.3. One locus encoding NWD2/KIAA1239 at 4p14 showed associations in both European [HR = 0.50 (0.38–0.66), P = 6.92 × 10−7] and Japanese populations [HR = 0.79 (0.67–0.94), P = 0.007]. Conclusions: Based on the largest genomic investigation on the lung cancer prognosis of never smokers to date, we observed that lung cancer prognosis is affected by inherited genetic variants. Impact: We identified one locus near LMO7DN at genome-wide level and several potential prognostic genes with cis-effect on mRNA expression. Further functional genomics work is required to understand their role in tumor progression.

Insecticide use has been linked to increased risk of non‐Hodgkin lymphoma (NHL), however, findings of epidemiologic studies have been inconsistent, particularly for NHL subtypes. We analyzed 1690 NHL cases and 5131 controls in the North American Pooled Project (NAPP) to investigate self‐reported insecticide use and risk of NHL overall and by subtypes: follicular lymphoma (FL), diffuse large B‐cell lymphoma (DLBCL) and small lymphocytic lymphoma (SLL). Odds ratios (OR) and 95% confidence intervals for each insecticide were estimated using logistic regression. Subtype‐specific associations were evaluated using ASSET (Association analysis for SubSETs). Increased risks of multiple NHL subtypes were observed for lindane (OR = 1.60, 1.20‐2.10: FL, DLCBL, SLL), chlordane (OR = 1.59, 1.17‐2.16: FL, SLL) and DDT (OR = 1.36, 1.06‐1.73: DLBCL, SLL). Positive trends were observed, within the subsets with identified associations, for increasing categories of exposure duration for lindane (P trend = 1.7 × 10−4), chlordane (P trend = 1.0 × 10−3) and DDT (P trend = 4.2 × 10−3), however, the exposure‐response relationship was nonlinear. Ever use of pyrethrum was associated with an increased risk of FL (OR = 3.65, 1.45‐9.15), and the relationship with duration of use appeared monotonic (OR for >10 years: OR = 5.38, 1.75‐16.53; P trend = 3.6 × 10−3). Our analysis identified several novel associations between insecticide use and specific NHL subtypes, suggesting possible etiologic heterogeneity in the context of pesticide exposure., What's new? Insecticides are persistent environmental pollutants that have been linked to increased risk of non‐Hodgkin lymphoma (NHL). Although NHL encompasses a heterogeneous group of malignancies, few studies have examined subtype‐specific associations for insecticide exposure. Analyzing data from population‐based case‐control studies of lymphatic cancers, the authors of this study show that lindane, chlordane, and DDT are associated with increased risk of multiple NHL subtypes. Analyses further uncovered a novel link between increased follicular lymphoma risk and pyrethrum use. None of the insecticides investigated, however, were associated with all NHL subtypes, suggesting a role for etiologic heterogeneity in pesticide exposure and NHL risk.

Background Air pollution has been associated with increased mortality. However, updated evidence from cohort studies with detailed information on various risk factors is needed, especially in regions with low air pollution levels. We investigated the associations between long-term exposure to air pollution and mortality in a prospective cohort. Methods We studied 88,615 participants aged ≥30 years from an ongoing cohort study in Ontario, Canada from 2009 to 2017. Exposure to ambient fine particulate matter (PM2.5) and nitrogen dioxide (NO2) was estimated at participants’ residence. Cox proportional hazard models were used to investigate the associations between air pollution and non-accidental, cardiovascular, and respiratory mortality, adjusted for a wide array of individual-level and contextual covariates. Potential effect modification by socio-demographic and behavioral factors was also examined in exploratory stratified analyses. Results The fully adjusted hazard ratios (HRs) per 1 µg/m3 increment in PM2.5 were 1.037 [95% confidence interval (CI): 1.018, 1.057]¸ 1.083 (95% CI: 1.040, 1.128) and 1.109 (95% CI: 1.035, 1.187) for non-accidental, cardiovascular, and respiratory mortality, respectively. Positive associations were also found for NO2; the corresponding HRs per 1 ppb increment were 1.027 (95% CI: 1.021, 1.034), 1.032 (95% CI: 1.019, 1.046) and 1.044 (95% CI: 1.020, 1.068). We found suggestive evidence of stronger associations in physically active participants, smokers, and those with lower household income. Conclusions Long-term exposure to PM2.5 and NO2 was associated with increased risks for non-accidental, cardiovascular, and respiratory mortality, suggesting potential benefits of further improvement in air quality even in low-exposure environments.

Background: Paradoxically epidemiological data illustrate a negative relationship between dietary folate intake and colorectal cancer (CRC) risk. The occurrence and progression of CRC may be influenced by variants in some key enzyme coding genes in the folate metabolic pathway. We investigated the correlation between genetic variants in methionine synthase reductase (MTRR) and methylenetetrahydrofolate reductase (MTHFR) and CRC survival. Methods: This study used data collected from the Newfoundland Familial Colorectal Cancer Study. A total of 532 patients diagnosed with CRC for the first time from 1999 to 2003 were enrolled, and their mortality were tracked until April 2010. DNA samples were genotyped by Illumina’s integrated quantum 1 million chip. Cox models were established to assess 33 tag single-nucleotide polymorphisms in MTRR and MTHFR in relation to overall survival (OS), disease-free survival (DFS) and CRC-specific survival. Results: The MTRR and MTHFR genes were associated with DFS and CRC-specific survival in CRC patients at the gene level. After multiple comparison adjustment, MTRR rs1801394 A (vs. G) allele was associated with increased DFS (p = 0.024), while MTHRT rs3737966 (G vs. A), rs4846049 (T vs. G), rs1476413 (A vs. G), rs1801131 (C vs. A), rs12121543 (A vs. C), rs1801133 (C vs. T), rs4846052 (T vs. C), rs2066471 (A vs. G) and rs7533315 (T vs. C) were related to worse CRC-specific survival. Additionally, significant interactions were seen among pre-diagnostic alcohol consumption with MTRR rs1801394, rs3776467, rs326124, rs162040, and rs3776455, with superior OS associated with those protective variant alleles limited to patients with alcohol consumption under the median. The MTHFR rs3737966 (G vs. A) allele seemed to be detrimental to CRC survival only among subjects with fruit intake below the median. Conclusions: Polymorphic variants in MTRR and MTHFR genes that code for key enzymes for folate metabolism may be associated with survival in patients with CRC. The gene-CRC outcome association seems modulated by alcohol drinking and fruit intake.

Head trauma in early childhood has been hypothesized as a potential risk factor for childhood brain tumours (CBTs). However, head trauma has not been extensively studied in the context of CBTs and existing studies have yielded conflicting results. A population- and hospital-based case-control study of children 0-15 years with newly diagnosed CBTs from 1997-2003 recruited across Ontario through pediatric oncology centres was conducted. Controls were frequency-matched with cases by age, sex and geographical region. The association was assessed based on multivariable logistic regressions, accounting for child's age, sex, ethnicity, highest level of maternal education, and maternal pack-years of smoking during the pregnancy. Analyses were conducted separately based on age of first head trauma, sex and histology. A latency period analysis was conducted. Overall, based on 280 cases and 919 controls, CBTs were not significantly associated with previous history of head trauma (OR 1.34, 95% CI 0.96, 1.86), head trauma severity, number of head injuries, nor head or neck X-rays or computed tomography (CT) examinations. Results were consistent across sexes and histological subtypes. However, head trauma within the first year of life was significantly associated with CBTs (OR 2.00, 95% CI 1.01, 3.98), but the association diminished when adjusted for X-ray or CT occurring during the same time period (OR 1.62, 95% CI 0.75, 3.49), albeit limited sample size. Overall, no association was observed between head trauma and CBTs among all children, while head trauma occurring within first year of life may warrant further investigation in future research. This article is protected by copyright. All rights reserved.

OBJECTIVES: Some epidemiological studies have suggested positive associations between glyphosate use and non-Hodgkin lymphoma (NHL), but evidence is inconsistent and few studies could evaluate histological sub-types. Here, associations between glyphosate use and NHL incidence overall and by histological sub-type were evaluated in a pooled analysis of case–control studies. METHODS: The analysis included 1690 NHL cases [647 diffuse large B-cell lymphoma (DLBCL), 468 follicular lymphoma (FL), 171 small lymphocytic lymphoma (SLL), and 404 other sub-types] and 5131 controls. Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for NHL overall and sub-types with self-reported ever/never, duration, frequency, and lifetime-days of glyphosate use. RESULTS: Subjects who ever used glyphosate had an excess of NHL overall (OR 1.43, 95% CI 1.11–1.83). After adjustment for other pesticides, the OR for NHL overall with "ever use" was 1.13 (95% CI 0.84–1.51), with a statistically significant association for handling glyphosate >2 days/year (OR 1.73, 95% CI 1.02–2.94, P-trend=0.2). In pesticide-adjusted sub-type analyses, the ordinal measure of lifetime-days was statistically significant (P=0.03) for SLL, and associations were elevated, but not statistically significant, for ever years or days/year of use. Handling glyphosate >2 days/year had an excess of DLBCL (OR 2.14, 95% CI 1.07–4.28; P-trend=0.2). However, as with the other sub-types, consistent patterns of association across different metrics were not observed. CONCLUSIONS: There was some limited evidence of an association between glyphosate use and NHL in this pooled analysis. Suggestive associations, especially for SLL, deserve additional attention.

Background Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with an estimated prevalence of 4–21% in reproductive aged women. Recently, the Ovarian Cancer Association Consortium (OCAC) reported a decreased risk of invasive ovarian cancer among women with self-reported PCOS. However, given the limitations of self-reported PCOS, the validity of these observed associations remains uncertain. Therefore, we sought to use Mendelian randomization with genetic markers as a proxy for PCOS, to examine the association between PCOS and ovarian cancer. Methods Utilizing 14 single nucleotide polymorphisms (SNPs) previously associated with PCOS we assessed the association between genetically predicted PCOS and ovarian cancer risk, overall and by histotype, using summary statistics from a previously conducted genome-wide association study (GWAS) of ovarian cancer among European ancestry women within the OCAC (22 406 with invasive disease, 3103 with borderline disease and 40 941 controls). Results An inverse association was observed between genetically predicted PCOS and invasive ovarian cancer risk: odds ratio (OR)=0.92 [95% confidence interval (CI)=0.85–0.99; P = 0.03]. When results were examined by histotype, the strongest inverse association was observed between genetically predicted PCOS and endometrioid tumors (OR = 0.77; 95% CI = 0.65–0.92; P = 0.003). Adjustment for individual-level body mass index, oral contraceptive use and parity did not materially change the associations. Conclusion Our study provides evidence for a relationship between PCOS and reduced ovarian cancer risk, overall and among specific histotypes of invasive ovarian cancer. These results lend support to our previous observational study results. Future studies are needed to understand mechanisms underlying this association.

Background Having a first-degree relative (FDR) with colorectal cancer (CRC) is a significant risk factor for CRC. Counseling for FDRs regarding CRC risk factors and personalized risk is important to improve knowledge and screening compliance. Methods A 3-arm randomized controlled trial compared tailored in-person and telephone CRC counseling interventions with controls among FDRs who were not mutation carriers for known hereditary cancer syndromes, but who were considered to be at an increased risk based on family history. It was hypothesized that both telephone and in-person approaches would increase CRC knowledge, screening adherence, perceived risk accuracy, and psychosocial functioning compared with controls. The authors anticipated greater satisfaction with the in-person approach. CRC knowledge, risk perception, psychosocial functioning, and intention to screen were assessed at baseline and at 2-week and 2-month follow-ups (primary endpoint). Results A total of 278 FDRs (mean age, 47.4 years, standard deviation, 11.38 years) participated. At baseline, participants reported low to moderate CRC knowledge and overestimations of risk. Screening adherence was 73.7%. At 2 months, participants in the in-person arm and telephone arm demonstrated improvements in knowledge and perceived risk and were not found to be statistically different from each other. However, when comparing each intervention with controls, knowledge in the in-person arm was found to be statistically significantly higher, but the difference between the telephone and control arms was not. Cancer-related stress reduced over time in all groups. Intervention benefits were maintained at 1 year. Baseline screening intent/adherence were high, and therefore did not reach statistically significant improvement. Conclusions Tailored in-person or telephone formats for providing CRC risk counseling, incorporating behavioral interventions, appear to improve knowledge and risk perceptions, with high client satisfaction.

Background: Despite a poor 5-year survival rate of 45%, survival following a diagnosis of epithelial ovarian cancer stabilizes after 10 years. Although various clinical and tumor characteristics are established prognostic factors, the role of epidemiologic risk factors on short- versus long-term survival are unclear. The aim of this study was to evaluate the association between various hormonal, reproductive, and lifestyle risk factors on ovarian cancer mortality by survival trajectory time intervals across the survivorship phase. Methods: This population-based retrospective cohort study included 1,421 unselected women diagnosed with epithelial ovarian cancer from 1995 to 2004 in Ontario, Canada. Clinical information was obtained from medical records, risk factor information from telephone interview, and vital status was updated by linkage to the Ontario Cancer Registry up until 2020. We examined clinical risk factors, hormonal and reproductive related factors, lifestyle factors, and family history. Extended Cox proportional hazards models with Heaviside functions were used to estimate the association between risk factors and mortality by survival trajectory time interval ( Results: After a mean follow-up of 11.6 years, 65% (n=926) subjects died of which 51% (n=731) were due to ovarian cancer. Clinical factors such as late stage and presence of residual disease were strongly associated with short-term mortality, which attenuated over survival time. Stage IV disease significantly increased the risk of mortality compared to stage I disease for the survival interval within 3 years of diagnosis (HR 50.05; 95% CI 6.78, 369.57), however this association declined for survival beyond 10 years (HR 2.76; 95% CI 1.35, 5.65). Similarly, presence of residual disease increased the risk of mortality in the short-term (HR 2.47; 95% CI 1.40, 4.34), yet attenuated for long-term survival (HR 1.26; 95% CI 0.83, 1.93). Risk factors such as breastfeeding, smoking, and BMI were not associated with short-term survival, but significantly associated with long-term survival. History of breastfeeding decreased the risk of mortality (HR 0.65; 95% CI 0.46, 0.93), while a history of smoking (HR 1.75; 95% CI 1.27, 2.40) and obesity (HR 1.81; 95% CI 1.24, 2.65) increased the risk of mortality among long-term survivors. Conclusions: This study confirmed that clinical risk factors such as stage at ovarian cancer diagnosis and residual disease following debulking surgery are important prognostic factors in the short-term survival trajectory while breastfeeding, smoking, and BMI play a stronger role for long-term ovarian cancer survival. These findings suggest a role of modifiable factors in improving long-term outcomes across the survivorship phase. Citation Format: Shana Jean Kim, Barry Rosen, John R. McLaughlin, Harvey Risch, Shelly S. Tworoger, Steven A. Narod, Joanne Kotsopoulos. Epidemiologic risk factors and survival trajectories among epithelial ovarian cancer survivors: A population-based cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5906.

Background: Arsenic is a highly prevalent environmental toxin and an established carcinogen for cancers of the skin, bladder, and lung. Emerging evidence also suggests that arsenic exposure may be a risk factor for breast and other cancers. Previous studies have been conducted in populations with endemically high levels of arsenic; however, the impact of chronic exposure to low levels is not known. Thus, the purpose of this study was to describe the arsenic exposure in Canadian adults and to evaluate the association between arsenic status and cancer risk. Methods: The Canadian Health Measures Survey (CHMS) is an ongoing, nationally representative survey that collects self-reported and objective health measures, including biomonitoring data, from participants in biennial cycles. This analysis utilized total, inorganic and organic urinary arsenic biomarkers (µg/L) from Cycles 1-5 (2007-2017) of the CHMS. Incident cancers were ascertained through a linkage to the Canadian Cancer Registry. Arsenic exposure was described using weighted percentiles, and Cox proportional hazards regression models were used to estimate the association between arsenic exposure and cancer risk (overall and site-specific). Results: This analysis included 10,000 individuals, aged 18-80. The median total urinary arsenic level was 7.5 ug/g of creatinine. Preliminary models showed that levels of inorganic arsenic exposure above the geometric mean (> 4.5 µg/L) were associated with a 3-fold increased risk of developing any cancer (HR = 3.58; 95%CI 1.63-7.85), compared to those with lower levels. Site-specific risk modelling is ongoing and preliminary results will be presented. Significance: This study found inorganic arsenic exposure may be associated with an increased risk of developing cancer. To our knowledge, this study is the first to ascertain national estimates of arsenic exposure and provide insight on the relationship between arsenic exposure and cancer risk in Canadian adults. These findings are critical for developing population-level interventions to reduce the Canadian, and global, cancer burden. Citation Format: Katherine Pullella, Vicky C. Chang, Shelley A. Harris, Anthony J. Hanley, John R. McLaughlin, Jan Lubinski, Steven A. Narod, Joanne Kotsopoulos. Examining the association between arsenic exposure and cancer risk among Canadian adults [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5895.

The German Social Accident Insurance supported this study (grant number FP 271)., Hovanec J, Siemiatycki J, Conway DI, Olsson A, Guenel P, Luce D, Jöckel KH, Pohlabeln H, Ahrens W, Karrasch S, Wichmann HE, Gustavsson P, Consonni D, Merletti F, Richiardi L, Lorenzo S, Fortes C, Parent MÉ, McLaughlin JR, Demers P, Landi MT, Caporaso N, Fernández-Tardón G, Zaridze D, Świątkowska B, Pándics T, Lissowska J, Fabianova E, Field JK, Mates D, Bencko V, Foretova L, Janout V, Kromhout H, Vermeulen R, Boffetta P, Straif K, Schüz J, Casjens S, Pesch B, Brüning T, Behrens T.

COVID-19 has highlighted the need for credible epidemiological models to inform pandemic policy. Traditional mechanisms of commissioning research are ill-suited to guide policy during a rapidly evolving pandemic. At the same time, contracting with a single centre of expertise has been criticized for failing to reflect challenges inherent in specific modelling approaches.This report describes an alternative approach to mobilizing scientific expertise. Ontario's COVID-19 Modelling Consensus Table (MCT) was created in March 2020 to enable rapid communication of credible estimates of the impact of COVID-19 and to accelerate learning on how the disease is spreading and what could slow its transmission. The MCT is a partnership between the province and academic modellers and consists of multiple groups of experts, health system leaders, and senior decision-makers. Armed with Ministry of Health data, the MCT meets once per week to share results from modelling exercises, generate consensus judgements of the likely future impact of COVID-19, and discuss decision-makers' priorities.The MCT has enabled swift access to data for participants, a structure for developing consensus estimates and communicating these to decision-makers, credible models to inform health system planning, and increased transparency in public reporting of COVID-19 data. It has also facilitated the rapid publication of research findings and its incorporation into government policy.The MCT approach is one way to quickly draw on scientific advice outside of government and public health agencies. Beyond speed, this approach allows for nimbleness as experts from different organizations can be added as needed. It also shows how universities and research institutes have a role to play in crisis situations, and how this expertise can be marshalled to inform policy while respecting academic freedom and confidentiality.RéSUMé: LIEU: La COVID-19 a mis en évidence le besoin de modèles épidémiologiques crédibles pour éclairer la politique pandémique. Les mécanismes habituels pour commander des travaux de recherche sont peu propices à orienter les politiques lors d’une pandémie qui évolue rapidement. En même temps, la passation de contrats avec un seul centre d’expertise est critiquée, car elle ne tient pas compte des difficultés inhérentes de certaines approches de modélisation. INTERVENTION: Le présent rapport décrit une approche de rechange pour mobiliser le savoir scientifique. L’Ontario a créé en mars 2020 une Table de concertation sur la modélisation (TCM) qui permet de communiquer de façon rapide et fiable les estimations des effets de la COVID-19 et d’apprendre plus vite comment la maladie se propage et ce qui pourrait en ralentir la transmission. La TCM, un partenariat entre les modélisateurs de la province et des milieux universitaires, est composée de plusieurs groupes d’experts, de dirigeants du système de santé et de décideurs de haut niveau. Armée des données du ministère de la Santé, la TCM se réunit une fois par semaine pour partager les résultats d’exercices de modélisation, générer des jugements consensuels sur les futurs effets probables de la COVID-19 et discuter des priorités des décideurs. RéSULTATS: La TCM rend possible un accès rapide aux données pour les participants, une structure pour élaborer des estimations consensuelles et les communiquer aux décideurs, des modèles fiables pour éclairer la planification du système de santé, ainsi qu’une transparence accrue dans la communication des données sur la COVID-19 au public. Elle facilite aussi la publication rapide des résultats de recherche et leur intégration dans la politique gouvernementale. CONSéQUENCES: L’approche de la TCM est un moyen d’obtenir rapidement des conseils scientifiques à l’extérieur du gouvernement et des organismes de santé publique. Au-delà de sa rapidité, cette approche offre une grande souplesse, car des experts de différents organismes peuvent être ajoutés au besoin. Elle montre aussi que les universités et les établissements de recherche ont un rôle à jouer dans les situations de crise, et qu’il est possible de mobiliser leurs compétences pour éclairer les politiques tout en respectant la liberté et la confidentialité des milieux de la recherche et de l’enseignement.

BACKGROUND: While childbearing protects against risk of epithelial ovarian cancer (EOC), few studies have explored the impact on maternal EOC risk of sex of offspring, which may affect the maternal environment during pregnancy. METHODS: We performed a pooled analysis among parous participants from 12 case-controls studies comprising 6,872 EOC patients and 9,101 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable logistic regression for case-control associations and polytomous logistic regression for histotype-specific associations, all adjusted for potential confounders. RESULTS: In general, no associations were found between offspring sex and EOC risk. However, compared to bearing only female offspring, bearing one or more male offspring was associated with increased risk of mucinous EOC (OR=1.45; 95%CI=1.01–2.07), which appeared to be limited to women reporting menarche before age 13 compared to later menarche (OR=1.71 vs 0.99; P-interaction=0.02). Bearing increasing numbers of male offspring was associated with greater risks of mucinous tumors (OR=1.31, 1.84, 2.31, for 1, 2 and 3 or more male offspring, respectively; trend-p = 0.005). Stratifying by hormonally-associated conditions suggested that compared to bearing all female offspring, bearing a male offspring was associated with lower risk of endometrioid cancer among women with a history of adult acne, hirsutism, or polycystic ovary syndrome (OR=0.49, 95%CI=0.28–0.83) but with higher risk among women without any of those conditions (OR=1.64 95%CI=1.14–2.34; P-interaction=0.003). CONCLUSION: Offspring sex influences the childbearing-EOC risk relationship for specific histotypes and conditions. These findings support the differing etiologic origins of EOC histotypes and highlight the importance of EOC histotype-specific epidemiologic studies. These findings also suggest the need to better understand how pregnancy affects EOC risk

Family history (FH) of a first-degree relative with colorectal cancer (CRC) is associated with two to fourfold increased risk, yet screening uptake is suboptimal despite proven mortality reduction. We developed a FH-based CRC Risk Triage/Management tool for family physicians (FPs), and educational booklet for patients with CRC FH. This report describes physician referral and patient screening behavior 5 and 10 years post-educational intervention, and factors associated with screening. Longitudinal cohort study. FPs/patients in Ontario and Newfoundland, Canada were sent questionnaires at baseline (2005), 5 and 10 years (2015) following tool/booklet receipt. FPs were asked about CRC screening, patients about FH, screening type and timing. “Correct” screening was concordance with tool recommendations. Results reported for 29/121 (24%) FPs and 98/297 (33%) patients who completed all 3 questionnaires. Over 10 years 2/3 patients received the correct CRC screening test at appropriate timing (baseline 75%, 5-year 62%, 10-year 65%). About half reported their FP recommended CRC screening (5-year 51%, 10-year 63%). Fewer than half the patients correctly assessed their CRC risk (44%, 40%, 41%). Patients were less likely to have correct screening timing if female (RR 0.78; 95% CI 0.61, 0.99; p = 0.045). Patients were less likely to have both correct test and timing if moderate/high CRC risk (RR 0.66; 95% CI 0.47, 0.93; p = 0.017) and more likely if their physician recommended screening (RR1.69; 95% CI 1.15, 2.49; p = 0.007). Physician discussion of CRC risk and screening can positively impact patient screening behavior. Efforts are particularly needed for women and patients at moderate/high CRC risk.

The CAPUA study was supported by FIS-FEDER/Spain grant numbers FIS-01/310, FIS-PI03-0365, and FIS-07-BI060604, FICYT/Asturias grant numbers FICYT PB02-67 and FICYT IB09-133, and the University Institute of Oncology (IUOPA), of the University of Oviedo and the Ciber de Epidemiologia y Salud Pública. CIBERESP, SPAIN (...), Ji, X., Mukherjee, S., Landi, M.T., Bosse, Y., Joubert, P., Zhu, D., Gorlov, I., Xiao, X., Han, Y., Gorlova, O., Hung, R.J., Brhane, Y., Carreras-Torres, R., Christiani, D.C., Caporaso, N., Johansson, M., Liu, G., Bojesen, S.E., Le Marchand, L., Albanes, D., Bickeböller, H., Aldrich, M.C., Bush, W.S., Tardon, A., Rennert, G., Chen, C., Byun, J., Dragnev, K.H., Field, J.K., Kiemeney, L.F., Lazarus, P., Zienolddiny, S., Lam, S., Schabath, M.B., Andrew, A.S., Bertazzi, P.A., Pesatori, A.C., Diao, N., Su, L., Song, L., Zhang, R., Leighl, N., Johansen, J.S., Mellemgaard, A., Saliba, W., Haiman, C., Wilkens, L., Fernandez-Somoano, A., Fernandez-Tardon, G., Heijden, E.H.F.M., Kim, J.H., Davies, M.P.A., Marcus, M.W., Brunnström, H., Manjer, J., Melander, O., Muller, D.C., Overvad, K., Trichopoulou, A., Tumino, R., Goodman, G.E., Cox, A., Taylor, F., Woll, P., Wichmann, E., Muley, T., Risch, A., Rosenberger, A., Grankvist, K., Johansson, M., Shepherd, F., Tsao, M.-S., Arnold, S.M., Haura, E.B., Bolca, C., Holcatova, I., Janout, V., Kontic, M., Lissowska, J., Mukeria, A., Ognjanovic, S., Orlowski, T.M., Scelo, G., Swiatkowska, B., Zaridze, D., Bakke, P., Skaug, V., Butler, L.M., Offit, K., Srinivasan, P., Bandlamudi, C., Hellmann, M.D., Solit, D.B., Robson, M.E., Rudin, C.M., Stadler, Z.K., Taylor, B.S., Berger, M.F., Houlston, R., McLaughlin, J., Stevens, V., Nickle, D.C., Obeidat, M., Timens, W., Artigas, M.S., Shete, S., Brenner, H., Chanock, S., Brennan, P., McKay, J.D., Amos, C.I.

Background Body mass index (BMI) is a complex phenotype that may interact with genetic variants to influence colorectal cancer risk. Methods We tested multiplicative statistical interactions between BMI (per 5 kg/m2) and approximately 2.7 million single nucleotide polymorphisms with colorectal cancer risk among 14 059 colorectal cancer case (53.2% women) and 14 416 control (53.8% women) participants. All analyses were stratified by sex a priori. Statistical methods included 2-step (ie, Cocktail method) and single-step (ie, case-control logistic regression and a joint 2-degree of freedom test) procedures. All statistical tests were two-sided. Results Each 5 kg/m2 increase in BMI was associated with higher risks of colorectal cancer, less so for women (odds ratio [OR] = 1.14, 95% confidence intervals [CI] = 1.11 to 1.18; P = 9.75 × 10–17) than for men (OR = 1.26, 95% CI = 1.20 to 1.32; P = 2.13 × 10–24). The 2-step Cocktail method identified an interaction for women, but not men, between BMI and a SMAD7 intronic variant at 18q21.1 (rs4939827; Pobserved = .0009; Pthreshold = .005). A joint 2-degree of freedom test was consistent with this finding for women (joint P = 2.43 × 10–10). Each 5 kg/m2 increase in BMI was more strongly associated with colorectal cancer risk for women with the rs4939827-CC genotype (OR = 1.24, 95% CI = 1.16 to 1.32; P = 2.60 × 10–10) than for women with the CT (OR = 1.14, 95% CI = 1.09 to 1.19; P = 1.04 × 10–8) or TT (OR = 1.07, 95% CI = 1.01 to 1.14; P = .02) genotypes. Conclusion These results provide novel insights on a potential mechanism through which a SMAD7 variant, previously identified as a susceptibility locus for colorectal cancer, and BMI may influence colorectal cancer risk for women.

BACKGROUND: Understanding the complex interaction of risk factors that increase the likelihood of developing common diseases is challenging. The Canadian Partnership for Tomorrow Project (CPTP) is a prospective cohort study created as a population-health research platform for assessing the effect of genetics, behaviour, family health history and environment (among other factors) on chronic diseases. METHODS: Volunteer participants were recruited from the general Canadian population for a confederation of 5 regional cohorts. Participants were enrolled in the study and core information obtained using 2 approaches: attendance at a study assessment centre for all study measures (questionnaire, venous blood sample and physical measurements) or completion of the core questionnaire (online or paper), with later collection of other study measures where possible. Physical measurements included height, weight, percentage body fat and blood pressure. Participants consented to passive follow-up through linkage with administrative health databases and active follow-up through recontact. All participant data across the 5 regional cohorts were harmonized. RESULTS: A total of 307 017 participants aged 30–74 from 8 provinces were recruited. More than half provided a venous blood sample and/or other biological sample, and 33% completed physical measurements. A total of 709 harmonized variables were created; almost 25% are available for all participants and 60% for at least 220 000 participants. INTERPRETATION: Primary recruitment for the CPTP is complete, and data and biosamples are available to Canadian and international researchers through a data-access process. The CPTP will support research into how modifiable risk factors, genetics and the environment interact to affect the development of cancer and other chronic diseases, ultimately contributing evidence to reduce the global burden of chronic disease.

Background: Polycystic ovary syndrome (PCOS), and one of its distinguishing characteristics, oligomenorrhea, have both been associated with ovarian cancer risk in some but not all studies. However, these associations have been rarely examined by ovarian cancer histotypes, which may explain the lack of clear associations reported in previous studies. Methods: We analyzed data from 14 case–control studies including 16,594 women with invasive ovarian cancer (n = 13,719) or borderline ovarian disease (n = 2,875) and 17,718 controls. Adjusted study-specific ORs were calculated using logistic regression and combined using random-effects meta-analysis. Pooled histotype-specific ORs were calculated using polytomous logistic regression. Results: Women reporting menstrual cycle length >35 days had decreased risk of invasive ovarian cancer compared with women reporting cycle length ≤35 days [OR = 0.70; 95% confidence interval (CI) = 0.58–0.84]. Decreased risk of invasive ovarian cancer was also observed among women who reported irregular menstrual cycles compared with women with regular cycles (OR = 0.83; 95% CI = 0.76–0.89). No significant association was observed between self-reported PCOS and invasive ovarian cancer risk (OR = 0.87; 95% CI = 0.65–1.15). There was a decreased risk of all individual invasive histotypes for women with menstrual cycle length >35 days, but no association with serous borderline tumors (Pheterogeneity = 0.006). Similarly, we observed decreased risks of most invasive histotypes among women with irregular cycles, but an increased risk of borderline serous and mucinous tumors (Pheterogeneity < 0.0001). Conclusions: Our results suggest that menstrual cycle characteristics influence ovarian cancer risk differentially based on histotype. Impact: These results highlight the importance of examining ovarian cancer risk factors associations by histologic subtype. Cancer Epidemiol Biomarkers Prev; 27(2); 174–82. ©2017 AACR.

Background: Arsenic is an established carcinogen for cancers of the skin, bladder and lungs; it is also the most prevalent environmental toxin, resulting in all Canadians being exposed to some extent. In a recent prospective study of a low-exposure population, our team found that women in the highest quartile of circulating arsenic had a significant 13-fold increased risk of developing breast cancer, compared to the lowest quartile. This suggests that even at low-doses, arsenic may be an important risk factor for breast, and potentially other cancers not previously recognized. To date, the sources of arsenic in Canada, a low-exposure population, are unclear. Objectives: To describe the status of arsenic exposure, identify the key predictors of arsenic status, and evaluate the relationship between arsenic exposure and cancer risk within the Canadian population. Methods: Using data from Cycles 1-5 (2007-2017) of the Canadian Health Measures Survey (CHMS), exposure data (e.g., diet, water), demographic information, and urinary arsenic biomarkers will be analyzed. The CHMS is an ongoing, nationally representative survey, collecting objective health measures and food intake information from participants in biennial cycles. Data will be described using weighted percentages or means, and arsenic levels (total and speciated urinary arsenic metabolite concentrations) will be reported by percentile. Weighted multivariate regression models will be used to identify predictors of total urinary arsenic. Linkage to the Canadian Cancer Registry will be performed to ascertain incident cancers, and Cox proportional hazards regression used to estimate the relationship between arsenic status and cancer risk (total and site-specific). Results: This analysis included 15,700 individuals, aged 18-80. The median total urinary arsenic level was 7.5 ug/g of creatinine. Significant predictors of total urinary arsenic levels were found to be weekly intake of fish and seafood (β= 0.3, 95%CI 0.27,0.33, P < 0.001), grains (β=-0.02, 95%CI -0.02, -0.01, P< 0.001) and consumption of well and/or cistern water (β = 0.13, 95%CI 0.04, 0.22, P=0.005). Linkage and data analysis are ongoing. Impact: This work is the first to ascertain national exposure estimates to an environmental carcinogen. Fish, seafood, grains, and consumption of well and/or cistern water represent significant predictors of total urinary arsenic levels in Canada. Ultimately, this information is needed to develop critical population-level intervention strategies to reduce the Canadian, and global burden of cancer. Citation Format: Katherine Pullella, Shelley A. Harris, John R. McLaughlin, Jan Lubinski, Steven A. Narod, Joanne Kotsopoulos. Evaluating the relationship between arsenic exposure and cancer risk in Canada [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 857.

Many clinical features of lung cancer are different in women and men. Sex steroid hormones exert effects in nonreproductive organs, such as the lungs. The association between menstrual and childbearing factors and the risk of lung cancer among women is still debated. We performed a pooled analysis of eight studies contributing to the International Lung Cancer Consortium (4,386 cases and 4,177 controls). Pooled associations between menstrual or reproductive factors and lung cancer were estimated using multivariable unconditional logistic regression. Subgroup analyses were done for menopause status, smoking habits and histology. We found no strong support for an association of age at menarche and at menopause with lung cancer, but peri/postmenopausal women were at higher risk compared to premenopausal (OR 1.47, 95% CI 1.11-1.93). Premenopausal women showed increased risks associated with parity (OR 1.74, 95% CI 1.03-2.93) and number of children (OR 2.88, 95% CI 1.21-6.93 for more than 3 children; p for trend 0.01) and decreased with breastfeeding (OR 0.54, 95% CI 0.30-0.98). In contrast, peri/postmenopausal subjects had ORs around unity for the same exposures. No major effect modification was exerted by smoking status or cancer histology. Menstrual and reproductive factors may play a role in the genesis of lung cancer, yet the mechanisms are unclear, and smoking remains the most important modifiable risk factor. More investigations in large well-designed studies are needed to confirm these findings and to clarify the underlying mechanisms of gender differences in lung cancer risk.

Objective Preventive breast surgery and MRI screening are offered to unaffected BRCA mutation carriers. The clinical benefit of these two modalities has not been evaluated among mutation carriers with a history of ovarian cancer. Thus, we sought to determine whether or not BRCA mutation carriers with ovarian cancer would benefit from preventive mastectomy or from MRI screening. Methods First, the annual mortality rate for ovarian cancer patients was estimated for a cohort of 178 BRCA mutation carriers from Ontario, Canada. Next, the actuarial risk of developing breast cancer was estimated using an international registry of 509 BRCA mutation carriers with ovarian cancer. A series of simulations was conducted to evaluate the reduction in the probability of death (from all causes) associated with mastectomy and with MRI-based breast surveillance. Cox proportional hazards models were used to evaluate the impacts of mastectomy and MRI screening on breast cancer incidence as well as on all-cause mortality. Results Twenty (3.9%) of the 509 patients developed breast cancer within ten years following ovarian cancer diagnosis. The actuarial risk of developing breast cancer at ten years post-diagnosis, conditional on survival from ovarian cancer and other causes of mortality was 7.8%. Based on our simulation results, among all BRCA mutation-carrying patients diagnosed with stage III/IV ovarian cancer at age 50, the chance of dying before age 80 was reduced by less than 1% with MRI and by less than 2% with mastectomy. Greater improvements in survival with MRI or mastectomy were observed for women who had already survived 10years after ovarian cancer, and for women with stage I or II ovarian cancer. Conclusions Among BRCA mutation-carrying ovarian cancer patients without a personal history of breast cancer, neither preventive mastectomy nor MRI screening is warranted, except for those who have survived ovarian cancer without recurrence for ten years and for those with early stage ovarian cancer.

A high proportion of ovarian cancers from women who carry germline mutations in mismatch repair (MMR) genes demonstrate microsatellite instability (MSI). The utility of pre-screening ovarian cancer specimens for MSI to identify potential patients for germline screening for MMR mutations is uncertain. 656 women with malignant ovarian cancer underwent both MSI testing and germline mutation testing for large rearrangements in three MMR genes, MLH1, MSH2 and MSH6. Germline DNA sequencing data for the same genes was available. Among the 656 women, only four (0.6%) carried a clearly pathogenic MMR mutation. All four cancers from patients with mutations had loss of two or more microsatellite markers (MSI-high). Eighty-four of 652 (13.0%) women without a mutation had MSI-high ovarian cancers. Using MSI-high as a prescreening criterion, the sensitivity of MSI testing to identify germline MMR gene mutations was 100% and the positive predictive value was 4.5%. Germline mutations in MLH1, MSH2 and MSH6 are rare among unselected cases of ovarian cancer. Patients with germline mutations often will have MSI-positive cancers and pre-screening of ovarian cancer specimens may be an efficient way of identifying patients with Lynch syndrome.

Purpose The purpose of this study was to investigate associations between pesticide exposures and risk of Hodgkin lymphoma (HL) using data from the North American Pooled Project (NAPP). Methods Three population-based studies conducted in Kansas, Nebraska, and six Canadian provinces (HL = 507, Controls = 3886) were pooled to estimate odds ratios and 95% confidence intervals for single (never/ever) and multiple (0, 1, 2–4, ≥ 5) pesticides used, duration (years) and, for select pesticides, frequency (days/year) using adjusted logistic regression models. An age-stratified analysis (≤ 40/ > 40 years) was conducted when numbers were sufficient. Results In an analysis of 26 individual pesticides, ever use of terbufos was significantly associated with HL (OR: 2.53, 95% CI 1.04–6.17). In age-stratified analyses, associations were stronger among those ≤ 40 years of age. No significant associations were noted among those > 40 years old; however, HL cases ≤ 40 were three times more likely to report ever using dimethoate (OR: 3.76 95% CI 1.02–33.84) and almost twice as likely to have ever used malathion (OR: 1.86 95% CI 1.00–3.47). Those ≤ 40 years of age reporting use of 5 + organophosphate insecticides had triple the odds of HL (OR: 3.00 95% CI 1.28–7.03). Longer duration of use of 2,4-D, ≥ 6 vs. 0 years, was associated with elevated odds of HL (OR: 2.59 95% CI 1.34–4.97). Conclusion In the NAPP, insecticide use may increase the risk of HL, but results are based on small numbers.