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Background: Breast cancer has been associated with monogenic, polygenic, and epidemiologic (clinical, reproductive, and lifestyle) risk factors, but studies evaluating the combined effects of these factors have been limited., Methods: We extended previous work in breast cancer risk modeling, incorporating pathogenic variants (PV) in six breast cancer predisposition genes and a 105-SNP polygenic risk score (PRS), to include an epidemiologic risk score (ERS) in a sample of non-Hispanic White women drawn from prospective cohorts and population-based case-control studies, with 23,518 cases and 22,832 controls, from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium., Results: The model predicts 4.4-fold higher risk of breast cancer for postmenopausal women with no predisposition PV and median PRS, but with the highest versus lowest ERS. Overall, women with CHEK2 PVs had >20% lifetime risk of breast cancer. However, 15.6% of women with CHEK2 PVs and a family history of breast cancer, and 45.1% of women with CHEK2 PVs but without a family history of breast cancer, had low (<20%) predicted lifetime risk and thus were below the threshold for MRI screening. CHEK2 PV carriers at the 10th percentile of the joint distribution of ERS and PRS, without a family history of breast cancer, had a predicted lifetime risk similar to the general population., Conclusions: These results illustrate that an ERS, alone and combined with the PRS, can contribute to clinically relevant risk stratification., Impact: Integrating monogenic, polygenic, and epidemiologic risk factors in breast cancer risk prediction models may inform personalized screening and prevention efforts., (©2024 American Association for Cancer Research.)

Introduction: Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent, potentially carcinogenic chemicals. Previous studies investigating PFAS exposure and prostate cancer yielded mixed findings. We aimed to investigate associations between PFAS exposure and incident prostate cancer in a large cohort of U.S. men, overall and by selected demographic, lifestyle, and medical-related characteristics., Methods: We conducted a case-cohort study among Cancer Prevention Study-II LifeLink Cohort participants who, at baseline (1998-2001), had serum specimens collected and no prior cancer diagnosis. The study included all men diagnosed with prostate cancer (n = 1610) during follow-up (baseline-June 30, 2015) and a random sub-cohort of 500 men. PFAS concentrations [perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonate (PFOS), perfluorononanoic acid (PFNA), and perfluorooctanoic acid (PFOA)] were measured in stored serum specimens. We used multivariable Cox proportional hazards models to estimate associations between PFAS concentrations and prostate cancer, overall and by selected characteristics (grade, stage, family history, age, education, smoking status, and alcohol consumption)., Results: Prostate cancer hazards were slightly higher among men with concentrations in the highest (Q4) vs lowest quartile (Q1) for PFHxS [hazard ratio (HR) (95% CI): 1.18 (0.88-1.59)] and PFOS [HR (95% CI): 1.18 (0.89-1.58)], but not for PFNA or PFOA. However, we observed heterogeneous associations by age, family history of prostate cancer (PFHxS), alcohol consumption (PFHxS), and education (PFNA). For example, no meaningful associations were observed among men aged <70 years at serum collection, but among men aged ≥70 years, HRs (95% CIs) comparing Q4 to Q1 were PFHxS 1.54 (1.02-2.31) and PFOS 1.62 (1.08-2.44). No meaningful heterogeneity in associations were observed by tumor grade or stage., Conclusions: Our findings do not clearly support an association between the PFAS considered and prostate cancer. However, positive associations observed in some subgroups, and consistently positive associations observed for PFHxS warrant further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Importance: Pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2 , and PALB2 are associated with increased breast cancer risk. However, it is unknown whether breast cancer risk differs by PV type or location in carriers ascertained from the general population., Objective: To evaluate breast cancer risks associated with PV type and location in ATM, BRCA1, BRCA2, CHEK2 , and PALB2 ., Design: Age adjusted case-control association analysis for all participants, subsets of PV carriers, and women with no breast cancer family history in population-based and clinical testing cohorts., Setting: Twelve US population-based studies within the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium, and breast cancer cases from the UK-Biobank and an Ambry Genetics clinical testing cohort., Participants: 32,247 women with and 32,544 age-matched women without a breast cancer diagnosis from CARRIERS; 237 and 1351 women with BRCA2 PVs and breast cancer from the UKBB and Ambry Genetics, respectively., Exposures: PVs in ATM, BRCA1, BRCA2, CHEK2, and PALB2., Main Outcomes and Measures: PVs were grouped by type and location within genes and assessed for risks of breast cancer (odds ratios (OR), 95% confidence intervals (CI), and p-values) using logistic regression. Mean ages at diagnosis were compared using linear regression., Results: Compared to women carrying BRCA2 exon 11 protein truncating variants (PTVs) in the CARRIERS population-based study, women with BRCA2 ex13-27 PTVs (OR=2.7, 95%CI 1.1-7.9) and ex1-10 PTVs (OR=1.6, 95%CI 0.8-3.5) had higher breast cancer risks, lower rates of ER-negative breast cancer (ex13-27 OR=0.5, 95%CI 0.2-0.9; ex1-10 OR=0.5, 95%CI 0.1-1.0), and earlier age of breast cancer diagnosis (ex13-27 5.5 years, p<0.001; ex1-10 2.4 years, p=0.17). These associations with ER-negative breast cancer and age replicated in a high-risk clinical cohort and the population-based UK Biobank cohort. No differences in risk or age at diagnosis by gene region were observed for PTVs in other predisposition genes., Conclusions and Relevance: Population-based and clinical high-risk cohorts establish that PTVs in exon 11 of BRCA2 are associated with reduced risk of breast cancer, later age at diagnosis, and greater risk of ER-negative disease. These differential risks may improve individualized risk prediction and clinical management for women carrying BRCA2 PTVs., Key Points: Question: Does ATM , BRCA1 , BRCA2 , CHEK2 and PALB2 pathogenic variant type and location influence breast cancer risk in population-based studies? Findings: Breast cancer risk and estrogen receptor status differ based on the type and location of pathogenic variants in BRCA2 . Women carrying protein truncating variants in exon 11 have a lower breast cancer risk in the population-based cohorts, older age at diagnosis and higher rates of estrogen receptor negative breast cancer than women with exon 1-10 or exon 13-27 truncation variants in population-based and clinical testing cohorts. Meaning: Incorporating pathogenic variant type and location in cancer risk models may improve individualized risk prediction.

Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS, and previous findings indicate that case-control likelihood ratios (LRs) outperform odds ratios for variant classification. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyzed germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 303,925 unaffected controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observed 11,227 BRCA1 and BRCA2 variants, with 6,921 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control LR evidence was highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.4% specificity for BRCA1 and 92.2% sensitivity and 86.6% specificity for BRCA2 . This approach provides case-control evidence for 785 unclassified variants, that can serve as a valuable element for clinical classification.

Breast cancer is a heterogeneous disease with variable survival outcomes. Pathologists grade the microscopic appearance of breast tissue using the Nottingham criteria, which are qualitative and do not account for noncancerous elements within the tumor microenvironment. Here we present the Histomic Prognostic Signature (HiPS), a comprehensive, interpretable scoring of the survival risk incurred by breast tumor microenvironment morphology. HiPS uses deep learning to accurately map cellular and tissue structures to measure epithelial, stromal, immune, and spatial interaction features. It was developed using a population-level cohort from the Cancer Prevention Study-II and validated using data from three independent cohorts, including the Prostate, Lung, Colorectal, and Ovarian Cancer trial, Cancer Prevention Study-3, and The Cancer Genome Atlas. HiPS consistently outperformed pathologists in predicting survival outcomes, independent of tumor-node-metastasis stage and pertinent variables. This was largely driven by stromal and immune features. In conclusion, HiPS is a robustly validated biomarker to support pathologists and improve patient prognosis., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Previous epidemiological studies found associations between exposure to per- and polyfluoroalkyl substances (PFAS) and some cancer types. Many studies considered highly exposed populations, so relevance to less-exposed populations can be uncertain. Additionally, many studies considered only cancer site, not histology., Objectives: We conducted a case-cohort study within the American Cancer Society's prospective Cancer Prevention Study II (CPS-II) LifeLink cohort to examine associations between PFAS exposure and risk of selected cancers, considering histologic subtypes., Methods: Serum specimens were collected from cohort participants during the period 1998-2001. This study included a subcohort (500 men, 499 women) randomly selected from participants without prior cancer diagnoses at serum collection, and all participants with incident (after serum collection) first cancers of the breast (females only, n = 786 ), bladder ( n = 401 ), kidney ( n = 158 ), pancreas ( n = 172 ), prostate (males only, n = 1,610 ) or hematologic system ( n = 635 ). PFAS concentrations [perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA)] were measured in stored serum. We assessed associations between PFAS concentrations and incident cancers, by site and histologic subtype, using multivariable Cox proportional hazards models stratified by sex and controlling for age and year at blood draw, education, race/ethnicity, smoking, and alcohol use., Results: Serum PFOA concentrations were positively associated with renal cell carcinoma of the kidney among women [hazard ratio (HR) and 95% confidence interval (CI) per PFOA doubling: 1.54 (95% CI: 1.05, 2.26)] but not men. Among men, we observed a positive association between PFHxS concentrations and chronic lymphocytic leukemia/small lymphocytic lymphoma [CLL/SLL, HR and 95% CI per PFHxS doubling: 1.34 (95% CI: 1.02, 1.75)]. We observed some heterogeneity of associations by histologic subtype within sites., Discussion: This study supports the previously observed association between PFOA and renal cell carcinoma among women and suggests an association between PFHxS and CLL/SLL among men. Consideration of histologic subtypes might be important in future studies of PFAS-cancer associations. https://doi.org/10.1289/EHP13174.

Background: Educational attainment is a social determinant of health and frequently used as an indicator of socioeconomic status. Educational attainment is a predictor of cancer mortality, but associations with site-specific cancer incidence are variable. The aim of this study was to evaluate the association of educational attainment and site-specific cancer incidence adjusting for known risk factors in a large prospective cohort., Methods: Men and women enrolled in the American Cancer Society's Cancer Prevention Study-II Nutrition Cohort who were cancer free at baseline were included in this study (n = 148,965). Between 1992 and 2017, 22,810 men and 17,556 women were diagnosed with incident cancer. Cox proportional hazards regression models were used to estimate age- and multivariable-adjusted risk and 95% confidence intervals of total and site-specific cancer incidence in persons with lower versus higher educational attainment., Results: Educational attainment was inversely associated with age-adjusted cancer incidence among men but not women. For specific cancer sites, the multivariable-adjusted risk of cancer in the least versus most educated individuals remained significant for colon, rectum, and lung cancer among men and lung and breast cancer among women., Conclusions: Educational attainment is associated with overall and site-specific cancer risk though adjusting for cancer risk factors attenuates the association for most cancer sites., Impact: This study provides further evidence that educational attainment is an important social determinant of cancer but that its effects are driven by associated behavioral risk factors suggesting that targeting interventions toward those with lower educational attainment is an important policy consideration., (©2023 American Association for Cancer Research.)

Detailed knowledge of phylogeography is important for control of mosquito species involved in the transmission of human infectious diseases. Anopheles messeae is a geographically widespread and genetically diverse dominant vector of malaria in Eurasia. A closely related species, An. daciae, was originally distinguished from An. messeae based on five nucleotide substitutions in its ribosomal DNA (rDNA). However, the patterns of phylogeographic history of these species in Eurasia remain poorly understood. Here, using internal transcribed spacer 2 (ITS2) of rDNA and karyotyping for the species identification we determined the composition of five Anopheles species in 28 locations in Eurasia. Based on the frequencies of 11 polymorphic chromosomal inversions used as genetic markers, a large-scale population genetics analysis was performed of 1932 mosquitoes identified as An. messeae, An. daciae and their hybrids. The largest genetic differences between the species were detected in the X sex chromosome suggesting a potential involvement of this chromosome in speciation. The frequencies of autosomal inversions in the same locations differed by 13%-45% between the species demonstrating a restricted gene flow between the species. Overall, An. messeae was identified as a diverse species with a more complex population structure than An. daciae. The clinal gradients in frequencies of chromosomal inversions were determined in both species implicating their possible involvement in climate adaptations. The frequencies of hybrids were low ~1% in northern Europe but high up to 50% in south-eastern populations. Thus, our study revealed critical differences in patterns of phylogeographic history between An. messeae and An. daciae in Eurasia. This knowledge will help to predict the potential of the malaria transmission in the northern territories of the continent., (© 2023 The Authors. Molecular Ecology published by John Wiley & Sons Ltd.)

Background: Phylogenetic analyses of closely related species of mosquitoes are important for better understanding the evolution of traits contributing to transmission of vector-borne diseases. Six out of 41 dominant malaria vectors of the genus Anopheles in the world belong to the Maculipennis Group, which is subdivided into two Nearctic subgroups (Freeborni and Quadrimaculatus) and one Palearctic (Maculipennis) subgroup. Although previous studies considered the Nearctic subgroups as ancestral, details about their relationship with the Palearctic subgroup, and their migration times and routes from North America to Eurasia remain controversial. The Palearctic species An. beklemishevi is currently included in the Nearctic Quadrimaculatus subgroup adding to the uncertainties in mosquito systematics., Results: To reconstruct historic relationships in the Maculipennis Group, we conducted a phylogenomic analysis of 11 Palearctic and 2 Nearctic species based on sequences of 1271 orthologous genes. The analysis indicated that the Palearctic species An. beklemishevi clusters together with other Eurasian species and represents a basal lineage among them. Also, An. beklemishevi is related more closely to An. freeborni, which inhabits the Western United States, rather than to An. quadrimaculatus, a species from the Eastern United States. The time-calibrated tree suggests a migration of mosquitoes in the Maculipennis Group from North America to Eurasia about 20-25 million years ago through the Bering Land Bridge. A Hybridcheck analysis demonstrated highly significant signatures of introgression events between allopatric species An. labranchiae and An. beklemishevi. The analysis also identified ancestral introgression events between An. sacharovi and its Nearctic relative An. freeborni despite their current geographic isolation. The reconstructed phylogeny suggests that vector competence and the ability to enter complete diapause during winter evolved independently in different lineages of the Maculipennis Group., Conclusions: Our phylogenomic analyses reveal migration routes and adaptive radiation timing of Holarctic malaria vectors and strongly support the inclusion of An. beklemishevi into the Maculipennis Subgroup. Detailed knowledge of the evolutionary history of the Maculipennis Subgroup provides a framework for examining the genomic changes related to ecological adaptation and susceptibility to human pathogens. These genomic variations may inform researchers about similar changes in the future providing insights into the patterns of disease transmission in Eurasia., (© 2023. The Author(s).)

Nighttime light exposure may increase cancer risk by disrupting the circadian system. However, there is no well-established survey method for measuring ambient light. In the Cancer Prevention Study-3, 732 men and women answered a light survey based on seven environments. The light environment in the past year was assessed twice, one year apart, and four one-week diaries were collected between the annual surveys. A total of 170 participants wore a meter to measure photopic illuminance and circadian stimulus (CS). Illuminance and CS values were estimated for lighting environments from measured values and evaluated with a cross validation approach. The kappas for self-reported light environment comparing the two annual surveys were 0.61 on workdays and 0.49 on non-workdays. Kappas comparing the annual survey to weekly diaries were 0.71 and 0.57 for work and non-workdays, respectively. Agreement was highest for reporting of darkness (95.3%), non-residential light (86.5%), and household light (75.6%) on workdays. Measured illuminance and CS identified three peaks of light (darkness, indoor lighting, and outdoor daytime light). Estimated illuminance and CS were correlated with the measured values overall (r = 0.77 and r = 0.67, respectively) but were less correlated within each light environment (r = 0.23-0.43). The survey has good validity to assess ambient light for studies of human health.

Glioma is an aggressive neoplasm of the brain with poorly understood etiology. A limited number of pathogens have been examined as glioma risk factors, but data from prospective studies with infection status determined before disease are lacking. Herpesviruses comprise a large family of DNA viruses that infect humans and are linked to a range of chronic diseases. We conducted a prospective evaluation of the association between antibody to six human herpesviruses and glioma risk in the Janus Serum Bank (Janus) and the Cancer Prevention Study-II (CPS-II). In Janus and CPS-II, the risk for glioma was not related to seroprevalence of herpes simplex virus-1, varicella zoster virus, or human herpes viruses 6A or 6B. In Janus, seropositivity to either the Epstein Barr virus (EBV) EA[D] or VCAp18 antigen was associated with a lower risk of glioma (ORs: 0.55 [95% CI 0.32-0.94] and 0.57 [95% CI 0.38-0.85]). This inverse association was consistent by histologic subtype and was observed for gliomas diagnosed up to two decades following antibody measurement. In Janus, seropositivity to at least one of three examined cytomegalovirus (CMV) antigens (pp150, pp52, pp28) was associated with an increased risk of nonglioblastoma (OR: 2.08 [95% CI 1.07-4.03]). This association was limited to tumors diagnosed within 12 years of antibody measurement. In summary, we report evidence of an inverse association between exposure to EBV and glioma. We further report that CMV exposure may be related to a higher likelihood of the nonglioblastoma subtype., (© 2022 UICC.)

Background: Genome-wide association studies (GWAS) have identified more than 200 susceptibility loci for breast cancer, but these variants explain less than a fifth of the disease risk. Although gene-environment interactions have been proposed to account for some of the remaining heritability, few studies have empirically assessed this., Methods: We obtained genotype and risk factor data from 46,060 cases and 47,929 controls of European ancestry from population-based studies within the Breast Cancer Association Consortium (BCAC). We built gene expression prediction models for 4,864 genes with a significant (P<0.01) heritable component using the transcriptome and genotype data from the Genotype-Tissue Expression (GTEx) project. We leveraged predicted gene expression information to investigate the interactions between gene-centric genetic variation and 14 established risk factors in association with breast cancer risk, using a mixed-effects score test., Results: After adjusting for number of tests using Bonferroni correction, no interaction remained statistically significant. The strongest interaction observed was between the predicted expression of the C13orf45 gene and age at first full-term pregnancy (P GXE =4.44×10 -6 )., Conclusion: In this transcriptome-informed genome-wide gene-environment interaction study of breast cancer, we found no strong support for the role of gene expression in modifying the associations between established risk factors and breast cancer risk., Impact: Our study suggests a limited role of gene-environment interactions in breast cancer risk., Competing Interests: Conflict of interest disclosure statement: The authors declare no potential conflicts of interest.

Purpose: The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years., Methods: A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs., Results: The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in BRCA1 , BRCA2 , and PALB2 were found in 3.42% of women diagnosed with estrogen receptor (ER)-negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in CHEK2 , PALB2 , BRCA2 , and BRCA1 were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in BRCA1 , BRCA2 , and PALB2 ., Conclusion: This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with BRCA1 and BRCA2 PVs and perhaps with PALB2 and CHEK2 PVs should be considered for magnetic resonance imaging screening., Competing Interests: Jeffrey N. WeitzelSpeakers' Bureau: AstraZeneca Amal YussufEmployment: Ambry Genetics Celine M. VachonStock and Other Ownership Interests: Exact SciencesResearch Funding: GRAILPatents, Royalties, Other Intellectual Property: Breast Density softwareTravel, Accommodations, Expenses: GRAIL Tina PesaranEmployment: Ambry Genetics/Konica MinoltaTravel, Accommodations, Expenses: Ambry Genetics/Konica Minolta Irene M. OngEmployment: Propeller HealthStock and Other Ownership Interests: AyrFlo Rachid KaramEmployment: Ambry GeneticsResearch Funding: Ambry GeneticsTravel, Accommodations, Expenses: Ambry Genetics Holly LaDucaEmployment: Ambry GeneticsStock and Other Ownership Interests: Ambry Genetics Jill S. DolinskyEmployment: Ambry Genetics Elizabeth ChaoEmployment: Ambry Genetics Eric C. PolleyResearch Funding: GRAIL Susan M. DomchekHonoraria: AstraZeneca, Clovis Oncology, Bristol Myers SquibbResearch Funding: AstraZeneca, Clovis OncologyOpen Payments Link: https://openpaymentsdata.cms.gov/physician/917904 Fergus J. CouchConsulting or Advisory Role: AstraZenecaSpeakers' Bureau: Ambry Genetics, QiagenResearch Funding: GRAILTravel, Accommodations, Expenses: GRAIL, QiagenOther Relationship: Ambry GeneticsNo other potential conflicts of interest were reported.

Toxoplasma gondii (T gondii) is a common parasite that shows affinity to neural tissue and may lead to the formation of cysts in the brain. Previous epidemiologic studies have suggested an association between glioma and increased prevalence of T gondii infection, but prospective studies are lacking. Therefore, we examined the association between prediagnostic T gondii antibodies and risk of glioma in two prospective cohorts using a nested case-control study design. Cases and matched controls were selected from the American Cancer Society's Cancer Prevention Study-II Nutrition Cohort (CPSII-NC) (n = 37 cases and 74 controls) and the Norwegian Cancer Registry's Janus Serum Bank (Janus) (n = 323 cases and 323 controls). Blood samples collected prior to diagnosis were analyzed for antibodies to two T gondii surface antigens (p22 and sag-1), with individuals considered seropositive if antibodies to either antigen were detected. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (95% CI) for each cohort. In both cohorts, a suggestive increase in glioma risk was observed among those infected with T gondii (OR: 2.70; 95% CI: 0.96-7.62 for CPSII-NC; OR: 1.32, 95% CI: 0.85-2.07 for Janus), particularly among participants with high antibody titers specific to the sag-1 antigen (CPSII-NC OR: 3.35, 95% CI: 0.99-11.38; Janus OR: 1.79, 95% CI: 1.02-3.14). Our findings provide the first prospective evidence of an association between T gondii infection and risk of glioma. Further studies with larger case numbers are needed to confirm a potential etiologic role for T gondii in glioma., (© 2021 UICC.)

Glioma is an aggressive primary tumor of the brain with a poorly understood etiology. We studied the association of 4 human polyomaviruses (HPyV)-JC virus (JCV), BK virus (BKV), human polyomavirus 6 (HPyV6), and Merkel cell polyomavirus (MCPyV) with glioma risk within the Cancer Prevention Study II in the US (CPS-II) and the Janus Serum Bank in Norway. Cohort participants subsequently diagnosed with glioma from the CPS-II (n = 37) and Janus Serum Bank (n = 323), a median of 6.9 and 15.4 years after blood collection, respectively, were matched to individual controls on age, sex, and date of blood draw. Serum antibodies to the major viral capsid protein (VP1) were used to establish infection history for each polyomavirus. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. In the Janus Serum Bank, MCPyV infection was associated with a higher risk of glioma overall (OR: 1.56; 95% CI 1.10, 2.19). A modest, nonsignificant positive association with MCPyV infection was also observed in CPS-II (OR: 1.29; 95% CI 0.54, 3.08). In both cohorts, glioma risk was not significantly related to infection with JCV, BKV or HPyV6. The present study suggests that MCPyV infection may increase glioma risk.

Background: The malaria mosquito Anopheles punctipennis, a widely distributed species in North America, is capable of transmitting human malaria and is actively involved in the transmission of the ungulate malaria parasite Plasmodium odocoilei. However, molecular diagnostic tools based on Internal Transcribed Spacer 2 (ITS2) of ribosomal DNA are lacking for this species. Anopheles punctipennis is a former member of the Anopheles maculipennis complex but its systematic position remains unclear., Methods: In this study, ITS2 sequences were obtained from 276 An. punctipennis specimens collected in the eastern and midwestern United States and a simple and robust Restriction Fragment Length Polymorphism approach for species identification was developed. The maximum-likelihood phylogenetic tree was constructed based on ITS2 sequences available through this study and from GenBank for 20 species of Anopheles., Results: The analysis demonstrated a consistent ITS2 sequence length and showed no indications of intragenomic variation among the samples based on ITS2, suggesting that An. punctipennis represents a single species in the studied geographic locations. In this study, An. punctipennis was found in urban, rural, and forest settings, suggesting its potential broad role in pathogen transmission. Phylogeny based on ITS2 sequence comparison demonstrated the close relationship of this species with other members of the Maculipennis group., Conclusions: This study developed molecular tools based on ITS2 sequences for the malaria vector An. punctipennis and clarified the phylogenetic position of the species within the Maculipennis group.

Background: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants., Methods: In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed., Results: Pathogenic variants in 12 established breast cancer-predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1 , RAD51C , and RAD51D were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM , CDH1 , and CHEK2 were associated with an increased risk of estrogen receptor-positive breast cancer. Pathogenic variants in 16 candidate breast cancer-predisposition genes, including the c.657&#95;661del5 founder pathogenic variant in NBN , were not associated with an increased risk of breast cancer., Conclusions: This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.)., (Copyright © 2021 Massachusetts Medical Society.)

Cadmium and lead are persistent environmental toxins that are known or probable carcinogens, based on evidence for causality for nonhematologic cancers. Associations of these metals with risk of non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) are unknown but biologically plausible. To examine the associations of circulating levels of lead and cadmium exposure with risk of B-cell NHL (B-NHL) and multiple myeloma, we conducted a nested case-control study among 299 incident B-cell NHLs and 76 MM cases within the Cancer Prevention Study-II Nutrition Cohort (CPS-II NC). Each case was incidence-density matched to two eligible controls on age, race, sex and blood draw date. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) for lymphoid malignancies overall and stratified by subtype. We observed a significant positive association between high erythrocyte lead concentration and risk of lymphoid malignancies overall (RR = 1.16, 95% CI: 1.02-1.33 per 17.6 μg/L (1 standard deviation [SD])) and follicular lymphoma in particular (RR = 1.80, 95% CI: 1.15-2.80 per SD). In contrast, there was no association between erythrocyte cadmium and risk of B-NHL (RR = 0.89, 95% CI: 0.75-1.06 per 0.37 μg/L [1 SD]), or any B-NHL subtypes; but a strong inverse association with MM risk (RR = 0.59, 95% CI: 0.38-0.89, per SD). Results from our study suggest a positive association between erythrocyte lead level and risk of lymphoid malignancies and a possible inverse association between cadmium and myeloma. Additional research is needed to confirm and further explore these findings., (© 2020 UICC.)

Introduction: Muscle-strengthening activity (MSA) has beneficial effects on hypertension, glucose homeostasis, and other health conditions; however, its association with mortality is not as well understood., Methods: We analyzed data from the Cancer Prevention Study-II Nutrition Cohort (data collection 1982-2014), a prospective US cohort that consisted of 72,462 men and women who were free of major chronic diseases; 18,034 of the cohort died during 13 years of follow-up (2001-2014). We used Cox proportional hazards modeling, controlling for various potential confounding factors, to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for MSA (none, >0 to <1 h/wk, 1 to <2 h/wk, and ≥2 h/wk) in relation to mortality risk, independent of and in combination with aerobic physical activity., Results: The association between MSA and mortality appeared to be nonlinear (quadratic trend P value, <.001). After multivariable adjustment and comparison with no MSA, engaging in less than 2 hours per week of MSA was associated with lowered all-cause mortality (>0 to <1 h/wk: HR = 0.88, 95% CI, 0.82-0.94; 1 to <2 h/wk: HR = 0.90, 95% CI, 0.84-0.97), but engaging in 2 or more hours per week was not associated with reduced risk (HR = 1.01; 95% CI, 0.92-1.09). Associations were similar but not significant for cancer mortality. Engaging in >0 to <1 hr/wk of MSA was associated with a 19% lower risk (HR = 0.81; 95% CI, 0.71-0.92) of cardiovascular disease mortality, but more time spent in MSA was not associated with reduced risk (quadratic trend P value =.005). Associations did not vary by amount of moderate-to-vigorous aerobic physical activity., Conclusion: Engaging in ≥2 hours per week of MSA was associated with lower all-cause mortality, independent of aerobic activity. Reasons for the lack of association with higher amounts of MSA are unclear. Our findings support recommending muscle-strengthening activities for overall health.

Background: Height and weight are commonly used metrics in epidemiologic studies to calculate body mass index. Large cohort studies generally assess height and weight by self-report rather than by measurement. The aim of this study was to assess the validity of self-reported height and weight in the Cancer Prevention Study-3 (CPS-3), a large, nationwide cohort recruited by the American Cancer Society between 2006-2013., Methods: In a subset of CPS-3 participants (n = 2,643), weight and height were assessed at the same time via self-report and in-person measurement. BMI was calculated and classified underweight (<18.5 kg/m2), normal (18.5-<25 kg/m2), overweight (25-<30 kg/m2), or obese (≥30 kg/m2). Self-reported and measured height, weight, and BMI were compared using mean differences and Bland-Altman plots and examined by sex, race/ethnicity, education, marital status, age group, and BMI category., Results: Men and women slightly overreported height and underreported weight. BMI calculated from self-reported data was lower than for measured data for men and women. In analyses stratified by race/ethnicity, age, education, and marital status, older women and women with less than a college degree overreported height. Approximately 13% of men and 7% of women were misclassified into a lower self-reported BMI category, with misclassification of BMI being greatest in obese men and women., Conclusions: Overall, height, weight, and BMI were well-reported, and this study further suggests that BMI computed from self-reported weight and height is a valid measure in men and women across different socio-demographic groups., Competing Interests: The authors have declared that no competing interests exist.

Cadmium and lead have been classified as carcinogens by the International Agency for Research on Cancer. However, their associations with breast cancer risk are unknown despite their persistence in the environment and ubiquitous human exposure. We examined associations of circulating levels of cadmium and lead with breast cancer risk in three case-control studies nested within the Cancer Prevention Study-II (CPS-II) LifeLink Cohort, European Prospective Investigation into Cancer and Nutrition - Italy (EPIC-Italy) and the Northern Sweden Health and Disease Study (NSHDS) cohorts. Metal levels were measured in stored erythrocytes from 1,435 cases and 1,433 controls using inductively coupled plasma-mass spectrometry. Summary relative risks (RR) and 95% confidence intervals (CI) were calculated using random-effects models with each study result weighted by the within- and between-study variances. I 2 values were calculated to estimate proportion of between study variation. Using common cut-points, cadmium levels were not associated with breast cancer risk in the CPS-II cohort (continuous RR = 1.01, 95% CI 0.76-1.34), but were inversely associated with risk in the EPIC- Italy (continuous RR = 0.80, 95% CI 0.61-1.03) and NSHDS cohorts (continuous RR = 0.73, 95% CI 0.54-0.97). The inverse association was also evident in the meta-analysis (continuous RR = 0.84, 95% CI 0.69-1.01) with low between-study heterogeneity. Large differences in lead level distributions precluded a meta-analysis of their association with breast cancer risk; no associations were found in the three studies. Adult cadmium and lead levels were not associated with higher risk of breast cancer in our large meta-analysis., (© 2018 UICC.)

Background: The glycemic potential and energy density (ED) of diet may influence endometrial cancer risk. Although glycemic load (GL) is considered a probable risk factor for endometrial cancer, no studies have evaluated the association of total dietary ED with risk. Methods: We evaluated associations of ED, GL, and glycemic index (GI) with postmenopausal endometrial cancer incidence. Analyses included 30,997 postmenopausal women from the Cancer Prevention Study II Nutrition Cohort with no previous history of cancer or diabetes, who provided information on diet, lifestyle, and medical history in 1999 and were followed for cancer incidence through June 2013. Multivariable-adjusted HRs and 95% confidence intervals were estimated for quartiles (Q) of total dietary ED, GL, and GI in relation to endometrial cancer incidence using Cox proportional hazards regression models. Results: During a median follow-up time of 13.6 years, 425 endometrial cancer cases were identified. Median dietary ED was 1.5 kcal/g [interquartile range (IQR) = 1.3-1.7 kcal/g]. Median (IQR) GL and GI were 113.7 (100.5-126.8) and 52.5 (50.4-54.5), respectively. After adjustment for age, use of hormone replacement therapy, physical activity, and body mass index (kg/m 2 ), neither ED, GL, nor GI were associated with endometrial cancer risk. Conclusions: We found no associations of ED, GL, or GI with endometrial cancer risk. Impact: These results do not support an association between total dietary ED, GL, or GI and risk of postmenopausal endometrial cancer. Cancer Epidemiol Biomarkers Prev; 27(1); 113-5. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Household water treatment (HWT) provides a means for vulnerable populations to take charge of their own drinking water quality as they patiently wait for the pipe to finally reach them. In many low-income countries, however, promoters have not succeeded in scaling up the intervention among the target population or securing its consistent and sustained use. Carbon financing can provide the funding for reaching targeted populations with effective HWT solutions and the incentives to ensure their long-term uptake. Nevertheless, programs have been criticized because they do not actually reduce carbon emissions. We summarize the background and operation of carbon financing of HWT interventions, including the controversial construct of "suppressed demand". We agree that these programs have limited potential to reduce greenhouse gas emissions and that their characterization of trading "carbon for water" is misleading. Nevertheless, we show that the Kyoto Protocol expressly encouraged the use of suppressed demand as a means of allowing low-income countries to benefit from carbon financing provided it is used to advance development priorities such as health. We conclude by recommending changes to existing criteria for eligible HWT programs that will help ensure that they meet the conditions of microbiological effectiveness and actual use that will improve their potential for health gains.