Policies, Guidelines, and Practices Supporting Women's Menstruation, Menstrual Disorders and Menopause at Work: A Critical Global Scoping Review.

(1) Objectives: This paper presents a scoping review of global evidence relating to interventions (i.e., policies, practices, guidelines, and legislation) aimed at supporting women to manage menstruation, menstrual disorders, and menopause at work. (2) Methods: Databases including Medline (Ebsco), CINAHL (Ebsco), Scopus, Web of Science, APA PsychInfo (Ebsco), Humanities International Complete (Ebsco), Academic Search Premier (Ebsco), HeinOnline and OSH Update, and Google Scholar were searched in May 2022. (3) Results: Of 1181 unique articles screened, 66 articles are included. Less half of the articles (42%, 28/66) presented/reviewed an intervention related to women's workplace health. A total of 55 out of the 66 articles are set across 13 countries with the remaining 12 articles described as multi-country studies or reviews. Half of the articles presenting/reviewing an intervention were grey literature, with several undertaken in UK and EU member countries. Interventions focusing on supporting women with menopause at work were the most common (43%, 12/28), followed by menstruation (25%, 7/28) and menstrual disorders (7%, 2/28). Across the reviewed articles, recommendations were categorised as adjustments to the physical work environment, information and training needs, and policy and processes. Few articles explicitly presented or affirmed a design-process and/or evaluation tied to their intervention. In lieu of design-process, this review categorises the rationales driving the development of an intervention as: pronatalist, economic rationalism, gendered occupational health concern, cultural shift towards gender equity objectives, and efforts to reduced shame and stigma. (4) Conclusions: There is a growing body of evidence aimed at understanding women's experiences of managing their menstrual and reproductive health in the workplace and how this impacts their work/career trajectories. However, little research is explicitly concerned with exploring or understanding interventions, including their design or evaluation. Most articles report menopause guidelines and are typically confined to the UK and EU-member countries. Despite the prevalence of menstrual disorders (e.g., endometriosis and polycystic ovarian syndrome (PCOS)) there is limited literature focused on how women might be supported to manage symptoms associated with these conditions at work. Accordingly, future policies should consider how women can be better supported to manage menstruation and menstrual disorders at work and recognise the importance of co-design during policy development and post-intervention evaluation. Further research needs to be undertaken on the impact of workplace policies on both employers and employees.

Reparations for people living with dementia: Recognition, accountability, change, now!

There is a significant and longstanding problem of harm to people living with dementia in long term care institutions ('LTC institutions', referred to by others as 'care homes', 'nursing homes', 'long term care', 'residential aged care facilities'), along with a failure to redress the harm or hold people accountable for this harm. This article reports on an Australian project that found reparations must be a response to harm to people living with dementia in residential aged care. Using a disability human rights methodology, focus groups were conducted with people living with dementia, care partners and family members, advocates and lawyers to explore perspectives on why and how to redress harm to people living with dementia in Australian LTC institutions. Researchers found four key themes provide the basis for the necessity and design of a reparative approach to redress - recognition, accountability, change, now. The article calls for further attention to reparations in dementia scholarship, with a particular focus on the role that can be played in the delivery of reparations by the LTC industry, dementia practitioners, and dementia scholars. Ultimately, this article provides a new understanding of responses to violence, abuse, neglect and other harms experienced by people living with dementia in LTC institutions, which centres justice, rights, and transformative change.

Profiling the Somatic Mutational Landscape of Breast Tumors from Hispanic/Latina Women Reveals Conserved and Unique Characteristics.

Somatic mutational profiling is increasingly being used to identify potential targets for breast cancer. However, limited tumor-sequencing data from Hispanic/Latinas (H/L) are available to guide treatment. To address this gap, we performed whole-exome sequencing (WES) and RNA sequencing on 146 tumors and WES of matched germline DNA from 140 H/L women in California. Tumor intrinsic subtype, somatic mutations, copy-number alterations, and expression profiles of the tumors were characterized and compared with data from tumors of non-Hispanic White (White) women in The Cancer Genome Atlas (TCGA). Eight genes were significantly mutated in the H/L tumors including PIK3CA, TP53, GATA3, MAP3K1, CDH1, CBFB, PTEN, and RUNX1; the prevalence of mutations in these genes was similar to that observed in White women in TCGA. Four previously reported Catalogue of Somatic Mutations in Cancer (COSMIC) mutation signatures (1, 2, 3, 13) were found in the H/L dataset, along with signature 16 that has not been previously reported in other breast cancer datasets. Recurrent amplifications were observed in breast cancer drivers including MYC, FGFR1, CCND1, and ERBB2, as well as a recurrent amplification in 17q11.2 associated with high KIAA0100 gene expression that has been implicated in breast cancer aggressiveness. In conclusion, this study identified a higher prevalence of COSMIC signature 16 and a recurrent copy-number amplification affecting expression of KIAA0100 in breast tumors from H/L compared with White women. These results highlight the necessity of studying underrepresented populations. SIGNIFICANCE: Comprehensive characterization of genomic and transcriptomic alterations in breast tumors from Hispanic/Latina patients reveals distinct genetic alterations and signatures, demonstrating the importance of inclusive studies to ensure equitable care for patients. See related commentary by Schmit et al., p. 2443.

Whole exome sequencing and replication for breast cancer among Hispanic/Latino women identifies FANCM as a susceptibility gene for estrogen-receptor-negative breast cancer.

Introduction: Breast cancer (BC) is one of the most common cancers globally. Genetic testing can facilitate screening and risk-reducing recommendations, and inform use of targeted treatments. However, genes included in testing panels are from studies of European-ancestry participants. We sequenced Hispanic/Latina (H/L) women to identify BC susceptibility genes. Methods: We conducted a pooled BC case-control analysis in H/L women from the San Francisco Bay area, Los Angeles County, and Mexico (4,178 cases and 4,344 controls). Whole exome sequencing was conducted on 1,043 cases and 1,188 controls and a targeted 857-gene panel on the remaining samples. Using ancestry-adjusted SKAT-O analyses, we tested the association of loss of function (LoF) variants with overall, estrogen receptor (ER)-positive, and ER-negative BC risk. We calculated odds ratios (OR) for BC using ancestry-adjusted logistic regression models. We also tested the association of single variants with BC risk. Results: We saw a strong association of LoF variants in FANCM with ER-negative BC (p=4.1×10-7, OR [CI]: 6.7 [2.9-15.6]) and a nominal association with overall BC risk. Among known susceptibility genes, BRCA1 (p=2.3×10-10, OR [CI]: 24.9 [6.1-102.5]), BRCA2 (p=8.4×10-10, OR [CI]: 7.0 [3.5-14.0]), and PALB2 (p=1.8×10-8, OR [CI]: 6.5 [3.2-13.1]) were strongly associated with BC. There were nominally significant associations with CHEK2, RAD51D, and TP53. Conclusion: In H/L women, LoF variants in FANCM were strongly associated with ER-negative breast cancer risk. It previously was proposed as a possible susceptibility gene for ER-negative BC, but is not routinely tested in clinical practice. Our results demonstrate that FANCM should be added to BC gene panels.

Reparations for Harms Experienced in Residential Aged Care.

This paper explores the possibility of reparations for harms suffered by people in residential aged care, focusing on experiences of people with dementia. We first explain how systemic and structural harms occur within residential aged care and outline how they constitute human rights violations. Using Australia as a case study, we then consider the limitations of court-based approaches to pursuit of redress and the current absence of redress from policy responses. We then propose an expansive and multifaceted notion of redress as reparations, where governments, residential aged care operators, medical and legal professionals, and civil society engage in ongoing recognition of harms and specific actions to prevent recurrence. By drawing on the United Nations Convention on the Rights of Persons with Disabilities and the Van Boven Principles, we consider the application to aged care of the framework of access to justice and reparations for human rights violations. This framework encompasses inclusive and accessible processes to access reparations for individuals in such forms as compensation and rehabilitation, and collective reparations, including apologies and public education. In order to ensure that reparations support the prevention of further harm in aged care, the design of redress could form part of broader government strategies directed toward increasing funding and access to community-based support, care, and accommodation, and enhancing the human rights of people with dementia.

Methylation biomarkers of polybrominated diphenyl ethers (PBDEs) and association with breast cancer risk at the time of menopause.

BACKGROUND: Exposure to polybrominated diphenyl ethers (PBDEs) may influence risk of developing post-menopausal breast cancer. Although mechanisms are poorly understood, epigenetic regulation of gene expression may play a role. OBJECTIVES: To identify DNA methylation (DNAm) changes associated with PBDE serum levels and test the association of these biomarkers with breast cancer risk. METHODS: We studied 397 healthy women (controls) and 133 women diagnosed with breast cancer (cases) between ages 40 and 58 years who participated in the California Teachers Study. PBDE levels were measured in blood. Infinium Human Methylation EPIC Bead Chips were used to measure DNAm. Using multivariable linear regression models, differentially methylated CpG sites (DMSs) and regions (DMRs) associated with serum PBDE levels were identified using controls. For top-ranked DMSs and DMRs, targeted next-generation bisulfite sequencing was used to measure DNAm for 133 invasive breast cancer cases and 301 age-matched controls. Conditional logistic regression was used to evaluate associations between DMSs and DMRs and breast cancer risk. RESULTS: We identified 15 DMSs and 10 DMRs statistically significantly associated with PBDE levels (FDR < 0.05). Methylation changes in a DMS at BMP8B and DMRs at TP53 and A2M-AS1 were statistically significantly (FDR < 0.05) associated with breast cancer risk. CONCLUSION: We show for the first time that serum PBDE levels are associated with differential methylation and that PBDE-associated DNAm changes in blood are associated with breast cancer risk.

Prostate cancer in young men represents a distinct clinical phenotype: gene expression signature to predict early metastases.

AIM: Several genomic signatures are available to predict Prostate Cancer (CaP) outcomes based on gene expression in prostate tissue. However, no signature was tailored to predict aggressive CaP in younger men. We attempted to develop a gene signature to predict the development of metastatic CaP in young men. METHODS: We measured genome-wide gene expression for 119 tumor and matched benign tissues from prostatectomies of men diagnosed at ≤ 50 years and > 70 years and identified age-related differentially expressed genes (DEGs) for tissue type and Gleason score. Age-related DEGs were selected using the improved Prediction Analysis of Microarray method (iPAM) to construct and validate a classifier to predict metastasis using gene expression data from 1,232 prostatectomies. Accuracy in predicting early metastasis was quantified by the area under the curve (AUC) of receiver operating characteristic (ROC), and abundance of immune cells in the tissue microenvironment was estimated using gene expression data. RESULTS: Thirty-six age-related DEGs were selected for the iPAM classifier. The AUC of five-year survival ROC for the iPAM classifier was 0.87 (95%CI: 0.78-0.94) in young (≤ 55 years), 0.82 (95%CI: 0.76-0.88) in middle-aged (56-70 years), and 0.69 (95%CI: 0.55-0.69) in old (> 70 years) patients. Metastasis-associated immune responses in the tumor microenvironment were more pronounced in young and middle-aged patients than in old ones, potentially explaining the difference in accuracy of prediction among the groups. CONCLUSION: We developed a genomic classifier with high precision to predict early metastasis for younger CaP patients and identified age-related differences in immune response to metastasis development.

Common Susceptibility Loci for Male Breast Cancer.

BACKGROUND: The etiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study of MBC identified 2 predisposition loci for the disease, both of which were also associated with risk of FBC. METHODS: We performed genome-wide single nucleotide polymorphism genotyping of European ancestry MBC case subjects and controls in 3 stages. Associations between directly genotyped and imputed single nucleotide polymorphisms with MBC were assessed using fixed-effects meta-analysis of 1380 cases and 3620 controls. Replication genotyping of 810 cases and 1026 controls was used to validate variants with P values less than 1 × 10-06. Genetic correlation with FBC was evaluated using linkage disequilibrium score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score and MBC. All statistical tests were 2-sided. RESULTS: The genome-wide association study identified 3 novel MBC susceptibility loci that attained genome-wide statistical significance (P < 5 × 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen receptor-positive FBC. Men in the top quintile of genetic risk had a fourfold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 × 10-30). CONCLUSIONS: These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic etiology with FBC and identifying a fourfold high-risk group of susceptible men.

Creating a dementia enabling university using a Knowledge Translation approach: Innovative practice.

Universities can promote social impact by developing a dementia literate workforce. The Dementia Enabling University Strategy utilised a knowledge translation framework in an Australian university to inspire and support academics to engage students and consider how their skills and knowledge could contribute to the creation of more supportive environments for people with dementia. Dementia Enabling University Strategy ran across eight disciplines: law, media, social sciences, public health, engineering, business, marketing and psychology and was successful in engaging university academics and students. However, a longer term strategy is needed to embed 'dementia' as core business to the university impact agenda.

Human Rights and the Confinement of People Living with Dementia in Care Homes.

This paper responds to growing concerns in human rights practice and scholarship about the confinement of people living with dementia in care homes. Moving beyond the existing focus in human rights scholarship on the role of restrictive practices in confinement, the paper broadens and nuances our understanding of confinement by exploring the daily facilitators of confinement in the lives of people with dementia. The paper draws on data from focus groups and interviews with people living with dementia, care partners, aged care workers, and lawyers and advocates about Australian care homes. It argues that microlevel interrelated and compounding factors contribute to human rights abuses of people living with dementia related to limits on freedom of movement and community access of people living with dementia, at times irrespective of the use of restrictive practices. These factors include immobilization and neglect of residents, limited and segregated recreational activities, concerns about duty of care and liability, apprehension of community exclusion, and pathologization and subversion of resistance. It is necessary to challenge the organizational, cultural, economic, and social dynamics that shape day-to-day, microlevel, routine, and compounding factors that remove the agency of people living with dementia and in turn facilitate entrenched and systematic human rights breaches in care homes.

Pathogenic and likely pathogenic variants in PALB2, CHEK2, and other known breast cancer susceptibility genes among 1054 BRCA-negative Hispanics with breast cancer.

BACKGROUND: Breast cancer (BC) is the most common cancer and related cause of mortality among Hispanics, yet susceptibility has been understudied. BRCA1 and BRCA2 (BRCA) mutations explain less than one-half of hereditary BC, and the proportion associated with other BC susceptibility genes is unknown. METHODS: Germline DNA from 1054 BRCA-mutation-negative Hispanic women with hereditary BC (BC diagnosed at age <51 years, bilateral BC, breast and ovarian cancer, or BC diagnosed at ages 51-70 years with ≥2 first-degree or second-degree relatives who had BC diagnosed at age <70 years), 312 local controls, and 887 multiethnic cohort controls was sequenced and analyzed for 12 known and suspected, high-penetrance and moderate-penetrance cancer susceptibility genes (ataxia telangiectasia mutated [ATM], breast cancer 1 interacting protein C-terminal helicase 1 [BRIP1], cadherin 1 [CDH1], checkpoint kinase 2 [CHEK2], nibrin [NBN], neurofibromatosis type 1 [NF1], partner and localizer of BRCA2 [PALB2], phosphatase and tensin homolog [PTEN], RAD51 paralog 3 [RAD51C], RAD51D, serine/threonine kinase 11 [STK11], and TP53). RESULTS: Forty-nine (4.6%) pathogenic or likely pathogenic variants (PVs) in 47 of 1054 participants (4.5%), including 21 truncating frameshift, 20 missense, 5 nonsense, and 4 splice variants, were identified in CHEK2 (n = 20), PALB2 (n = 18), ATM (n = 5), TP53 (n = 3), BRIP1 (n = 2), and CDH1 and NF1 (both n = 1) and none were identified in NBN, PTEN, STK11, RAD51C, or RAD51D. Nine participants carried the PALB2 c.2167_2168del PV (0.85%), and 14 carried the CHEK2 c.707T>C PV (1.32%). CONCLUSIONS: Of 1054 BRCA-negative, high-risk Hispanic women, 4.5% carried a PV in a cancer susceptibility gene, increasing understanding of hereditary BC in this population. Recurrent PVs in PALB2 and CHEK2 represented 47% (23 of 49) of the total, suggesting a founder effect. Accurate classification of variants was enabled by carefully controlling for ancestry and the increased identification of at-risk Hispanics for screening and prevention.

Molecular subtypes of triple-negative breast cancer in women of different race and ethnicity.

Molecular subtypes of triple negative breast cancer (TNBC) are associated with variation in survival and may assist in treatment selection. However, the association of patient race or ethnicity with subtypes of TNBC and clinical outcome has not been addressed. Using nCounter Gene Expression Codesets, we classified TNBCs into subtypes: basal-like immune-activated (BLIA), basal-like immunosuppressed (BLIS), luminal androgen receptor (LAR), and mesenchymal (MES) in 48 Hispanic, 12 African-American, 21 Asian, and 34 White patients. Mean age at diagnosis was significantly associated with subtype, with the youngest mean age (50 years) in MES and the oldest mean age (64 years) in LAR (p < 0.0005). Subtype was significantly associated with tumor grade (p = 0.0012) and positive lymph nodes (p = 0.021), with a marginally significant association of tumor stage (p = 0.076). In multivariate Cox-proportional hazards modeling, BLIS was associated with worst survival and LAR with best survival. Hispanics had a significantly higher proportion of BLIS (53%, p = 0.03), whereas Asians had a lower proportion of BLIS (19%, p = 0.05) and a higher proportion of LAR (38%, p = 0.06) compared to the average proportion across all groups. These differences in proportions of subtype across racial and ethnic groups may explain differences in their outcomes. Determining subtypes of TNBC facilitates understanding of the heterogeneity of the TNBCs and provides a foundation for developing subtype-specific therapies and better predictors of TNBC prognosis for all races and ethnicities.

Grade Experience of Online Nurse Practitioner Students: Effects of Taking More Than 1 Clinical Course per Term.

This study examined the grade experience for online nurse practitioner students (N = 3760) who took more than 1 clinical course per academic term as compared with those who did not. Students who had more than 1 clinical course per term had a greater percentage of clinical course failures than other students (2.1% vs 0.8%, P = .001). Nurse practitioner programs should develop clear policies and guidelines for students taking more than 1 clinical course at a time.

Discovery of mutations in homologous recombination genes in African-American women with breast cancer.

African-American women are more likely to develop aggressive breast cancer at younger ages and experience poorer cancer prognoses than non-Hispanic Caucasians. Deficiency in repair of DNA by homologous recombination (HR) is associated with cancer development, suggesting that mutations in genes that affect this process may cause breast cancer. Inherited pathogenic mutations have been identified in genes involved in repairing DNA damage, but few studies have focused on African-Americans. We screened for germline mutations in seven HR repair pathway genes in DNA of 181 African-American women with breast cancer, evaluated the potential effects of identified missense variants using in silico prediction software, and functionally characterized a set of missense variants by yeast two-hybrid assays. We identified five likely-damaging variants, including two PALB2 truncating variants (Q151X and W1038X) and three novel missense variants (RAD51C C135R, and XRCC3 L297P and V337E) that abolish protein-protein interactions in yeast two-hybrid assays. Our results add to evidence that HR gene mutations account for a proportion of the genetic risk for developing breast cancer in African-Americans. Identifying additional mutations that diminish HR may provide a tool for better assessing breast cancer risk and improving approaches for targeted treatment.

Primary Peritoneal Serous Carcinoma in Men: A Rare and Non-BRCA-associated Entity.

BACKGROUND: Primary peritoneal serous carcinoma (PPSC) is a rare neoplasm. The paucity of reported cases among men may provide insight to the cell of origin of PPSC. MATERIALS AND METHODS: A search for the ICD 0-3 code of PPSC (C48.2) in the following datasets: the Israeli National Cancer registry (INCR), the Surveillance, Epidemiology, and End Results (SEER) database in the USA, Israeli male BRCA carriers, male high-risk and BRCA carriers in a USA study, and the Italian Study on Male Breast Cancer (MBC) were performed. RESULTS: In the INCR dataset, 220 entries for C48.2 code were noted, with only one male (male:female ratio=0.0045). In the SEER dataset for histology codes of papillary/serous/ adenocarcinoma, 2,673 cases were recorded, with five males (male:female ratio=0.0018). None of the recorded US or Italian male BRCA carriers or MBC, or Israeli male BRCA carriers was diagnosed with PPSC. CONCLUSION: PPSC is a rare neoplasm, seemingly not associated with BRCA mutations in men, and fallopian tube epithelial cell implants may contribute to its development.

Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores.

Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10-6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10-9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.

Gene Expression Differences in Prostate Cancers between Young and Old Men.

Prostate cancer incidence is increasing in younger men. We investigated whether men diagnosed with Gleason 7 (3+4) T2 prostate cancer at younger ages (≤ 45 years, young cohort) had different mRNA and miRNA expression profiles than men diagnosed at older ages (71-74 years, older cohort). We identified differentially expressed genes (DEGs) related to tumor-normal differences between the cohorts. Subsequent pathway analysis of DEGs revealed that the young cohort had significantly more pronounced inflammatory and immune responses to tumor development compared to the older cohort. Further supporting a role of inflammation-induced immune-suppression in the development of early-onset prostate cancer, we observed significant up-regulation of CTLA4 and IDO1/TDO2 pathways in tumors of the young cohort. Moreover, over-expression of CTLA4 and IDO1 was significantly associated with biochemical recurrence. Our results provide clues on the mechanisms of tumor development and point to potential biomarkers for early detection and treatment for prostate cancer in young men.

Heart failure outcomes based on race and gender of patients in a medically undeserved area.

The purpose of this descriptive study was to investigate changes in quality of life (QoL), disease severity and exercise tolerance of heart failure (HF) patients in a medically underserved clinic based on race and gender. Despite advances in the treatment of HF over the past decade, incidence, morbidity and mortality for patients continue to rise while QoL declines. HF is common in African-Americans and women; however, there is limited research focusing on race and gender variables. Health related QoL, disease severity measured by B-type natriuretic peptide blood test (BNP) and ejection fraction (EF), and exercise tolerance measured by six minute walk test (6MWT) were assessed at admission and at 6 months in a convenience sample of 53 patients. Variables were compared by race and gender. The sample was 67.9% African American and 62.3% male. Men had greater improvements than women in QoL, BNP, and EF, while women had greater improvements in the 6MWT. African Americans had greater improvements than Whites in all four variables. Even in the presence of disease severity in patients with New York Heart Association (NYHA) Class III and IV HF, there were significant improvements in QoL, BNP, HF outcomes demonstrating the importance of developing culturally sensitive and gender-specific treatment plans.

Genome-wide association study of celiac disease in North America confirms FRMD4B as new celiac locus.

We performed a genome-wide association study (GWAS) of 1550 North American celiac disease cases and 3084 controls. Twelve SNPs, distributed across four regions (3p21.31, 4q27, 6q15, 6q25), were significantly associated with disease (p-value <1.0×10-7), and a further seven SNPs, across four additional regions (1q24.3, 10p15.1, 6q22.31, 17q21.32) had suggestive evidence (1.0×10-7 < p-value < 1.0×10-6). This study replicated a previous suggestive association within FRMD4B (3p14.1), confirming it as a celiac disease locus. All four regions with significant associations and two regions with suggestive results (1q24.3, 10p15.1) were known disease loci. The 6q22.31 and 10p11.23 regions were not replicated. A total of 410 SNPs distributed across the eight significant and suggestive regions were tested for association with dermatitis herpetiformis and microscopic colitis. Preliminary, suggestive statistical evidence for association with the two traits was found at chromosomes 3p21.31, 6q15, 6q25, 1q24.3 and 10p11.23, with future studies being required to validate the reported associations.

DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers.

Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7 × 10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 × 10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.