A genome-wide gene-based gene-environment interaction study of breast cancer in more than 90,000 women.

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 (PGXE=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.

Distinct Reproductive Risk Profiles for Intrinsic-Like Breast Cancer Subtypes: Pooled Analysis of Population-Based Studies.

BACKGROUND: Reproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER)-positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear. METHODS: Analyses included up to 23 353 cases and 71 072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2-like, HER2-enriched-like, and triple-negative breast cancer) and by invasiveness. All statistical tests were 2-sided. RESULTS: Compared with nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2-like, and HER2-enriched-like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46 for multiparous women with luminal A-like tumors 20 to less than 25 years after last birth and 45 to less than 50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95% CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95% CI = 0.79 to 1.34, for multiparous women 25 to less than 30 years after last birth). Older age at first birth (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) were associated with lower risk of triple-negative breast cancer but not with other disease subtypes. Younger age at menarche was associated with higher risk of all subtypes; older age at menopause was associated with higher risk of luminal A-like but not triple-negative breast cancer. Associations for in situ tumors were similar to luminal A-like. CONCLUSIONS: This large and comprehensive study demonstrates a distinct reproductive risk factor profile for triple-negative breast cancer compared with other subtypes, with implications for the understanding of disease etiology and risk prediction.

Association Between the BNT162b2 Messenger RNA COVID-19 Vaccine and the Risk of Sudden Sensorineural Hearing Loss.

IMPORTANCE: Identification of adverse events after vaccination increases awareness of vaccine-associated complications, leading to early diagnosis and treatment. Evidence remains scarce on the association between the BNT162b2 messenger RNA (mRNA) COVID-19 vaccine (Pfizer-BioNTech) and sudden sensorineural hearing loss (SSNHL). OBJECTIVE: To assess the association between the BNT162b2 mRNA COVID-19 vaccine and SSNHL. DESIGN, SETTING, AND PARTICIPANTS: This retrospective, population-based cohort study was performed from December 20, 2020, to May 31, 2021, using data from the largest health care organization in Israel. Patients 16 years or older who received the first vaccine dose between December 20, 2020, and April 30, 2021, and the second vaccine dose between January 10, 2021, and April 30, 2021, were included. EXPOSURES: Receipt of first and second BNT162b2 mRNA COVID-19 vaccine doses. MAIN OUTCOMES AND MEASURES: The main outcome was SSNHL based on International Classification of Diseases, Ninth Revision (ICD-9) codes in conjunction with concurrent prednisone dispensing. Observed cases of SSNHL, occurring within 21 days after each of the first and second vaccine doses, were compared with the expected cases based on the experience of the population in 2018 and 2019. Standardized incidence ratios (SIRs) and attributable risks were computed. RESULTS: Overall, 2 602 557 patients (mean [SD] age, 46.8 [19.6] years; 51.5% female) received the first dose of BNT162b2 mRNA COVID-19 vaccine, with 91 cases of SSNHL reported. Of these patients, 2 441 719 (93.8%) received the second vaccine dose, with 79 cases of SSNHL reported. The age- and sex-weighted SIRs were 1.35 (95% CI, 1.09-1.65) after the first vaccine dose and 1.23 (95% CI, 0.98-1.53) after the second vaccine dose. After the first vaccine dose, the estimated SIRs were more pronounced in female patients aged 16 to 44 years (SIR, 1.92; 95% CI, 0.98-3.43) and female patients 65 years or older (SIR, 1.68; 95% CI, 1.15-2.37). After the second vaccine dose, the highest estimated SIR was observed in male patients 16 to 44 years (SIR, 2.45; 95% CI, 1.36-4.07). The attributable risks were generally small, and the results were similar when 2019 was used as a reference to estimate the expected number of SSNHL cases. CONCLUSIONS AND RELEVANCE: This study suggests that the BNT162b2 mRNA COVID-19 vaccine might be associated with increased risk of SSNHL; however, the effect size is very small. Further studies are warranted to establish this possible association.

The factors associated with maternal consent to human papillomavirus vaccination among adolescents in Israel.

Purpose: To evaluate the knowledge and attitudes toward the human papillomavirus (HPV) vaccine among mothers of 8th graders in Israel, and to determine the factors associated with maternal consent to the HPV vaccine.Methods: We conducted a cross-sectional study among mothers of 8th grade students in 27 schools in Haifa and Northern districts of Israel during the 2016-17 school year. Data were collected using a structured telephone questionnaire.Results: 313 mothers answered the questionnaire (response rate = 91.8%). The mean knowledge level score was low (3.96 points [out of 10] ±2.68). Knowledge level was positively associated with Jewish nationality, being secular in religious practice and higher education. The attitude mean score was low-moderate (11.22 points [out of 18] ± 5.01). Attitude score was positively associated with Arab nationality. No significant association was found between knowledge level and attitudes. According to multivariate analysis, mothers' consent to the HPV vaccine was associated with the knowledge level score (OR = 0.82; 95%CI 0.68-0.98), the attitude score (OR = 1.76; 95%CI 1.53-2.02) and nationality (OR = 27.86, 95%CI 3.41-227.56).Conclusions: The knowledge level and attitudes toward the HPV vaccine were found to be unsatisfactory with racial disparities between Arabs and Jews. Jewish mothers compared with Arab mothers, mothers with a higher knowledge level or less positive attitudes were less likely to consent to the vaccine. These findings could contribute toward adapting programs to the different Israeli sectors in order to improve the rates of HPV vaccine receipt among adolescents.