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Cigarette smoking adversely affects many aspects of human health, and epigenetic responses to smoking may reflect mechanisms that mediate or defend against these effects. Prior studies of smoking and DNA methylation (DNAm), typically measured in leukocytes, have identified numerous smoking-associated regions (e.g., AHRR). To identify smoking-associated DNAm features in typically inaccessible tissues, we generated array-based DNAm data for 916 tissue samples from the GTEx (Genotype-Tissue Expression) project representing 9 tissue types (lung, colon, ovary, prostate, blood, breast, testis, kidney, and muscle). We identified 6,350 smoking-associated CpGs in lung tissue (n = 212) and 2,735 in colon tissue (n = 210), most not reported previously. For all 7 other tissue types (sample sizes 38-153), no clear associations were observed (false discovery rate 0.05), but some tissues showed enrichment for smoking-associated CpGs reported previously. For 1,646 loci (in lung) and 22 (in colon), smoking was associated with both DNAm and local gene expression. For loci detected in both lung and colon (e.g., AHRR, CYP1B1, CYP1A1), top CpGs often differed between tissues, but similar clusters of hyper- or hypomethylated CpGs were observed, with hypomethylation at regulatory elements corresponding to increased expression. For lung tissue, 17 hallmark gene sets were enriched for smoking-associated CpGs, including xenobiotic- and cancer-related gene sets. At least four smoking-associated regions in lung were impacted by lung methylation quantitative trait loci (QTLs) that co-localize with genome-wide association study (GWAS) signals for lung function (FEV1/FVC), suggesting epigenetic alterations can mediate the effects of smoking on lung health. Our multi-tissue approach has identified smoking-associated regions in disease-relevant tissues, including effects that are shared across tissue types., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: There is growing consensus that researchers should offer to return genetic results to participants, but returning results in lower-resource countries has received little attention. In this study, we return results on genetic susceptibility to arsenic toxicity to participants in a Bangladeshi cohort exposed to arsenic through naturally-contaminated drinking water. We examine the impact on behavioral changes related to exposure reduction., Methods: We enrolled participants from the Health Effects of Arsenic Longitudinal Study who had (1) high arsenic (≥150 μg/g creatinine) in a recent urine sample and (2) existing data on genetic variants impacting arsenic metabolism efficiency (AS3MT and FTCD). We used genetic data to recruit three study groups, each with n = 103: (1) efficient metabolizers (low-risk), (2) inefficient metabolizers (high-risk), and (3) a randomly-selected control group (NCT05072132). At baseline, all participants received information on the effects of arsenic and how to reduce exposure by switching to a low arsenic well. The two intervention groups also received their arsenic metabolism efficiency status (based on their genetic results). Changes in behavior and arsenic exposure were assessed using questionnaires and urine arsenic measures after six months., Results: Clear decreases in urine arsenic after six months were observed for all three groups. The inefficient group self-reported higher levels of attempted switching to lower arsenic wells than the other groups; however, there was no detectable difference in urine arsenic reduction among the three groups. Participants showed strong interest in receiving genetic results and found them useful. The inefficient group experienced higher levels of anxiety than the other groups. Among the efficient group, that receiving genetic results did not appear to hinder behavioral change., Conclusion: Returning genetic results increased self-reported exposure-reducing behaviors but did not have a detectable impact on reducing urine arsenic over and above a one-on-one educational intervention., 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., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Breast cancer is a heterogeneous disease, and the distribution of the different subtypes varies by race/ethnic category in the United States and by country. Established breast cancer-associated factors impact subtype-specific risk; however, these included limited or no representation of Latin American diversity. To address this gap in knowledge, we report a description of demographic, reproductive, and lifestyle breast cancer-associated factors by age at diagnosis and disease subtype for The Peruvian Genetics and Genomics of Breast Cancer (PEGEN-BC) study., Methods: The PEGEN-BC study is a hospital-based breast cancer cohort that includes 1943 patients diagnosed at the Instituto Nacional de Enfermedades Neoplásicas in Lima, Peru. Demographic and reproductive information, as well as lifestyle exposures, were collected with a questionnaire. Clinical data, including tumor Hormone Receptor (HR) status and Human Epidermal Growth Factor Receptor 2 (HER2) status, were abstracted from electronic medical records. Differences in proportions and mean values were tested using Chi-squared and one-way ANOVA tests, respectively. Multinomial logistic regression models were used for multivariate association analyses., Results: The distribution of subtypes was 52% HR+HER2-, 19% HR+HER2+, 16% HR-HER2-, and 13% HR-HER2+. Indigenous American (IA) genetic ancestry was higher, and height was lower among individuals with the HR-HER2+ subtype (80% IA vs. 76% overall, p =0.007; 152 cm vs. 153 cm overall, p =0.032, respectively). In multivariate models, IA ancestry was associated with HR-HER2+ subtype (OR=1.38,95%CI=1.06-1.79, p =0.017) and parous women showed increased risk for HR-HER2+ (OR=2.7,95%CI=1.5-4.8, p <0.001) and HR-HER2- tumors (OR=2.4,95%CI=1.5-4.0, p <0.001) compared to nulliparous women. Multiple patient and tumor characteristics differed by age at diagnosis (<50 vs. >=50), including ancestry, region of residence, family history, height, BMI, breastfeeding, parity, and stage at diagnosis ( p <0.02 for all variables)., Discussion: The characteristics of the PEGEN-BC study participants do not suggest heterogeneity by tumor subtype except for IA genetic ancestry proportion, which has been previously reported. Differences by age at diagnosis were apparent and concordant with what is known about pre- and post-menopausal-specific disease risk factors. Additional studies in Peru should be developed to further understand the main contributors to the specific age of onset and molecular disease subtypes in this population and develop population-appropriate predictive models for prevention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zavala, Casavilca-Zambrano, Navarro-Vásquez, Tamayo, Castañeda, Valencia, Morante, Calderón, Abugattas, Gómez, Fuentes, Liendo-Picoaga, Cotrina, Neciosup, Roque, Vásquez, Mas, Gálvez-Nino, Fejerman and Vidaurre.)

Inorganic arsenic is highly toxic and carcinogenic to humans. Exposed individuals vary in their ability to metabolize arsenic, and variability in arsenic metabolism efficiency (AME) is associated with risks of arsenic-related toxicities. Inherited genetic variation in the 10q24.32 region, near the arsenic methyltransferase (AS3MT) gene, is associated with urine-based measures of AME in multiple arsenic-exposed populations. To identify potential causal variants in this region, we applied fine mapping approaches to targeted sequencing data generated for exposed individuals from Bangladeshi, American Indian, and European American populations (n = 2,357, 557, and 648 respectively). We identified three independent association signals for Bangladeshis, two for American Indians, and one for European Americans. The size of the confidence sets for each signal varied from 4 to 85 variants. There was one signal shared across all three populations, represented by the same SNP in American Indians and European Americans (rs191177668) and in strong linkage disequilibrium (LD) with a lead SNP in Bangladesh (rs145537350). Beyond this shared signal, differences in LD patterns, minor allele frequency (MAF) (e.g., rs12573221 ~13% in Bangladesh ~0.2% among American Indians), and/or heterogeneity in effect sizes across populations likely contributed to the apparent population specificity of the additional identified signals. One of our potential causal variants influences AS3MT expression and nearby DNA methylation in numerous GTEx tissue types (with rs4919690 as a likely causal variant). Several SNPs in our confidence sets overlap transcription factor binding sites and cis-regulatory elements (from ENCODE). Taken together, our analyses reveal multiple potential causal variants in the 10q24.32 region influencing AME, including a variant shared across populations, and elucidate potential biological mechanisms underlying the impact of genetic variation on AME., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Chernoff et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Inorganic arsenic (iAs) is a carcinogen, and chronic exposure is associated with adverse health outcomes, including cancer and cardiovascular disease. Consumed iAs can undergo two methylation reactions catalyzed by arsenic methyltransferase ( AS3MT ), producing monomethylated and dimethylated forms of arsenic (MMA and DMA). Methylation of iAs helps facilitate excretion of arsenic in urine, with DMA composing the majority of arsenic species excreted. Past studies have identified genetic variation in the AS3MT (10q24.32) and FTCD (21q22.3) regions associated with arsenic metabolism efficiency (AME), measured as the proportion of each species present in urine (iAs%, MMA%, and DMA%), but their association with arsenic species present in blood has not been examined. We use data from three studies nested within the Health Effects and Longitudinal Study (HEALS)-the Nutritional Influences on Arsenic Toxicity Study, the Folate and Oxidative Stress study, and the Folic Acid and Creatine Trial-to examine the association of previously identified genetic variants with arsenic species in both urine and blood of 334 individuals. We confirm that the genetic variants in AS3MT and FTCD known to effect arsenic species composition in urine (an excreted byproduct of metabolism) have similar effects on arsenic species in blood (a tissue type that directly interacts with many organs, including those prone to arsenic toxicity). This consistency we observe provides further support for the hypothesis the AME SNPs identified to date impact the efficiency of arsenic metabolism and elimination, thereby influencing internal dose of arsenic and the dose delivered to toxicity-prone organs and tissues., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The Environmental Epidemiology. All rights reserved.)

Background: Breast cancer is the most common cancer among women in the U.S. and the leading cause of cancer death among Hispanics/Latinas (H/L). H/L are less likely than Non-H/L White (NHW) women to be diagnosed in the early stages of this disease. Approximately 5-10% of breast cancer can be attributed to inherited genetic mutations in high penetrance genes such as BRCA1/2 . Women with pathogenic variants in these genes have a 40-80% lifetime risk of breast cancer. Past studies have shown that genetic counseling can help women and their families make informed decisions about genetic testing and early cancer detection or risk-reduction strategies. However, H/L are 3.9-4.8 times less likely to undergo genetic testing than NHW women. We developed a program to outreach and educate the H/L community about hereditary breast cancer, targeting monolingual Spanish-speaking individuals in California. Through this program, we have assessed cancer screening behavior and identified women who might benefit from genetic counseling in a population that is usually excluded from cancer research and care., Materials and Methods: The "Tu Historia Cuenta" program is a promotores-based virtual outreach and education program including the cities of San Francisco, Sacramento, and Los Angeles. Participants responded to three surveys: a demographic survey, a breast cancer family history survey, and a feedback survey. Survey responses were described for participants and compared by area where the program took place using chi-square, Fisher exact tests, and t tests. Multinomial logistic regression models were used for multivariate analyses., Results and Conclusion: We enrolled 1042 women, 892 completed the cancer family history survey and 62 (7%) provided responses compatible with referral to genetic counseling. We identified 272 women (42.8% ages 40 to 74 years) who were due for mammograms, 250 women (24.7% ages 25 to 65 years) due for Papanicolaou test, and 189 women (71.6% ages 50+) due for colorectal cancer screening. These results highlight the need of additional support for programs that spread awareness about cancer risk and facilitate access to resources, specifically within the H/L community., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tamayo, Perez, Perez, Hernandez, Martinez, Huang, Zavala, Ziv, Neuhausen, Carvajal-Carmona, Duron and Fejerman.)

Women of Latin American origin in the United States are more likely to be diagnosed with advanced breast cancer and have a higher risk of mortality than non-Hispanic White women. Studies in U.S. Latinas and Latin American women have reported a high incidence of HER2 positive (+) tumors; however, the factors contributing to this observation are unknown. Genome-wide genotype data for 1,312 patients from the Peruvian Genetics and Genomics of Breast Cancer Study (PEGEN-BC) were used to estimate genetic ancestry. We tested the association between HER2 status and genetic ancestry using logistic and multinomial logistic regression models. Findings were replicated in 616 samples from Mexico and Colombia. Average Indigenous American (IA) ancestry differed by subtype. In multivariate models, the odds of having an HER2 + tumor increased by a factor of 1.20 with every 10% increase in IA ancestry proportion (95% CI, 1.07-1.35; P = 0.001). The association between HER2 status and IA ancestry was independently replicated in samples from Mexico and Colombia. Results suggest that the high prevalence of HER2 + tumors in Latinas could be due in part to the presence of population-specific genetic variant(s) affecting HER2 expression in breast cancer. SIGNIFICANCE: The positive association between Indigenous American genetic ancestry and HER2 + breast cancer suggests that the high incidence of HER2 + subtypes in Latinas might be due to population and subtype-specific genetic risk variants., (©2020 American Association for Cancer Research.)

Latina women in the U.S. have relatively low breast cancer incidence compared to Non-Latina White (NLW) or African American women but are more likely to be diagnosed with the more aggressive "triple negative" breast cancer (TNBC). Latinos in the U.S. are a heterogeneous group originating from different countries with different cultural and ancestral backgrounds. Little is known about the distribution of tumor subtypes in Latin American regions. Clinical records of 303 female Peruvian patients, from the Peruvian National Cancer Institute, were analyzed. Participants were diagnosed with invasive breast cancer between 2010 and 2015 and were identified as residing in either the Selva or Sierra region. We used Fisher's exact test for proportions and multivariable Cox Proportional Hazards Models to compare overall survival between regions. Women from the Selva region were more likely to be diagnosed with TNBC than women from the Sierra region (31% vs. 14%, p = 0.01). In the unadjusted Cox model, the hazard of mortality was 1.7 times higher in women from the Selva than the Sierra (p = 0.025); this survival difference appeared to be largely explained by differences in the prevalence of TNBC. Our results suggest that the distribution of breast cancer subtypes differs between highly Indigenous American women from two regions of Peru. Disentangling the factors that contribute to this difference will add valuable information to better target prevention and treatment efforts in Peru and improve our understanding of TNBC among all women. This study demonstrates the need for larger datasets of Latin American patients to address differences between Latino subpopulations and optimize targeted prevention and treatment., Competing Interests: The authors have declared that no competing interests exist.