Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer ...risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95% CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
Shift work is associated with an increased risk of cardiovascular diseases (CVD). Disruption of cortisol production is a potential underlying mechanism. This study explored the associations of ...diurnal quantity and pattern of cortisol production in relation to (1) current shift work status (exclusive day versus rotating days and nights), (2) years of past shift work and (3) parameters of rotating shift work (timing, length and intensity). Female hospital employees (160 day workers and 168 rotating shift workers) from southeastern Ontario, Canada, participated in a cross-sectional study. Participants completed a baseline questionnaire and measures of body height, weight, and waist circumference were taken. Midstream urine samples were collected over two separate 24-hour periods to measure creatinine-adjusted cortisol. Total diurnal cortisol production and pattern were described with two measures of the area under the curve. The effect of shift work on cortisol was modeled using multivariable linear regression analyses. Cortisol production in day workers and shift workers on their day shift were similar; however, shift workers on the night shift had flatter diurnal cortisol curves and produced less cortisol. This suggests that night work is associated with an acute attenuation of cortisol production.
Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that ...MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants.
We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia.
We identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p < 0.05. TWAS further identified two novel genes (SHOX2 and CRISPLD2) whose genetically predicted expression was significantly associated with MD phenotypes.
Our findings provided novel insight into the genetic background of MD phenotypes, and further demonstrated their shared genetic basis with breast cancer.
OBJECTIVE:To evaluate the association between exposure to chlorinated solvents and cancer.
METHODS:We conducted a case–control study of occupational exposures and cancer in Montreal, Quebec, Canada, ...including 3730 cancer cases and 533 population controls. Occupational exposures were derived using a combination of subject-reported job history and expert assessment. We examined the associations between two chemical families and six chlorinated solvents with 11 sites of cancer.
RESULTS:The majority of the associations examined were null, although many were based on small numbers. We found two significantly elevated odds ratios (ORs), one between perchloroethylene and prostate cancer (OR = 4.3; 95% CI1.4 to 13) and another between trichloroethylene and melanoma (OR = 3.2; 95% CI1.0 to 9.9).
CONCLUSIONS:There was little evidence of associations between chlorinated solvents and cancer. Limited power precludes strong inferences about absence of risk. We raise hypotheses about two possible associationsperchloroethylene with prostate cancer and trichloroethylene with melanoma.
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.
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.
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
gene and age at first full-term pregnancy (P
=4.44×10
).
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.
Our study suggests a limited role of gene-environment interactions in breast cancer risk.
Abstract
Over one million biopsies are performed annually in the U.S. to evaluate suspicious breast lesions. Most biopsies lead to a diagnosis of benign breast disease (BBD) and these women have a ...1.5- to fourfold increase in subsequent breast cancer (BC) risk compared with the general population. A polygenic risk score (PRS) including 313 common variants was developed to predict BC risk in the general population and has improved performance when added to existing BC prediction models. However, the value of PRS in risk prediction models among women with BBD has not been evaluated.
To evaluate the role of the established PRS, BBD, and BC risk, we pooled data from 15,194 white women (6,706 BC cases and 8,488 controls) participating in five Breast Cancer Association Consortium case-control studies. BC risk associations were evaluated by self-reported BBD history and combinations of PRS expressed in tertiles using odds ratios (OR), considering the lowest category of PRS among women without BBD as the referent. Associations were also assessed in an independent case-cohort study (831 BC cases and 1,845 controls) using hazard ratios (HR).
Among the case-control studies, the PRS was strongly associated with BC risk (OR=2.50 per standard deviation increase), and associations were similar in women with (OR=2.60) and without a history of BBD (OR=2.44, p-interaction=0.23). Women with BBD have a higher risk of BC than those without BBD within each level of PRS. Compared to women without BBD and in the lowest PRS category, those with BBD and PRS in the highest tertile had 5-fold increased odds of BC (OR = 5.38; 95% CI 4.73-6.13). Associations were similar in an independent case-cohort study.
These findings indicate that BBD history and PRS are independent contributors to BC risk, and consideration of both simultaneously could improve breast cancer risk prediction. Future studies are needed to integrate PRS with other risk measures to refine absolute BC risk prediction among BBD patients.
Associations of BC risk with combinations of PRS (tertiles) and history of BBD in five case-control studies and a case-cohort study from the Breast Cancer Association Consortium. Case-control studies Case-cohort study PRS score range History of BBD n BC cases n controls OR (95% CI)1 n BC cases n controls HR (95% CI)2 Tertile 1 (≤ -0.57) No 1009 2692 1.00 (Ref) 117 584 1.00 (Ref) Yes 508 902 1.54 (1.35-1.76) 69 163 2.05 (1.45-2.89) Tertile 2 (-0.58, -0.03) No 1469 2001 1.97 (1.78-2.17) 181 475 1.93 (1.48-2.51) Yes 760 798 2.65 (2.34-3.01) 108 170 2.99 (2.18-4.09) Tertile 3 (≥ -0.02) No 1910 1551 3.32 (3.01-3.67) 214 336 3.28 (2.52-4.26) Yes 1050 544 5.38 (4.73-6.13) 142 117 4.83 4.25-8.02) 1.Logistic regression analysis, adjusted for study site/genomic platform and age at enrollment. OR, odds ratio; CI, confidence interval.2.Cox proportional hazards regression analysis, accounting for the case-cohort study design and adjusted for age at enrollment. HR, hazard ratio; CI, confidence interval.
Citation Format: Stacey J. Winham, Mark Sherman, Robert Vierkant, Bryan McCauley, Christopher Scott, Mia Gaudet, Melissa Troester, Sandhya Pruthi, Derek Radisky, Amy Degnim, Kristan Aronson, Rachel Murphy, Pascal Guenel, Therese Truong, Jenny Chang-Claude, Heiko Becher, Montserrat Garcia-Closas, Stephen Chanock, Thomas Ahearn, Xiaohong Yang, Doug Easton, Manjeet Bolla, Celine Vachon, Breast Cancer Association Consortium. Association of polygenic risk scores with breast cancer risk among women with benign breast disease. abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5241.
This study investigated the efficacy of a POU water treatment system featuring sari-cloth filtration and/or Moringa oleifera coagulation as pre-treatments for solar disinfection (SODIS). Surface ...water from a peri-urban slum in Chennai, India, was treated and analysed for turbidity, organic content via chemical oxygen demand (COD) and microbiological quality via most probable number (MPN) enumeration of total coliforms. Pre-treatment with both moringa coagulation and sari-cloth filtration significantly improved the turbidity of raw water compared to no pre-treatment controls (P = 0.0002). Optimal moringa coagulation did not outperform sari-cloth filtration (P = 0.06), but combining optimal moringa coagulation with sari-cloth filtration significantly outperformed either pre-treatment independently with respect to turbidity (P = 0.016 and P = 0.0001, respectively). The addition of moringa was found to increase COD in treated water, with greater doses of moringa resulting in higher COD levels (P = 0.04). Increased organics may have encouraged the re-growth of coliform bacteria that was observed in those jars receiving moringa coagulant such that, with respect to MPN, those jars which were subject to optimal moringa coagulation did not outperform those undergoing sari-cloth filtration alone (P = 0.41). Sari-cloth filtration is recommended as a pre-treatment for SODIS whereas moringa is not, as further investigation on the relationship between organics and bacterial re-growth is necessary.
PDF
