Publications by authors named "Mary B Daly"

208 Publications

The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant.

Genet Med 2021 Jun 10. Epub 2021 Jun 10.

Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.

Purpose: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.

Methods: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS and CBC risk.

Results: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively.

Conclusion: The PRS can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.
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http://dx.doi.org/10.1038/s41436-021-01198-7DOI Listing
June 2021

Mothers' Diet and Family Income Predict Daughters' Healthy Eating.

Prev Chronic Dis 2021 Mar 18;18:E24. Epub 2021 Mar 18.

College of Social Work, University of Utah, Salt Lake City, Utah.

Introduction: Understanding the degree to which parents may influence healthy behaviors may provide opportunities to intervene among populations at increased risk of diseases, such as breast cancer. In this study, we examined the association between daughters' healthy eating habits and family lifestyle behaviors among girls and their families by using baseline data from the LEGACY (Lessons in Epidemiology and Genetics of Adult Cancer from Youth) Girls Study. Our objective was to examine the relationship between daughters' healthy eating and family lifestyle behaviors and to compare these associations between families with and without a history of breast cancer.

Methods: We examined demographic and lifestyle data from a cohort of 1,040 girls aged 6 to 13 years from year 1 (2011) of the LEGACY study. Half had a family history of breast cancer (BCFH). We used mixed-effects linear regression to assess the influence of the mother and father's physical activity, family relationship scores, the mother's diet, the family's income, and the daughter's sports participation, age, body mass index (BMI), and race/ethnicity on the daughter's Healthy Eating Index (HEI) score.

Results: Daughters' healthy eating was significantly correlated with the mother's diet (r[668] = 0.25, P = .003) and physical activity (r[970] = 0.12, P = .002), the father's physical activity (r[970] = 0.08, P = .01), and the family income (r[854] = 0.13, P = .006). Additionally, the mother's diet (β coefficient = 0.71, 95% CI, 0.46-0.88, P = .005) and family income (β coefficient = 3.28, 95% CI, 0.79-5.78, P = .002) significantly predicted a daughter's healthy eating. Analyses separated by family history status revealed differences in these associations. In families without a history of breast cancer, only the mother's diet (β coefficient = 0.62; 95% CI, 0.29-0.95; P = .001) significantly predicted the daughter's healthy eating. In families with a history of breast cancer, the mother's diet (β coefficient = 0.73, 95% CI, 0.42-1.03, P = .006) and family income (β coefficient = 6.24; 95% CI, 2.68-9.80; P = .004) significantly predicted a daughter's healthy eating.

Conclusion: A mother's diet and family income are related to the daughter's healthy eating habits, although differences exist among families by family history of breast cancer.
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http://dx.doi.org/10.5888/pcd18.200445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986974PMC
March 2021

Association of Risk-Reducing Salpingo-Oophorectomy With Breast Cancer Risk in Women With BRCA1 and BRCA2 Pathogenic Variants.

JAMA Oncol 2021 Apr;7(4):585-592

Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.

Importance: Women with pathogenic variants in BRCA1 and BRCA2 are at high risk of developing breast and ovarian cancers. They usually undergo intensive cancer surveillance and may also consider surgical interventions, such as risk-reducing mastectomy or risk-reducing salpingo-oophorectomy (RRSO). Risk-reducing salpingo-oophorectomy has been shown to reduce ovarian cancer risk, but its association with breast cancer risk is less clear.

Objective: To assess the association of RRSO with the risk of breast cancer in women with BRCA1 and BRCA2 pathogenic variants.

Design, Setting, And Participants: This case series included families enrolled in the Breast Cancer Family Registry between 1996 and 2000 that carried an inherited pathogenic variant in BRCA1 (498 families) or BRCA2 (378 families). A survival analysis approach was used that was designed specifically to assess the time-varying association of RRSO with breast cancer risk and accounting for other potential biases. Data were analyzed from August 2019 to November 2020.

Exposure: Risk-reducing salpingo-oophorectomy.

Main Outcomes And Measures: In all analyses, the primary end point was the time to a first primary breast cancer.

Results: A total of 876 families were evaluated, including 498 with BRCA1 (2650 individuals; mean [SD] event age, 55.8 [19.1] years; 437 White probands [87.8%]) and 378 with BRCA2 (1925 individuals; mean [SD] event age, 57.0 [18.6] years; 299 White probands [79.1%]). Risk-reducing salpingo-oophorectomy was associated with a reduced risk of breast cancer for BRCA1 and BRCA2 pathogenic variant carriers within 5 years after surgery (hazard ratios [HRs], 0.28 [95% CI, 0.10-0.63] and 0.19 [95% CI, 0.06-0.71], respectively), whereas the corresponding HRs were weaker after 5 years postsurgery (HRs, 0.64 [95% CI, 0.38-0.97] and 0.99 [95% CI; 0.84-1.00], respectively). For BRCA1 and BRCA2 pathogenic variant carriers who underwent RRSO at age 40 years, the cause-specific cumulative risk of breast cancer was 49.7% (95% CI, 40.0-60.3) and 52.7% (95% CI, 47.9-58.7) by age 70 years, respectively, compared with 61.0% (95% CI, 56.7-66.0) and 54.0% (95% CI, 49.3-60.1), respectively, for women without RRSO.

Conclusions And Relevance: Although the primary indication for RRSO is the prevention of ovarian cancer, it is also critical to assess its association with breast cancer risk in order to guide clinical decision-making about RRSO use and timing. The results of this case series suggest a reduced risk of breast cancer associated with RRSO in the immediate 5 years after surgery in women carrying BRCA1 and BRCA2 pathogenic variants, and a longer-term association with cumulative breast cancer risk in women carrying BRCA1 pathogenic variants.
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http://dx.doi.org/10.1001/jamaoncol.2020.7995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907985PMC
April 2021

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Nat Commun 2021 02 17;12(1):1078. Epub 2021 Feb 17.

Copenhagen General Population Study, Herlev and Gentofte Hospital Copenhagen University Hospital, Herlev, Denmark.

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
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http://dx.doi.org/10.1038/s41467-020-20496-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890067PMC
February 2021

Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2021 01 6;19(1):77-102. Epub 2021 Jan 6.

The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.
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http://dx.doi.org/10.6004/jnccn.2021.0001DOI Listing
January 2021

Efficacy of a multimedia intervention in facilitating breast cancer patients' clinical communication about sexual health: Results of a randomized controlled trial.

Psychooncology 2021 May 23;30(5):681-690. Epub 2020 Dec 23.

Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

Objective: Many women with breast cancer (BC) hesitate to raise sexual concerns clinically. We evaluated a multimedia intervention to facilitate BC patients' communication about sexual/menopausal health, called Starting the Conversation (STC).

Methods: Female BC patients (N = 144) were randomly assigned to either STC (20-min video, workbook, and resource guide) or control (resource guide only). Audio-recorded dialogue from patients' next oncology clinic encounter was coded for patients' sexual health communication. Self-report surveys assessed patients' beliefs about sexual health communication, self-efficacy for clinical interactions, sexual function/activity, anxiety/depression symptoms, and quality of life at baseline, post-intervention, and 2-month follow-up. T-tests or mixed-effects logistic regression compared study arms.

Results: Women in the STC arm were more likely to raise the topic of sexual health (51%; OR = 2.62 [1.02, 6.69], p = 0.04) and ask a sexual health question (40%; OR = 2.85 [1.27, 6.38], p = 0.01) during their clinic encounter than those in the control arm (30% and 19% for raise and ask, respectively). At follow-up, women in the STC arm showed greater improvements in sexual health communication self-efficacy (p = 0.009) and in anxiety symptoms (p = 0.03), and more women were sexually active at follow-up, compared to the control arm (OR = 1.5, 70% vs. 46%, p = 0.04).

Conclusions: The STC intervention facilitated women's clinical communication about sexual health and reduced women's anxiety, possibly due to increased confidence in expressing their medical needs. Helpful information gained from clinical discussions could have improved women's willingness or ability to engage in sexual activity. Future studies should identify aspects of the clinical encounter most critical to improving women's sexual outcomes.
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http://dx.doi.org/10.1002/pon.5613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113064PMC
May 2021

Comparing 5-Year and Lifetime Risks of Breast Cancer using the Prospective Family Study Cohort.

J Natl Cancer Inst 2021 Jun;113(6):785-791

Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.

Background: Clinical guidelines often use predicted lifetime risk from birth to define criteria for making decisions regarding breast cancer screening rather than thresholds based on absolute 5-year risk from current age.

Methods: We used the Prospective Family Cohort Study of 14 657 women without breast cancer at baseline in which, during a median follow-up of 10 years, 482 women were diagnosed with invasive breast cancer. We examined the performances of the International Breast Cancer Intervention Study (IBIS) and Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk models when using the alternative thresholds by comparing predictions based on 5-year risk with those based on lifetime risk from birth and remaining lifetime risk. All statistical tests were 2-sided.

Results: Using IBIS, the areas under the receiver-operating characteristic curves were 0.66 (95% confidence interval = 0.63 to 0.68) and 0.56 (95% confidence interval = 0.54 to 0.59) for 5-year and lifetime risks, respectively (Pdiff < .001). For equivalent sensitivities, the 5-year incidence almost always had higher specificities than lifetime risk from birth. For women aged 20-39 years, 5-year risk performed better than lifetime risk from birth. For women aged 40 years or older, receiver-operating characteristic curves were similar for 5-year and lifetime IBIS risk from birth. Classifications based on remaining lifetime risk were inferior to 5-year risk estimates. Results were similar using BOADICEA.

Conclusions: Our analysis shows that risk stratification using clinical models will likely be more accurate when based on predicted 5-year risk compared with risks based on predicted lifetime and remaining lifetime, particularly for women aged 20-39 years.
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http://dx.doi.org/10.1093/jnci/djaa178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168075PMC
June 2021

Common Childhood Viruses and Pubertal Timing: The LEGACY Girls Study.

Am J Epidemiol 2021 05;190(5):766-778

Earlier pubertal development is only partially explained by childhood body mass index; the role of other factors, such as childhood infections, is less understood. Using data from the LEGACY Girls Study (North America, 2011-2016), we prospectively examined the associations between childhood viral infections (cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV) 1, HSV2) and pubertal timing. We measured exposures based on seropositivity in premenarcheal girls (n = 490). Breast and pubic hair development were classified based on mother-reported Tanner Stage (TS) (TS2+ compared with TS1), adjusting for age, body mass index, and sociodemographic factors. The average age at first blood draw was 9.8 years (standard deviation, 1.9 years). The prevalences were 31% CMV+, 37% EBV+, 14% HSV1+, 0.4% HSV2+, and 16% for both CMV+/EBV+ coinfection. CMV+ infection without coinfection was associated with developing breasts an average of 7 months earlier (hazard ratio (HR) = 2.12, 95% confidence interval (CI): 1.32, 3.40). CMV infection without coinfection and HSV1 and/or HSV2 infection were associated with developing pubic hair 9 months later (HR = 0.41, 95% CI: 0.24, 0.71, and HR = 0.42, 95% CI: 0.22, 0.81, respectively). Infection was not associated with menarche. If replicated in larger cohorts with blood collection prior to any breast development, this study supports the hypothesis that childhood infections might play a role in altering pubertal timing.
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http://dx.doi.org/10.1093/aje/kwaa240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096486PMC
May 2021

Prepubertal Internalizing Symptoms and Timing of Puberty Onset in Girls.

Am J Epidemiol 2021 02;190(3):431-438

Stressful environments have been associated with earlier menarche. We hypothesized that anxiety, and possibly other internalizing symptoms, are also associated with earlier puberty in girls. The Lessons in Epidemiology and Genetics of Adult Cancer From Youth (LEGACY) Girls Study (2011-2016) included 1,040 girls aged 6-13 years at recruitment whose growth and development were assessed every 6 months. Prepubertal maternal reports of daughter's internalizing symptoms were available for breast onset (n = 447), pubic hair onset (n = 456), and menarche (n = 681). Using Cox proportional hazard regression, we estimated prospective hazard ratios and 95% confidence intervals for the relationship between 1 standard deviation of the percentiles of prepubertal anxiety, depression, and somatization symptoms and the timing of each pubertal outcome. Multivariable models included age, race/ethnicity, study center, maternal education, body mass index percentile, and family history of breast cancer. Additional models included maternal self-reported anxiety. A 1-standard deviation increase in maternally reported anxiety in girls at baseline was associated with earlier subsequent onset of breast (hazard ratio (HR) = 1.22, 95% confidence interval (CI): 1.09, 1.36) and pubic hair (HR = 1.15, 95% CI: 1.01, 1.30) development, but not menarche (HR = 0.94, 95% CI: 0.83, 1.07). The association of anxiety with earlier breast development persisted after adjustment for maternal anxiety. Increased anxiety in young girls may indicate risk for earlier pubertal onset.
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http://dx.doi.org/10.1093/aje/kwaa223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086416PMC
February 2021

Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk.

Am J Hum Genet 2020 11 5;107(5):837-848. Epub 2020 Oct 5.

Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong; Hong Kong Sanatorium and Hospital, Department of Pathology, Happy Valley, Hong Kong.

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS was quantified using Cox regression analyses. We assessed PRS interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10 percentile and 20.5% at the 90 percentile of PRS. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.
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http://dx.doi.org/10.1016/j.ajhg.2020.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675034PMC
November 2020

Prevalence of pathogenic variants in DNA damage response and repair genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer.

Sci Rep 2020 08 11;10(1):13518. Epub 2020 Aug 11.

Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA.

Pathogenic variants (PVs) in multiple genes are known to increase the risk of early-onset renal cancer (eoRC). However, many eoRC patients lack PVs in RC-specific genes; thus, their genetic risk remains undefined. Here, we determine if PVs in DNA damage response and repair (DDRR) genes are enriched in eoRC patients undergoing cancer risk assessment. Retrospective review of de-identified results from 844 eoRC patients, undergoing testing with a multi-gene panel, for a variety of indications, by Ambry Genetics. PVs in cancer-risk genes were identified in 12.8% of patients-with 3.7% in RC-specific, and 8.55% in DDRR genes. DDRR gene PVs were most commonly identified in CHEK2, BRCA1, BRCA2, and ATM. Among the 2.1% of patients with a BRCA1 or BRCA2 PV, < 50% reported a personal history of hereditary breast or ovarian-associated cancer. No association between age of RC diagnosis and prevalence of PVs in RC-specific or DDRR genes was observed. Additionally, 57.9% patients reported at least one additional cancer; breast cancer being the most common (40.1% of females, 2.5% of males). Multi-gene testing including DDRR genes may provide a more comprehensive risk assessment in eoRC patients. Further validation is needed to characterize the association with eoRC.
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http://dx.doi.org/10.1038/s41598-020-70449-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419503PMC
August 2020

Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants.

Genet Med 2020 10 15;22(10):1653-1666. Epub 2020 Jul 15.

Royal Devon & Exeter Hospital, Department of Clinical Genetics, Exeter, UK.

Purpose: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers.

Methods: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort.

Results: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10) carriers. The associations in the prospective cohort were similar.

Conclusion: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.
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http://dx.doi.org/10.1038/s41436-020-0862-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521995PMC
October 2020

Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk.

Sci Rep 2020 06 16;10(1):9688. Epub 2020 Jun 16.

Department of Gynecology and Obstetrics, University of Tübingen, Tübingen, Germany.

In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.
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http://dx.doi.org/10.1038/s41598-020-65665-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297796PMC
June 2020

Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019.

J Clin Oncol 2020 08 9;38(24):2798-2811. Epub 2020 Jun 9.

Advocate Aurora Health, Milwaukee, WI.

Purpose: Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services.

Methods: A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider).

Results: Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing-initial testing of priority genes followed by expanded testing-was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included and mismatch repair genes, with broader testing, such as , for clinical trial eligibility. was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for carriers, with consideration in , and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches.

Conclusion: This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.
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http://dx.doi.org/10.1200/JCO.20.00046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430215PMC
August 2020

Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

Nat Genet 2020 06 18;52(6):572-581. Epub 2020 May 18.

Molecular Medicine Unit, Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
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http://dx.doi.org/10.1038/s41588-020-0609-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808397PMC
June 2020

Longitudinal follow-up after telephone disclosure in the randomized COGENT study.

Genet Med 2020 08 7;22(8):1401-1406. Epub 2020 May 7.

Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA, USA.

Purpose: To better understand the longitudinal risks and benefits of telephone disclosure of genetic test results in the era of multigene panel testing.

Methods: Adults who were proceeding with germline cancer genetic testing were randomized to telephone disclosure (TD) with a genetic counselor or in-person disclosure (IPD) (i.e., usual care) of test results. All participants who received TD were recommended to return to meet with a physician to discuss medical management recommendations.

Results: Four hundred seventy-three participants were randomized to TD and 497 to IPD. There were no differences between arms for any cognitive, affective, or behavioral outcomes at 6 and 12 months. Only 50% of participants in the TD arm returned for the medical follow-up appointment. Returning was associated with site (p < 0.0001), being female (p = 0.047), and not having a true negative result (p < 0.002). Mammography was lower at 12 months among those who had TD and did not return for medical follow-up (70%) compared with those who had TD and returned (86%) and those who had IPD (87%, adjusted p < 0.01).

Conclusion: Telephone disclosure of genetic test results is a reasonable alternative to in-person disclosure, but attention to medical follow-up may remain important for optimizing appropriate use of genetic results.
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http://dx.doi.org/10.1038/s41436-020-0808-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396300PMC
August 2020

NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 1.2020.

J Natl Compr Canc Netw 2020 04;18(4):380-391

Mayo Clinic Cancer Center.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic provide recommendations for genetic testing and counseling for hereditary cancer syndromes, and risk management recommendations for patients who are diagnosed with syndromes associated with an increased risk of these cancers. The NCCN panel meets at least annually to review comments, examine relevant new data, and reevaluate and update recommendations. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding criteria for high-penetrance genes associated with breast and ovarian cancer beyond BRCA1/2, pancreas screening and genes associated with pancreatic cancer, genetic testing for the purpose of systemic therapy decision-making, and testing for people with Ashkenazi Jewish ancestry.
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http://dx.doi.org/10.6004/jnccn.2020.0017DOI Listing
April 2020

Navigating the Intersection between Genomic Research and Clinical Practice.

Authors:
Mary B Daly

Cancer Prev Res (Phila) 2020 03;13(3):219-222

Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

The Risk Assessment Program (RAP) at Fox Chase Cancer Center (Philadelphia, PA) is a multi-generational prospective cohort, enhanced for personal and family history of cancer, consisting of over 10,000 individuals for whom data on personal and family history of cancer, risk factors, genetic and genomic data, health behaviors, and biospecimens are available. The RAP has a broad research agenda including the characterization of genes with known or potential relevance to cancer, gene-gene and gene-environment interactions, and their contribution to clinically useful risk assessment and risk reduction strategies. Increasingly, this body of research is identifying genetic changes which may have clinical significance for RAP research participants, leading us to confront the issue of whether to return genetic results emerging from research laboratories. This review will describe some of the important fundamental points that must be debated as we develop a paradigm for return of research results. The key issues to address as the scientific community moves toward adopting a policy of return of research results include the best criteria for determining which results to offer, the consent document components necessary to ensure that the participant makes a truly informed decision about receiving their results, and associated logistical and cost challenges..
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http://dx.doi.org/10.1158/1940-6207.CAPR-19-0267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080295PMC
March 2020

Transcriptome-wide association study of breast cancer risk by estrogen-receptor status.

Genet Epidemiol 2020 07 1;44(5):442-468. Epub 2020 Mar 1.

Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.
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http://dx.doi.org/10.1002/gepi.22288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987299PMC
July 2020

Evaluating a couple-based intervention addressing sexual concerns for breast cancer survivors: study protocol for a randomized controlled trial.

Trials 2020 Feb 12;21(1):173. Epub 2020 Feb 12.

Department of Psychiatry & Behavioral Sciences, Duke University Medical Center, DUMC 90399, Durham, NC, 27708, USA.

Background: Sexual concerns are distressing for breast cancer survivors and interfere with their intimate relationships. This study evaluates the efficacy of a four-session couple-based intervention delivered via telephone, called Intimacy Enhancement (IE). The IE intervention is grounded in social cognitive theory and integrates evidence-based techniques from cognitive behavioral couple therapy and sex therapy to address survivors' sexual concerns and enhance their and their partners' sexual, relationship, and psychological outcomes.

Methods: This trial is designed to evaluate the efficacy of the IE intervention in improving survivors' sexual function, the primary study outcome. Secondary outcomes include survivors' sexual distress, partners' sexual function, and survivors' and partners' relationship intimacy and quality as well as psychological distress (depressive symptoms and anxiety symptoms). Additional aims are to examine whether treatment effects on patient sexual function are mediated by sexual communication and self-efficacy for coping with sexual concerns and to explore whether survivor age and race/ethnicity moderate intervention effects on survivors' sexual function. Eligible adult female breast cancer survivors reporting sexual concerns and their intimate partners are recruited from two academic sites in the USA and are randomized to either the IE intervention or to a control condition of equal length offering education and support around breast cancer-related health topics (Living Healthy Together). The target sample size is 120 couples. Self-report outcome measures are administered to participants in both conditions at baseline (T1), post-treatment (T2), 3 months post-treatment (T3), and 6 months post-treatment (T4).

Discussion: Evidence-based interventions are needed to address sexual concerns for breast cancer survivors and to enhance their and their intimate partners' sexual, relationship, and psychological well-being. This randomized controlled trial will allow us to examine the efficacy of a novel couple-based intervention delivered via telephone for breast cancer survivors experiencing sexual concerns and their intimate partners, in comparison with an attention control. Findings of this study could influence clinical care for women with breast cancer and inform theory guiding cancer-related sexual rehabilitation.

Trial Registration: ClinicalTrials.gov, NCT03930797. Registered on 24 April 2019.
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http://dx.doi.org/10.1186/s13063-019-3975-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014745PMC
February 2020

A network analysis to identify mediators of germline-driven differences in breast cancer prognosis.

Nat Commun 2020 01 16;11(1):312. Epub 2020 Jan 16.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.
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http://dx.doi.org/10.1038/s41467-019-14100-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965101PMC
January 2020

Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers.

Breast Cancer Res 2020 01 16;22(1). Epub 2020 Jan 16.

Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.

Background: The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective effect but may be substantially biased. Prospective studies have had limited power, particularly for BRCA2 mutation carriers. Further, previous studies have not considered the effect of RRSO in the context of natural menopause.

Methods: A multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers was followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women.

Results: There was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94-1.61) or BRCA2 (HR = 0.88; 95% CI 0.62-1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40-1.15) and 1.07 (95% CI 0.69-1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26-0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar.

Conclusion: We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO.
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http://dx.doi.org/10.1186/s13058-020-1247-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966793PMC
January 2020

Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.

Nat Genet 2020 01 7;52(1):56-73. Epub 2020 Jan 7.

Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.
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http://dx.doi.org/10.1038/s41588-019-0537-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974400PMC
January 2020

Accuracy of Risk Estimates from the iPrevent Breast Cancer Risk Assessment and Management Tool.

JNCI Cancer Spectr 2019 Dec 19;3(4):pkz066. Epub 2019 Sep 19.

See the Notes section for the full list of authors' affiliations.

Background: iPrevent is an online breast cancer (BC) risk management decision support tool. It uses an internal switching algorithm, based on a woman's risk factor data, to estimate her absolute BC risk using either the International Breast Cancer Intervention Study (IBIS) version 7.02, or Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm version 3 models, and then provides tailored risk management information. This study assessed the accuracy of the 10-year risk estimates using prospective data.

Methods: iPrevent-assigned 10-year invasive BC risk was calculated for 15 732 women aged 20-70 years and without BC at recruitment to the Prospective Family Study Cohort. Calibration, the ratio of the expected (E) number of BCs to the observed (O) number and discriminatory accuracy were assessed.

Results: During the 10 years of follow-up, 619 women (3.9%) developed BC compared with 702 expected (E/O = 1.13; 95% confidence interval [CI] =1.05 to 1.23). For women younger than 50 years, 50 years and older, and -mutation carriers and noncarriers, E/O was 1.04 (95% CI = 0.93 to 1.16), 1.24 (95% CI = 1.11 to 1.39), 1.13 (95% CI = 0.96 to 1.34), and 1.13 (95% CI = 1.04 to 1.24), respectively. The C-statistic was 0.70 (95% CI = 0.68 to 0.73) overall and 0.74 (95% CI = 0.71 to 0.77), 0.63 (95% CI = 0.59 to 0.66), 0.59 (95% CI = 0.53 to 0.64), and 0.65 (95% CI = 0.63 to 0.68), respectively, for the subgroups above. Applying the newer IBIS version 8.0b in the iPrevent switching algorithm improved calibration overall (E/O = 1.06, 95% CI = 0.98 to 1.15) and in all subgroups, without changing discriminatory accuracy.

Conclusions: For 10-year BC risk, iPrevent had good discriminatory accuracy overall and was well calibrated for women aged younger than 50 years. Calibration may be improved in the future by incorporating IBIS version 8.0b.
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http://dx.doi.org/10.1093/jncics/pkz066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901082PMC
December 2019

Alcohol Consumption, Cigarette Smoking, and Risk of Breast Cancer for and Mutation Carriers: Results from The BRCA1 and BRCA2 Cohort Consortium.

Cancer Epidemiol Biomarkers Prev 2020 02 2;29(2):368-378. Epub 2019 Dec 2.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.

Background: Tobacco smoking and alcohol consumption have been intensively studied in the general population to assess their effects on the risk of breast cancer, but very few studies have examined these effects in and mutation carriers. Given the high breast cancer risk for mutation carriers and the importance of and in DNA repair, better evidence on the associations of these lifestyle factors with breast cancer risk is essential.

Methods: Using a large international pooled cohort of and mutation carriers, we conducted retrospective (5,707 mutation carriers and 3,525 mutation carriers) and prospective (2,276 mutation carriers and 1,610 mutation carriers) analyses of alcohol and tobacco consumption using Cox proportional hazards models.

Results: For both and mutation carriers, none of the smoking-related variables was associated with breast cancer risk, except smoking for more than 5 years before a first full-term pregnancy (FFTP) when compared with parous women who never smoked. For mutation carriers, the HR from retrospective analysis (HR) was 1.19 [95% confidence interval (CI), 1.02-1.39] and the HR from prospective analysis (HR) was 1.36 (95% CI, 0.99-1.87). For mutation carriers, smoking for more than 5 years before an FFTP showed an association of a similar magnitude, but the confidence limits were wider (HR = 1.25; 95% CI, 1.01-1.55 and HR = 1.30; 95% CI, 0.83-2.01). For both carrier groups, alcohol consumption was not associated with breast cancer risk.

Conclusions: The finding that smoking during the prereproductive years increases breast cancer risk for mutation carriers warrants further investigation.

Impact: This is the largest prospective study of mutation carriers to assess these important risk factors.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0546DOI Listing
February 2020

Alcohol consumption, cigarette smoking, and familial breast cancer risk: findings from the Prospective Family Study Cohort (ProF-SC).

Breast Cancer Res 2019 11 28;21(1):128. Epub 2019 Nov 28.

Department of Epidemiology, Mailman School of Public Health, Columbia University, 722 W. 168th Street, Room 1611, New York, NY, 10032, USA.

Background: Alcohol consumption and cigarette smoking are associated with an increased risk of breast cancer (BC), but it is unclear whether these associations vary by a woman's familial BC risk.

Methods: Using the Prospective Family Study Cohort, we evaluated associations between alcohol consumption, cigarette smoking, and BC risk. We used multivariable Cox proportional hazard models to estimate hazard ratios (HR) and 95% confidence intervals (CI). We examined whether associations were modified by familial risk profile (FRP), defined as the 1-year incidence of BC predicted by Breast Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), a pedigree-based algorithm.

Results: We observed 1009 incident BC cases in 17,435 women during a median follow-up of 10.4 years. We found no overall association of smoking or alcohol consumption with BC risk (current smokers compared with never smokers HR 1.02, 95% CI 0.85-1.23; consuming ≥ 7 drinks/week compared with non-regular drinkers HR 1.10, 95% CI 0.92-1.32), but we did observe differences in associations based on FRP and by estrogen receptor (ER) status. Women with lower FRP had an increased risk of ER-positive BC associated with consuming ≥ 7 drinks/week (compared to non-regular drinkers), whereas there was no association for women with higher FRP. For example, women at the 10th percentile of FRP (5-year BOADICEA = 0.15%) had an estimated HR of 1.46 (95% CI 1.07-1.99), whereas there was no association for women at the 90th percentile (5-year BOADICEA = 4.2%) (HR 1.07, 95% CI 0.80-1.44). While the associations with smoking were not modified by FRP, we observed a positive multiplicative interaction by FRP (p = 0.01) for smoking status in women who also consumed alcohol, but not in women who were non-regular drinkers.

Conclusions: Moderate alcohol intake was associated with increased BC risk, particularly for women with ER-positive BC, but only for those at lower predicted familial BC risk (5-year BOADICEA < 1.25). For women with a high FRP (5-year BOADICEA ≥ 6.5%) who also consumed alcohol, being a current smoker was associated with increased BC risk.
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http://dx.doi.org/10.1186/s13058-019-1213-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883541PMC
November 2019

Association of Genomic Domains in and with Prostate Cancer Risk and Aggressiveness.

Cancer Res 2020 02 13;80(3):624-638. Epub 2019 Nov 13.

Unité de Prévention et d'Epidémiologie Génétique, Centre Léon Bérard, Lyon, France.

Pathogenic sequence variants (PSV) in or () are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 and 171 male PSV carriers with prostate cancer, and 3,388 and 2,880 male PSV carriers without prostate cancer. PSVs in the 3' region of (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; = 0.0002). No genotype-phenotype associations were detected for PSVs in . These results demonstrate that specific PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-1840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553241PMC
February 2020

The :p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

NPJ Breast Cancer 2019 1;5:38. Epub 2019 Nov 1.

25University of Texas MD Anderson Cancer Center, Department of Breast Medical Oncology, Houston, TX USA.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes , , , , and are associated with breast cancer risk. , which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants :p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of or . These three variants were also studied functionally by measuring survival and chromosome fragility in patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that :p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44,  = 0.034 and OR = 3.79;  = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for :p.Arg658* and found that also :p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96;  = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with :p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat -associated tumors.
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http://dx.doi.org/10.1038/s41523-019-0127-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825205PMC
November 2019