Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers. © 2013 Couch et al

State of the world’s plants and fungi 2020

Kew’s State of the World’s Plants and Fungi project provides assessments of our current knowledge of the diversity of plants and fungi on Earth, the global threats that they face, and the policies to safeguard them. Produced in conjunction with an international scientific symposium, Kew’s State of the World’s Plants and Fungi sets an important international standard from which we can annually track trends in the global status of plant and fungal diversity

Understanding the genetic complexity of puberty timing across the allele frequency spectrum

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease

The value of navigators in breast cancer management in a South African hospital

Background: Specialist breast cancer nurses (BCNs) have improved the psychological care and follow-up rates of breast cancer (BC) patients. This study sought to determine if breast cancer research workers (BCRWs) as de facto BCNs impacted patients' adherence to treatment by comparing groups with and without these patient navigators; hence assessing our need for BCNs. Methods: Two groups BC patients booked for primary chemotherapy compared. Study group 1 (SG1): no BCRWs/BCNs. Study group 2 (SG2): BCRWs involvement. Assessment of numbers completing primary chemotherapy, undergoing surgery post-neoadjuvant chemotherapy and BCRWs interventions. Results: SG1: n = 281, 25-89y, mean 52.7y, Stage 4: 35.6%, Stage 3: 64.4%. SG2: n = 154, 21-85y, mean 52.6y, Stage 4: 47.4%, Stage 3: 43.3%, Stage 2: 9%. Primary chemotherapy not completed SG1: 40.2% (113) versus SG2: 13.5% (21); p < 0.00001. SG1: 88% not completing were lost to follow-up. Excluding peri-chemotherapy deaths and discontinuation: SG1: 37.1% did not complete chemotherapy versus SG2: 2.6%, p < 0.00001. SG2: BCRWs: 107 interventions for 58 (37.7%) patients. Therapeutic breast surgery SG1: 103/181 (56.9%) versus SG2: 66/81 (81.5%); p < 0.0001. SG1: main reasons for not having surgery: lost to follow-up during (n = 58) or after (n = 9) chemotherapy. Follow-up SG2: 12-43 months, mortality: 52% (80/154), no lost to follow-ups. SG1: No mortality data. Conclusions: In our setting, BC patients often do not attend or complete treatments. In this study, BCRWs as de-facto BCNs were beneficial for BC patient care, improving chemotherapy compliance and therapeutic surgical interventions. This highlights the need for BCNs for the management of BC patients in South Africa