Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10−8) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER- negative loci combined account for ~11% of familial relative risk for ER- negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction

Fanconi Anemia Complementation Group D2 (FANCD2) Functions Independently of BRCA2- and RAD51-Associated Homologous Recombination in Response to DNA Damage

The BRCA2 breast cancer tumor suppressor is involved in the repair of double strand breaks and broken replication forks by homologous recombination through its interaction with DNA repair protein Rad51. Cells defective in BRCA2-FANCD1 are extremely sensitive to mitomycin C (MMC) similarly to cells deficient in any of the Fanconi anemia (FA) complementation group proteins (FANC). These observations suggest that the FA pathway and the BRCA2 and Rad51 repair pathway may be linked, although a functional connection between these pathways in DNA damage signaling remains to be determined. Here, we systematically investigated the interaction between these pathways. We show that in response to DNA damage, BRCA2-dependent Rad51 nuclear focus formation was normal in the absence of FANCD2 and that FANCD2 nuclear focus formation and mono-ubiquitination appeared normal in BRCA2-deficient cells. We report that the absence of BRCA2 substantially reduced homologous recombination repair of DNA breaks, whereas the absence of FANCD2 had little effect. Furthermore, we established that depletion of BRCA2 or Rad51 had a greater effect on cell survival in response to MMC than depletion of FANCD2 and that depletion of BRCA2 in FANCD2 mutant cells further sensitized these cells to MMC. Our results suggest that FANCD2 mediates double strand DNA break repair independently of Rad51-associated homologous recombination

Germline variation in ADAMTSL1 is associated with prognosis following breast cancer treatment in young women

To identify genetic variants associated with breast cancer prognosis we conduct a meta-analysis of overall survival (OS) and disease-free survival (DFS) in 6042 patients from four cohorts. In young women, breast cancer is characterized by a higher incidence of adverse pathological features, unique gene expression profiles and worse survival, which may relate to germline variation. To explore this hypothesis, we also perform survival analysis in 2315 patients agedPeer reviewe

Molecular markers of risk of subsequent invasive breast cancer in women with ductal carcinoma in situ: protocol for a population-based cohort study

INTRODUCTION: Ductal carcinoma in situ (DCIS) of the breast is a non-obligate precursor of invasive breast cancer (IBC). Many DCIS patients are either undertreated or overtreated. The overarching goal of the study described here is to facilitate detection of patients with DCIS at risk of IBC development. Here, we propose to use risk factor data and formalin-fixed paraffin-embedded (FFPE) DCIS tissue from a large, ethnically diverse, population-based cohort of 8175 women with a first diagnosis of DCIS and followed for subsequent IBC to: identify/validate miRNA expression changes in DCIS tissue associated with risk of subsequent IBC; evaluate ipsilateral IBC risk in association with two previously identified marker sets (triple immunopositivity for p16, COX-2, Ki67; Oncotype DX Breast DCIS score); examine the association of risk factor data with IBC risk. METHODS AND ANALYSIS: We are conducting a series of case-control studies nested within the cohort. Cases are women with DCIS who developed subsequent IBC; controls (2/case) are matched to cases on calendar year of and age at DCIS diagnosis. We project 485 cases/970 controls in the aim focused on risk factors. We estimate obtaining FFPE tissue for 320 cases/640 controls for the aim focused on miRNAs; of these, 173 cases/346 controls will be included in the aim focused on p16, COX-2 and Ki67 immunopositivity, and of the latter, 156 case-control pairs will be included in the aim focused on the Oncotype DX Breast DCIS score®. Multivariate conditional logistic regression will be used for statistical analyses. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Institutional Review Boards of Albert Einstein College of Medicine (IRB 2014-3611), Kaiser Permanente Colorado, Kaiser Permanente Hawaii, Henry Ford Health System, Mayo Clinic, Marshfield Clinic Research Institute and Hackensack Meridian Health, and from Lifespan Research Protection Office. The study results will be presented at meetings and published in peer-reviewed journals

Conflicting Interpretation of Genetic Variants and Cancer Risk by Commercial Laboratories as Assessed by the Prospective Registry of Multiplex Testing

Altres ajuts: Ambry Genetics, Myriad Genetics, Novartis (I), Pfizer (I)Massively parallel sequencing allows simultaneous testing of multiple genes associated with cancer susceptibility. Guidelines are available for variant classification; however, interpretation of these guidelines by laboratories and providers may differ and lead to conflicting reporting and, potentially, to inappropriate medical management. We describe conflicting variant interpretations between Clinical Laboratory Improvement Amendments-approved commercial clinical laboratories, as reported to the Prospective Registry of Multiplex Testing (PROMPT), an online genetic registry. Clinical data and genetic testing results were gathered from 1,191 individuals tested for inherited cancer susceptibility and self-enrolled in PROMPT between September 2014 and October 2015. Overall, 518 participants (603 genetic variants) had a result interpreted by more than one laboratory, including at least one submitted to ClinVar, and these were used as the final cohort for the current analysis. Of the 603 variants, 221 (37%) were classified as a variant of uncertain significance (VUS), 191 (32%) as pathogenic, and 34 (6%) as benign. The interpretation differed among reporting laboratories for 155 (26%). Conflicting interpretations were most frequently reported for CHEK2 and ATM, followed by RAD51C, PALB2, BARD1, NBN, and BRIP1. Among all participants, 56 of 518 (11%) had a variant with conflicting interpretations ranging from pathogenic/likely pathogenic to VUS, a discrepancy that may alter medical management. Conflicting interpretation of genetic findings from multiplex panel testing used in clinical practice is frequent and may have implications for medical management decisions

Novel patient-derived xenograft mouse model for pancreatic acinar cell carcinoma demonstrates single agent activity of oxaliplatin

Additional file 4: Figure S3. Integrated genomic viewer (IGV) of BRCA2 gene. IGV displays genomic data of the PA-018 PAAC PDTX model. Chromosome 13 (Chr 13) is shown and 5bp deletions are found after position 32907365 (c.1755_1759del5), this region resides on exon 10 of BRCA2. The bottom of the image shows the nucleotides and amino acids that correspond to the reference sequence of the BRCA2 gene and protein

Functional restoration of BRCA2 protein by secondary BRCA2 mutations in BRCA2-mutated ovarian carcinoma

Acquired platinum resistance is a serious problem in the treatment of ovarian carcinomas. However, the mechanism of the drug resistance has not been elucidated. Here, we show functional significance of restoration of BRCA2 protein by secondary BRCA2 mutations in acquired drug resistance of BRCA2-mutated ovarian carcinoma. Three ovarian cancer cell lines (PEO1, PEO4, and PEO6) were derived from a BRCA2 mutation [5193C>G (Y1655X)] carrier with ovarian carcinoma with acquired cisplatin resistance and a secondary BRCA2 mutation [5193C>T (Y1655Y)] that canceled the inherited mutation. PEO1 was BRCA2 deficient and sensitive to cisplatin and a poly(ADP-ribose) polymerase inhibitor, AG14361, whereas PEO4 was resistant. PEO4 and PEO6, derived from ascites at the time of relapse with cisplatin resistance, had the secondary mutation and were BRCA2 proficient. In vitro cisplatin/AG14361 selection of PEO1 led to restoration of BRCA2 due to another secondary BRCA2 mutation. BRCA2 depletion sensitized BRCA2-restored PEO1 clones and PEO4 to cisplatin/AG14361. Thus, restoration of BRCA2 due to secondary BRCA2 mutation is involved in acquired drug resistance of BRCA2-mutated ovarian carcinoma

Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer

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