IntroductionThe distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling.MethodsSelection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach.ResultsER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)).ConclusionsThese results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0474-y) contains supplementary material, which is available to authorized users.
Background Most familial pancreatic cancer (FPC) remains unexplained. The identification of individuals with a high genetic risk of developing pancreatic adenocarcinoma (PC) is important to elucidate its biological basis and is critical to better define emerging strategies for the detection of early pancreatic neoplasms. Patients and methods A series of 225 consecutively enrolled patients with PC were tested for CDKN2A mutations. After personal and family cancer histories of all the patients had been reviewed, a subset of the patients were classified as FPC and were also tested for mutations in PALLD, PALB2, BRCA1 and BRCA2 as FPC candidate genes. Results The CDKN2A mutation rate in the 225 PC cases was 5.7%. The CDKN2A founder mutations, p.E27X and p.G101W, were predominant, but the mutation spectrum also included p.L65P, p.G67R and two novel, potentially pathogenic variants, promoter variant c.-201ACTC>CTTT and p.R144C. None of the patients with FPC harboured germline mutations in PALLD, PALB2 or BRCA2. One family was positive for the BRCA1 UV variant p.P727L. Strikingly, five of 16 patients with FPC (31%) carried CDKN2A mutations. Conclusion These findings suggest that a sizeable subset of Italian FPC families may carry CDKN2A mutations. This result may be of value for identifying the best candidates for future PC screening trials in Italy.
In these recently postmenopausal women, mammographic percent density is directly associated with circulating estradiol levels. Our results provide further support to the role of circulating hormones in breast cancer risk.
Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03–1.16), p = 2.7×10−3) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03–1.21, p = 4.8×10−3). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.
Double heterozygosity (DH) for BRCA1 and BRCA2 mutations is a very rare finding, particularly in non-Ashkenazi individuals, and only a few cases have been reported to date. In addition, little is known on the pathological features of the tumors that occur in DH cases and on their family history of cancer. Four carriers of pathogenic mutations in both BRCA1 and BRCA2 were identified among women who underwent genetic counseling for hereditary susceptibility to breast and ovarian carcinoma at three different Italian institutions. Clinical, pathological, and family history data were collected from medical records and during genetic counseling sessions. All identified DH cases developed breast carcinoma and three of them were also diagnosed with ovarian carcinoma. Mean ages of breast and ovarian cancer diagnosis were 42.7 and 48.6 years, respectively. The majority of breast cancers showed a BRCA1-related phenotype, being negative for hormone receptors and HER2. Two cases reported different gastrointestinal tumors among relatives. Although the individuals described in this study show more severe clinical features in comparison to previously reported BRCA1 and BRCA2 DH cases, our observations support the hypothesis of a non specific phenotype of DH cases in terms of age of disease onset. In addition, our observations indicate that in DH patients breast carcinogenesis appears to be driven mainly by the mutations in BRCA1. The possible association of DH for BRCA gene mutations with gastrointestinal tumors is in keeping with previous reports, but needs to be confirmed by further analyses.
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