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Proffered papers and posters submitted to the Fifth International Symposium on Hereditary Breast and Ovarian Cancer, BRCA: Twenty Years of Advances

ABSTRACT: Objectives: It is estimated that 1%–2% of individuals of Ashkenazi Jewish (aj) ancestry carry one of three pathogenic founder mutations in BRCA1 and BRCA2. Targeted testing for these mutations (BRCA1 187delAG and 5385insC, and BRCA2 6174delT) is therefore recommended for all aj breast and ovarian cancer patients, regardless of age of diagnosis or family history. Comprehensive analysis of both genes is recommended for a subset of aj patients in whom founder mutations are not identified, but estimates of the yield from comprehensive analysis in this population vary widely. Methods: We sought to establish the proportion of non-founder mutations in aj patients undergoing clinical testing in our laboratory from January 2006 through August 2013. Analysis included aj patients for whom: 1) comprehensive testing was ordered as the initial test, or 2) founder mutation testing was ordered with instructions to “reflex” to comprehensive analysis if negative. The latter group was limited to cases where the reflex testing was ordered on the original test request form, and not cancelled for any reason other than the detection of a founder mutation. Results: The percentage of non-founder mutations detected in these groups was 13% (104/802) and 7.2% (198/2769) respectively. We detected 189 unique non-founder mutations, 76 in BRCA1 and 113 in BRCA2. BRCA2 4075delGT was detected in 15 patients. The next most common mutations, found in 7 patients each, were BRCA1 5055delG, BRCA2 1982delA, and BRCA2 R3128X. Conclusions: Non-founder mutations make up between 13% and 7.2% of BRCA1 and BRCA2 mutations in patients reporting aj ancestry. These numbers may represent underestimates if some patients were ascertained for testing based on the identification of a founder mutation in a relative. These numbers suggest that the prevalence of non-founder mutations in aj individuals may be comparable to the prevalence of BRCA1/2 mutations in non-aj individuals.

SUBMITTER: Rosenthal E

PROVIDER: S-EPMC3997469 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Project description:The comprehensive assessment of inherited mutations in cancer susceptibility genes helps to optimize clinical decision-making. Conventional laboratory methods based on ngs focus on the detection of single nucleotide variants, small insertions/deletions, and certain copy-number changes in accessible regions of a patient’s dna. Other clinically significant alterations are invisible to these approaches, and for this reason their clinical impact is less well studied. We investigated the prevalence of technically challenging mutations in a large (n = 80,000) patient population focusing on 19 genes (including BRCA1 and BRCA2) associated with breast and/or ovarian cancer. Technical methods beyond conventional next-generation sequencing (ngs) were used to detect and confirm the presence of dna alterations in these patients. We found that 8.6% of patients with a potentially actionable result harbored a mutation not easily detected by conventional ngs sequencing or copy number methods. No single class of mutation was responsible for this—rather, a diversity of challenges was present. Most of these mutations were individually extremely rare, although some were recurrent. Many would have clinical relevance in either a germline or somatic context. Laboratory studies generally include few, if any, of these technically challenging variants. To help evaluate and improve methodologies across laboratories, we constructed a synthetic specimen containing 22 challenging variants in 7 cancer genes. This specimen was provided to collaborating laboratories who sequenced it using a total of 10 different ngs tests. Only 10 of the 22 challenging variants were detected by all tests, and just 3 tests detected all 22. Some but not all of these limitations were previously known. In summary, technically challenging pathogenic variants are collectively prevalent in patients, although methods to detect these variants are not yet uniformly implemented. The clinical data and specimen described here are now available and mght help improve the assessment of cancer risk internationally.

Project description:Stress diseases such as affective disorders are often characterized by a disturbed regulation of the hypothalamus-pituitary-adrenocortical (HPA) axis. This dysregulation can be explained by an impaired function of the receptors involved in the HPA-axis regulation, for example, the glucocorticoid receptors (GR). The regulation process of the HPA axis and the GR function are influenced by several genes, for instance by NR3C1 coding for the GR and also by FKBP5, a co-chaperone in the GR-complex. Binder et al. showed that common polymorphisms in FKBP5 are associated with increased FKBP5 protein expression as well as correlation between cortisol levels and peripheral blood FKBP5 mRNA expression. Regarding the effects of FKPB5 genotypes on psychosocial stress reaction, Ising and colleagues tested healthy subjects with the Trier Social Stress Test, a standardized paradigm to induce psychosocial stress. Subjects homozygous for any of the FKBP5 variants showed an incomplete normalization of the stress induced cortisol secretion. Recent studies demonstrated that FKBP5 and NR3C1 are involved in the endocrine stress reaction. Therefore, we expected changes of FKBP5 and NR3C1 mRNA expression in peripheral blood after exposure to a psychosocial stress situation. To address this, we performed a pilot study where we tested six healthy young men without history of psychiatric or severe somatic disorders and applied the trier social stress test (TSST). Before and after two consecutive TSSTs, we took blood samples with a venous catheter in order to measure ACTH and cortisol in plasma and mRNA expression of the candidate genes in peripheral blood. Blood cells were stabilized using PAXgene tubes, and gene expression was processed by qPCR. Briefly after the psychosocial stress the stress hormones ACTH and cortisol increased whereas the reaction to the second TSST was lower suggesting a habituation effect. These endocrine stress responses were followed by an alteration in FKBP5 gene expression, further underlining the importance of this gene for the neuroendocrine stress reaction. NR3C1 mRNA levels did not change after the TSST. Our preliminary data indicate an effect of psychosocial stress on the FKBP5 mRNA levels. Further research with larger samples sizes is required to replicate and extend these results.

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Proffered papers and posters submitted to the Fifth International Symposium on Hereditary Breast and Ovarian Cancer, BRCA: Twenty Years of Advances

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