Mutation analysis of BRCA1 and BRCA2 genes in Iranian high risk breast cancer families

Background: Telomerase is a ribonucleoprotein enzyme that synthesises telomeres after cell division and maintains chromosomal stability leading to cellular immortalization. Telomerase has been associated with negative prognostic indicators in some studies. The present study aims to detect any association between telomerase sub-units: hTERT and hTR and the prognostic indicators including tumour's size and grade, nodal status and patient's age. Methods: Tumour samples from 46 patients with primary invasive breast cancer and 3 patients with benign tumours were collected. RT-PCR analysis was used for the detection of hTR, hTERT, and PGM1 (as a housekeeping) genes expression. Results: The expression of hTR and hTERT was found in 31(67.4%) and 38 (82.6%) samples respectively. We observed a significant association between hTR gene expression and younger age at diagnosis (p = 0.019) when comparing patients ≤ 40 years with those who are older than 40 years. None of the benign tumours expressed hTR gene. However, the expression of hTERT gene was revealed in 2 samples. No significant association between hTR and hTERT expression and tumour's grade, stage and nodal status was seen. Conclusion: The expression of hTR and hTERT seems to be independent of tumour's stage. hTR expression probably plays a greater role in mammary tumourogenesis in younger women (≤ 40 years) and this may have therapeutic implications in the context of hTR targeting strategies

Presymptomatic breast cancer in Egypt: role of BRCA1 and BRCA2 tumor suppressor genes mutations detection

<p>Abstract</p> <p>Background</p> <p>Breast cancer is one of the most common diseases affecting women. Inherited susceptibility genes, <it>BRCA1 </it>and <it>BRCA2</it>, are considered in breast, ovarian and other common cancers etiology. <it>BRCA1 </it>and <it>BRCA2 </it>genes have been identified that confer a high degree of breast cancer risk.</p> <p>Objective</p> <p>Our study was performed to identify germline mutations in some exons of <it>BRCA1 </it>and <it>BRCA2 </it>genes for the early detection of presymptomatic breast cancer in females.</p> <p>Methods</p> <p>This study was applied on Egyptian healthy females who first degree relatives to those, with or without a family history, infected with breast cancer. Sixty breast cancer patients, derived from 60 families, were selected for molecular genetic testing of <it>BRCA1 </it>and <it>BRCA2 </it>genes. The study also included 120 healthy first degree female relatives of the patients, either sisters and/or daughters, for early detection of presymptomatic breast cancer mutation carriers. Genomic DNA was extracted from peripheral blood lymphocytes of all the studied subjects. Universal primers were used to amplify four regions of the <it>BRCA1 </it>gene (exons 2,8,13 and 22) and one region (exon 9) of <it>BRCA2 </it>gene using specific PCR. The polymerase chain reaction was carried out. Single strand conformation polymorphism assay and heteroduplex analysis were used to screen for mutations in the studied exons. In addition, DNA sequencing of the normal and mutated exons were performed.</p> <p>Results</p> <p>Mutations in both <it>BRCA1 </it>and <it>BRCA2 </it>genes were detected in 86.7% of the families. Current study indicates that 60% of these families were attributable to <it>BRCA1 </it>mutations, while 26.7% of them were attributable to <it>BRCA2 </it>mutations. Results showed that four mutations were detected in the <it>BRCA1 </it>gene, while one mutation was detected in the <it>BRCA2 </it>gene. Asymptomatic relatives, 80(67%) out of total 120, were mutation carriers.</p> <p>Conclusions</p> <p><it>BRCA1 </it>and <it>BRCA2 </it>genes mutations are responsible for a significant proportion of breast cancer. <it>BRCA </it>mutations were found in individuals with and without family history.</p

Second primary malignancies in patients with male breast cancer

An international multicentre study of first and second primary neoplasms associated with male breast cancer was carried out by pooling data from 13 cancer registries. Among a total of 3409 men with primary breast cancer, 426 (12.5%) developed a second neoplasia; other than breast cancer, a 34% overall excess risk of second primary neoplasia, affecting the small intestine (standardised incidence ratio, 4.95, 95% confidence interval, 1.35–12.7), rectum (1.78, 1.20–2.54), pancreas (1.93, 1.14–3.05), skin (nonmelanoma, 1.65, 1.16–2.29), prostate (1.61, 1.34–1.93) and lymphohaematopoietic system (1.63, 1.12–2.29). A total of 225 male breast cancers was recorded after cancers other than breast cancer, but an increase was found only after lymphohaematopoietic neoplasms. BRCA2 (and to some extent BRCA1) mutations may explain the findings for pancreatic and prostate cancers. Increases at other sites may be related to unknown factors or to chance. This large study shows that the risks for second discordant tumours after male breast cancer pose only a moderate excess risk

A novel de novo BRCA1 mutation in a Chinese woman with early onset breast cancer

Germline mutations in the two breast cancer susceptibility genes, BRCA1 and BRCA2 account for a significant portion of hereditary breast/ovarian cancer. De novo mutations such as multiple exon deletion are rarely occurred in BRCA1 and BRCA2. During our mutation screening for BRCA1/2 genes to Chinese women with risk factors for hereditary breast/ovarian cancer, we identified a novel germline mutation, consisting of a deletion from exons 1 to 12 in BRCA1 gene, in a patient diagnosed with early onset triple negative breast cancer with no family history of cancer. None of her parents carried the mutation and molecular analysis showed that this novel de novo germline mutation resulted in down-regulation of BRCA1 gene expression

Cancer risks among BRCA1 and BRCA2 mutation carriers

BRCA1 and BRCA2 mutations increase breast and ovarian cancer risks substantially enough to warrant risk reduction surgery, despite variable risk estimates. Underlying this variability are methodological issues, and also complex genetic and nongenetic effects. Although many modifying factors are unidentified, known factors can already be incorporated in individualised risk prediction

BRCA1 and BRCA2 germline mutation analysis in the Indonesian population

Specific mutations in BRCA1 and BRCA2 genes have been identified in specific populations and ethnic groups. However, little is known about the contribution of BRCA1 and BRCA2 mutations to breast cancers in the Indonesian population. One hundred-twenty moderate to high risk breast cancer patients were tested using PCR-DGGE, and any aberrant band was sequenced. Multiplex ligation-dependent probe amplification (MLPA) was performed on all samples to detect large deletions in the two genes. Twenty-three different mutations were detected in 30 individuals, ten were deleterious mutations and 20 were “unclassified variants” with uncertain clinical consequences. Three of seven (c.2784_2875insT, p.Leu1415X and del exon 13–15) and two of four (p.Glu2183X and p.Gln2894X) deleterious mutations that were found in BRCA1 and BRCA2 respectively, are novel. Several novel, pathogenic BRCA1 and BRCA2 germline mutations are found in early onset Indonesian breast cancer patients, these may therefore be specific for the Indonesian population

Full-Exon Pyrosequencing Screening of BRCA Germline Mutations in Mexican Women with Inherited Breast and Ovarian Cancer

Hereditary breast cancer comprises 10% of all breast cancers. The most prevalent genes causing this pathology are BRCA1 and BRCA2 (breast cancer early onset 1 and 2), which also predispose to other cancers. Despite the outstanding relevance of genetic screening of BRCA deleterious variants in patients with a history of familial cancer, this practice is not common in Latin American public institutions. In this work we assessed mutations in the entire exonic and splice-site regions of BRCA in 39 patients with breast and ovarian cancer and with familial history of breast cancer or with clinical features suggestive for BRCA mutations by massive parallel pyrosequencing. First we evaluated the method with controls and found 41–485 reads per sequence in BRCA pathogenic mutations. Negative controls did not show deleterious variants, confirming the suitability of the approach. In patients diagnosed with cancer we found 4 novel deleterious mutations (c.2805_2808delAGAT and c.3124_3133delAGCAATATTA in BRCA1; c.2639_2640delTG and c.5114_5117delTAAA in BRCA2). The prevalence of BRCA mutations in these patients was 10.2%. Moreover, we discovered 16 variants with unknown clinical significance (11 in exons and 5 in introns); 4 were predicted as possibly pathogenic by in silico analyses, and 3 have not been described previously. This study illustrates how massive pyrosequencing technology can be applied to screen for BRCA mutations in the whole exonic and splice regions in patients with suspected BRCA-related cancers. This is the first effort to analyse the mutational status of BRCA genes on a Mexican-mestizo population by means of pyrosequencing

A role of BRCA1 and BRCA2 germline mutations in breast cancer susceptibility within Sardinian population

<p>Abstract</p> <p>Background</p> <p>In recent years, numerous studies have assessed the prevalence of germline mutations in <it>BRCA1 </it>and <it>BRCA2 </it>genes in various cohorts. We here extensively investigated the prevalence and geographical distribution of <it>BRCA1-2 </it>mutations in the entire genetically-homogeneous Sardinian population. The occurrence of phenotypic characteristics which may be predictive for the presence of <it>BRCA1-2 </it>germline mutations was also evaluated.</p> <p>Methods</p> <p>Three hundred and forty-eight breast cancer patients presenting a familial recurrence of invasive breast or ovarian carcinoma with at least two affected family members were screened for <it>BRCA1-2 </it>mutations by DHPLC analysis and DNA sequencing. Association of <it>BRCA1 </it>and <it>BRCA2 </it>mutational status with clinical and pathological parameters was evaluated by Pearson's Chi-Squared test.</p> <p>Results and Conclusion</p> <p>Overall, 8 <it>BRCA1 </it>and 5 <it>BRCA2 </it>deleterious mutations were detected in 35/348 (10%) families; majority (23/35;66%) of mutations was found in <it>BRCA2 </it>gene. The geographical distribution of <it>BRCA1-2 </it>mutations was related to three specific large areas of Sardinia, reflecting its ancient history: <it>a</it>) the Northern area, linguistically different from the rest of the island (where a <it>BRCA2 c.8764_8765delAG </it>mutation with founder effect was predominant); <it>b</it>) the Middle area, land of the ancient Sardinian population (where <it>BRCA2 </it>mutations are still more common than <it>BRCA1 </it>mutations); and <it>c</it>) the South-Western area, with many Phoenician and Carthaginian locations (where <it>BRCA1 </it>mutations are prevalent). We also found that phenotypic features such as high tumor grading and lack of expression of estrogen/progesterone receptors together with age at diagnosis and presence of ovarian cancer in the family may be predictive for the presence of <it>BRCA1-2 </it>germline mutations.</p