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BRCA1 and BRCA2 mutation status and tumor characteristics in male breast cancer: a population-based study in Italy.
Cancer Res. 2003 Jan 15; 63(2):342-7.CR

Abstract

To investigate at the population level the impact of BRCA1/BRCA2 gene alterations in male breast cancer, we analyzed a population-based series of 25 male breast cancer cases from Florence, Central Italy. We combined mutational screening with the study of germ-line allele transcript levels and of tumor-associated losses of heterozygosity. Screening by protein truncation test and single-strand conformational polymorphism assay, followed by sequencing, revealed 4 pathogenetic mutations (4 of 25 = 16%; 95% confidence interval, 5-37%), 1 in BRCA1 and 3 in BRCA2, including mutations recurring in Central Italy (BRCA1 3345delAG and BRCA2 6696delTC). The a priori probability of carrying a mutation, estimated using BRCAPRO software, showed a good agreement between expected and observed mutations (14% versus 16%). A 7-fold association between germ-line mutations and family history of breast-ovarian cancer emerged. To investigate associations between BRCA1/BRCA2 status and clinicopathological characteristics, we analyzed the histopathological and immunophenotypic parameters of the tumors. A significant association emerged between mutation carrier status and high histological grade (P = 0.02). Furthermore, one BRCA2 carrier was affected with Paget's disease, an extremely rare male breast cancer histotype. Overall, BRCA1/2 mutations were observed to be strongly associated with positive c-erbB-2 immunostaining (P = 0.004). To evaluate germ-line allele expression, we used primer extension assays targeting frequent BRCA1 and BRCA2 polymorphisms. A BRCA2 allele transcript imbalance was found in one of four heterozygotes tested, all of them negative for germ-line mutations. BRCA1 transcript imbalances were not detected in nine heterozygotes analyzed. Losses of heterozygosity at one or more of nine loci in the BRCA2 region were found in 8 of 22 tumors tested. Interestingly, a case that was negative for BRCA1/BRCA2 germ-line mutations and that had a priori mutation probability <10% showed loss of heterozygosity at all three of the intragenic BRCA2 markers analyzed, which could be related to a somatic involvement of BRCA2. No losses of heterozygosity were detected at BRCA1. In conclusion, constitutional BRCA1/BRCA2 mutations accounted for 16% of the male breast cancer cases in this area of Central Italy. The detection of a BRCA2 germ-line transcript imbalance and of a somatic loss of BRCA2 among the cases that resulted negative for germ-line mutations suggests a role of this gene more relevant than indicated by conventional mutational analysis. A distinct pattern of characteristics indicative of aggressive behavior, including high-grade and c-erbB-2 expression, was evident in tumors from germ-line BRCA2 mutation carriers. This suggests that phenotypic characteristics may contribute to the identification of hereditary BRCA2-related male breast cancers and that these tumors might share a unique molecular pathway of cancer progression.

Authors+Show Affiliations

Department of Experimental Medicine and Pathology, University La Sapienza, 00161 Roma, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12543786

Citation

Ottini, Laura, et al. "BRCA1 and BRCA2 Mutation Status and Tumor Characteristics in Male Breast Cancer: a Population-based Study in Italy." Cancer Research, vol. 63, no. 2, 2003, pp. 342-7.
Ottini L, Masala G, D'Amico C, et al. BRCA1 and BRCA2 mutation status and tumor characteristics in male breast cancer: a population-based study in Italy. Cancer Res. 2003;63(2):342-7.
Ottini, L., Masala, G., D'Amico, C., Mancini, B., Saieva, C., Aceto, G., Gestri, D., Vezzosi, V., Falchetti, M., De Marco, M., Paglierani, M., Cama, A., Bianchi, S., Mariani-Costantini, R., & Palli, D. (2003). BRCA1 and BRCA2 mutation status and tumor characteristics in male breast cancer: a population-based study in Italy. Cancer Research, 63(2), 342-7.
Ottini L, et al. BRCA1 and BRCA2 Mutation Status and Tumor Characteristics in Male Breast Cancer: a Population-based Study in Italy. Cancer Res. 2003 Jan 15;63(2):342-7. PubMed PMID: 12543786.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - BRCA1 and BRCA2 mutation status and tumor characteristics in male breast cancer: a population-based study in Italy. AU - Ottini,Laura, AU - Masala,Giovanna, AU - D'Amico,Cristina, AU - Mancini,Biancamaria, AU - Saieva,Calogero, AU - Aceto,Gitana, AU - Gestri,Donella, AU - Vezzosi,Vania, AU - Falchetti,Mario, AU - De Marco,Manola, AU - Paglierani,Milena, AU - Cama,Alessandro, AU - Bianchi,Simonetta, AU - Mariani-Costantini,Renato, AU - Palli,Domenico, PY - 2003/1/25/pubmed PY - 2003/3/14/medline PY - 2003/1/25/entrez SP - 342 EP - 7 JF - Cancer research JO - Cancer Res VL - 63 IS - 2 N2 - To investigate at the population level the impact of BRCA1/BRCA2 gene alterations in male breast cancer, we analyzed a population-based series of 25 male breast cancer cases from Florence, Central Italy. We combined mutational screening with the study of germ-line allele transcript levels and of tumor-associated losses of heterozygosity. Screening by protein truncation test and single-strand conformational polymorphism assay, followed by sequencing, revealed 4 pathogenetic mutations (4 of 25 = 16%; 95% confidence interval, 5-37%), 1 in BRCA1 and 3 in BRCA2, including mutations recurring in Central Italy (BRCA1 3345delAG and BRCA2 6696delTC). The a priori probability of carrying a mutation, estimated using BRCAPRO software, showed a good agreement between expected and observed mutations (14% versus 16%). A 7-fold association between germ-line mutations and family history of breast-ovarian cancer emerged. To investigate associations between BRCA1/BRCA2 status and clinicopathological characteristics, we analyzed the histopathological and immunophenotypic parameters of the tumors. A significant association emerged between mutation carrier status and high histological grade (P = 0.02). Furthermore, one BRCA2 carrier was affected with Paget's disease, an extremely rare male breast cancer histotype. Overall, BRCA1/2 mutations were observed to be strongly associated with positive c-erbB-2 immunostaining (P = 0.004). To evaluate germ-line allele expression, we used primer extension assays targeting frequent BRCA1 and BRCA2 polymorphisms. A BRCA2 allele transcript imbalance was found in one of four heterozygotes tested, all of them negative for germ-line mutations. BRCA1 transcript imbalances were not detected in nine heterozygotes analyzed. Losses of heterozygosity at one or more of nine loci in the BRCA2 region were found in 8 of 22 tumors tested. Interestingly, a case that was negative for BRCA1/BRCA2 germ-line mutations and that had a priori mutation probability <10% showed loss of heterozygosity at all three of the intragenic BRCA2 markers analyzed, which could be related to a somatic involvement of BRCA2. No losses of heterozygosity were detected at BRCA1. In conclusion, constitutional BRCA1/BRCA2 mutations accounted for 16% of the male breast cancer cases in this area of Central Italy. The detection of a BRCA2 germ-line transcript imbalance and of a somatic loss of BRCA2 among the cases that resulted negative for germ-line mutations suggests a role of this gene more relevant than indicated by conventional mutational analysis. A distinct pattern of characteristics indicative of aggressive behavior, including high-grade and c-erbB-2 expression, was evident in tumors from germ-line BRCA2 mutation carriers. This suggests that phenotypic characteristics may contribute to the identification of hereditary BRCA2-related male breast cancers and that these tumors might share a unique molecular pathway of cancer progression. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/12543786/BRCA1_and_BRCA2_mutation_status_and_tumor_characteristics_in_male_breast_cancer:_a_population_based_study_in_Italy_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&amp;pmid=12543786 DB - PRIME DP - Unbound Medicine ER -