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      Prevalence and impact of founder mutations in hereditary breast cancer in Latin America

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          Abstract

          Approximately 10% of all cancers are considered hereditary and are primarily caused by germline, high penetrance mutations in cancer predisposition genes. Although most cancer predisposition genes are considered molecularly heterogeneous, displaying hundreds of different disease-causing sequence alterations, founder mutations have been identified in certain populations. In some Latin American countries, founder mutations associated with increased risk of breast and other cancers have been described. This is particularly interesting considering that in most of these countries, populations are highly admixed with genetic contributions from native populations and from the influx of several distinct populations of immigrants. In this article, we present a review of the scientific literature on the subject and describe current data available on founder mutations described in the most common breast cancer predisposition genes: BRCA1, BRCA2 and TP53.

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          Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database.

          The tumor suppressor gene TP53 is frequently mutated in human cancers. More than 75% of all mutations are missense substitutions that have been extensively analyzed in various yeast and human cell assays. The International Agency for Research on Cancer (IARC) TP53 database (www-p53.iarc.fr) compiles all genetic variations that have been reported in TP53. Here, we present recent database developments that include new annotations on the functional properties of mutant proteins, and we perform a systematic analysis of the database to determine the functional properties that contribute to the occurrence of mutational "hotspots" in different cancer types and to the phenotype of tumors. This analysis showed that loss of transactivation capacity is a key factor for the selection of missense mutations, and that difference in mutation frequencies is closely related to nucleotide substitution rates along TP53 coding sequence. An interesting new finding is that in patients with an inherited missense mutation, the age at onset of tumors was related to the functional severity of the mutation, mutations with total loss of transactivation activity being associated with earlier cancer onset compared to mutations that retain partial transactivation capacity. Furthermore, 80% of the most common mutants show a capacity to exert dominant-negative effect (DNE) over wild-type p53, compared to only 45% of the less frequent mutants studied, suggesting that DNE may play a role in shaping mutation patterns. These results provide new insights into the factors that shape mutation patterns and influence mutation phenotype, which may have clinical interest.
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            Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations.

            Germline mutations in the BRCA1 or BRCA2 tumour-suppressor genes are strong predictors of breast and/or ovarian cancer development. The contribution of these mutations to breast cancer risk within any specific population is a function of both their prevalence and their penetrance. Mutation prevalence varies among ethnic groups and may be influenced by founder mutations. Penetrance can be influenced by mutation-specific phenotypes and the potential modifying effects of the patient's own genetic and environmental background. Although estimates of both mutation prevalence and mutation penetrance rates are inconsistent and occasionally controversial, understanding them is crucial for providing accurate risk information to each patient.
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              Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms

              Familial cancer syndromes have helped to define the role of tumor suppressor genes in the development of cancer. The dominantly inherited Li-Fraumeni syndrome (LFS) is of particular interest because of the diversity of childhood and adult tumors that occur in affected individuals. The rarity and high mortality of LFS precluded formal linkage analysis. The alternative approach was to select the most plausible candidate gene. The tumor suppressor gene, p53, was studied because of previous indications that this gene is inactivated in the sporadic (nonfamilial) forms of most cancers that are associated with LFS. Germ line p53 mutations have been detected in all five LFS families analyzed. These mutations do not produce amounts of mutant p53 protein expected to exert a trans-dominant loss of function effect on wild-type p53 protein. The frequency of germ line p53 mutations can now be examined in additional families with LFS, and in other cancer patients and families with clinical features that might be attributed to the mutation.
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                Author and article information

                Journal
                gmb
                Genetics and Molecular Biology
                Genet. Mol. Biol.
                Sociedade Brasileira de Genética (Ribeirão Preto, SP, Brazil )
                1415-4757
                1678-4685
                2014
                : 37
                : 1 suppl 1
                : 234-240
                Affiliations
                [04] Rio de Janeiro RJ orgnameFundação Oswaldo Cruz orgdiv1Instituto Oswaldo Cruz orgdiv2Laboratório de Epidemiologia de Malformações Congênitas Brazil
                [02] Porto Alegre RS orgnameHospital de Clínicas de Porto Alegre orgdiv1Centro de Pesquisa Experimental orgdiv2Serviço de Genética Médica Brasil
                [01] Porto Alegre RS orgnameUniversidade Federal do Rio Grande do Sul orgdiv1Departamento de Genética Brazil
                [03] Rio de Janeiro RJ orgnameUniversidade Federal do Estado do Rio de Janeiro orgdiv1Departamento de Genética e Biologia Molecular Brasil
                Article
                S1415-47572014000200009 S1415-4757(14)03700100009
                10.1590/S1415-47572014000200009
                840fa4fe-4551-4232-aa58-08b9a055a443

                This work is licensed under a Creative Commons Attribution 4.0 International License.

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                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 53, Pages: 7
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                SciELO Brazil


                breast cancer genes,cancer predisposition,TP53,BRCA2,BRCA1
                breast cancer genes, cancer predisposition, TP53, BRCA2, BRCA1

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