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oai:uvadoc.uva.es:10324/644542026-04-09T10:27:04Zcom_10324_1134com_10324_931com_10324_894col_10324_1213

00925njm 22002777a 4500 dc Infante Sanz, María Del Mar author Duran Dominguez, María Mercedes author Acedo, Alberto author Sánchez Tapia, Eva María author Díez Gómez, Beatríz author Barroso, Alicia author García González, María author Feliubadalo, L. author Lasa, Adriana author Hoya, Miguel de la author Esteban Cardeñosa, Eva author Diez, Orland author Martinez Bouzas, Cristina author Godino, Javier author Teulé, Alexandra author Osorio, Ana author Lastra, Enrique author González Sarmiento, Rogelio author Miner, Cristina author Velasco, Eladio A. author 2013 BRCA2-c.2808_2811del (3036delACAA) is one of the most reported germ line mutations in non-Ashkenazi breast cancer patients. We investigated its genetic origin in 51 Spanish carrier families that were genotyped with 11 13q polymorphic markers. Three independent associated haplotypes were clearly distinguished accounting for 23 [west Castilla y León (WCL)], 20 [east Castilla y León (ECL)] and 6 (South of Spain) families. Mutation age was estimated with the Disequilibrium Mapping using Likelihood Estimation software in a range of 45–68 and 45–71 generations for WCL and ECL haplotypes, respectively. The most prevalent variants, c.2808_2811del and c.2803G > A, were located in a double-hairpin loop structure (c.2794–c.2825) predicted by Quikfold that was proposed as a mutational hotspot. To check this hypothesis, random mutagenesis was performed over a 923 bp fragment of BRCA2, and 86 DNA variants were characterized. Interestingly, three mutations reported in the mutation databases (c.2680G > A, c.2944del and c.2957dup) were replicated and 20 affected the same position with different nucleotide changes. Moreover, five variants were placed in the same hairpin loop of c.2808_2811del, and one affected the same position (c.2808A > G). In conclusion, our results support that at least three different mutational events occurred to generate c.2808_2811del. Other highly prevalent DNA variants, such as BRCA1-c.68_69delAG, BRCA2- c.5946delT and c.8537delAG, are concentrated in hairpin loops, suggesting that these structures may represent mutational hotspots. Carcinogenesis, 34 (11), pp. 2505-2511. 0143-3334 https://uvadoc.uva.es/handle/10324/64454 10.1093/carcin/bgt272 2505 11 2511 Carcinogenesis 34 1460-2180 The highly prevalent BRCA2 mutation c.2808_2811del (3036delACAA) is located in a mutational hotspot and has multiple origins