2026-04-27T20:01:19Zhttps://uvadoc.uva.es/oai/request

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

The highly prevalent BRCA2 mutation c.2808_2811del (3036delACAA) is located in a mutational hotspot and has multiple origins Infante Sanz, María Del Mar Duran Dominguez, María Mercedes Acedo, Alberto Sánchez Tapia, Eva María Díez Gómez, Beatríz Barroso, Alicia García González, María Feliubadalo, L. Lasa, Adriana Hoya, Miguel de la Esteban Cardeñosa, Eva Diez, Orland Martinez Bouzas, Cristina Godino, Javier Teulé, Alexandra Osorio, Ana Lastra, Enrique González Sarmiento, Rogelio Miner, Cristina Velasco, Eladio A. 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. 2024-01-11T12:40:12Z 2024-01-11T12:40:12Z 2013 info:eu-repo/semantics/article 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 eng http://dx.doi.org/10.1093/carcin/bgt272 info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by-nc-nd/4.0/ Attribution-NonCommercial-NoDerivatives 4.0 Internacional Oxford University Press SI