7 research outputs found
The highly prevalent BRCA2 mutation c.2808_2811del (3036delACAA) is located in a mutational hotspot and has multiple origins
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