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.
Cancer Genetics and.
Mar
M
Infante
Mercedes
M
Durán
Alberto
A
Acedo
Eva María
EM
Sánchez-Tapia
Beatriz
B
Díez-Gómez
Alicia
A
Barroso
María
M
García-González
Lídia
L
Feliubadaló
Adriana
A
Lasa
Miguel
M
de la Hoya
Eva
E
Esteban-Cardeñosa
Orland
O
Díez
Cristina
C
Martínez-Bouzas
Javier
J
Godino
Alexandre
A
Teulé
Ana
A
Osorio
Enrique
E
Lastra
Rogelio
R
González-Sarmiento
Cristina
C
Miner
Eladio A
EA
Velasco
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D024682:BRCA2 Protein / Q000235:genetics*; D020029:Base Pairing; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D005190:Family; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation / Q000235:genetics*; D011110:Polymorphism, Genetic; D011379:Prognosis; D013030:Spain
D024682:BRCA2 Protein; C551750:BRCA2 protein, human