Identification of a novel BRCA1 large genomic rearrangement in a Spanish breast/ovarian cancer family.
BACKGROUND
Alterations in BRCA1 gene are responsible for the majority of hereditary breast and/or ovarian cancers. However, the frequency of detected germline mutations is lower than expected by linkage analysis. Standard PCR-based screening methods are mainly used for detecting mutations, but the large genomic rearrangements are commonly overlooked. The purpose of this study was to confirm and characterize a novel deletion identified in BRCA1 gene which has not yet been reported to date.


METHODS
Multiplex ligation-dependent probe amplification was used to analyze BRCA1 rearrangements in 255 unrelated index patients with familial breast and/or ovarian cancer negative for BRCA1/BRCA2 mutations studied in Program of Genetic Counselling on Cancer of Valencia Community (Spain). The breakpoints of detected novel rearrangement were characterized by sequencing.


CONCLUSIONS
Five different rearrangements in the BRCA1 gene were identified in five unrelated index patients out of the 225 (2%). We found four large genomic rearrangements already described consisting in a 1A/1B and 2 deletion; deletion of exons 5-7; deletion of exons 8-13; exon 20 deletion. Additionally, we found the novel g.8097_22733del14637 deletion that encompasses exons 3-5. This deletion affects the RING domain of the BRCA1 protein and it is suggestive of having a negative impact on its function.


CONCLUSIONS
The new mutation here reported broadens the mutational spectrum of large rearrangements. Furthermore, the five large rearrangements found in patients non-carriers of BRCA1/BRCA2 mutations reinforce the need of studying BRCA1 large genomic rearrangements in genetic counselling programs.
Palanca Suela
Sarai
S
Laboratorio de Biología Molecular del Servicio de Biopatología Clínica, Escuela de Enfermería 7a planta, Hospital Universitario La Fe, Avd. Campanar 21, 46009, Valencia, Spain.
Esteban Cardeñosa
Eva
E
Barragán González
Eva
E
Oltra Soler
Silvestre
S
de Juan Jiménez
Inma
I
Chirivella González
Isabel
I
Segura Huerta
Angel
A
Guillén Ponce
Carmen
C
Martínez de Dueñas
Eduardo
E
Bolufer Gilabert
Pascual
P
D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D015321:Gene Rearrangement; D005820:Genetic Testing; D015894:Genome, Human; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010051:Ovarian Neoplasms / Q000453:epidemiology / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D017384:Sequence Deletion; D013030:Spain / Q000453:epidemiology
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004273:DNA, Neoplasm