Analysis of BRCA1 and BRCA2 genes in Spanish breast/ovarian cancer patients: a high proportion of mutations unique to Spain and evidence of founder effects.
We screened index cases from 410 Spanish breast/ovarian cancer families and 214 patients (19 of them males) with breast cancer for germ-line mutations in the BRCA1 and BRCA2 genes, using SSCP, PTT, CSGE, DGGE, and direct sequencing. We identified 60 mutations in BRCA1 and 53 in BRCA2. Of the 53 distinct mutations observed, 11 are novel and 12 have been reported only in Spanish families (41.5%). The prevalence of mutations in this set of families was 26.3%, but the percentage was higher in the families with breast and ovarian cancer (52.1%). The lowest proportion of mutations was found in the site-specific female breast cancer families (15.4%). Of the families with male breast cancer cases, 59.1% presented mutations in the BRCA2 gene. We found a higher frequency of ovarian cancer associated with mutations localized in the 5' end of the BRCA1 gene, but there was no association between the prevalence of this type of cancer and mutations situated in the ovarian cancer cluster region (OCCR) region of exon 11 of the BRCA2 gene. The mutations 187_188delAG, 330A>G, 5236G>A, 5242C>A, and 589_590del (numbered after GenBank U14680) account for 46.6% of BRCA1 detected mutations whereas 3036_3039del, 6857_6858del, 9254_9258del, and 9538_9539del (numbered after GenBank U43746) account for 56.6% of the BRCA2 mutations. The BRCA1 330A>G has a Galician origin (northwest Spain), and BRCA2 6857_6858del and 9254_9258del probably originated in Catalonia (northeast Spain). Knowledge of the spectrum of mutations and their geographical distribution in Spain will allow a more effective detection strategy in countries with large Spanish populations.
Díez
Orland
O
Servei de Genètica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. Odiez@hsp.santpau.es
Osorio
Ana
A
Durán
Mercedes
M
Martinez-Ferrandis
José Ignacio
JI
de la Hoya
Miguel
M
Salazar
Raquel
R
Vega
Ana
A
Campos
Berta
B
Rodríguez-López
Raquel
R
Velasco
Eladio
E
Chaves
Javier
J
Díaz-Rubio
Eduardo
E
Jesús Cruz
Juan
J
Torres
María
M
Esteban
Eva
E
Cervantes
Andrés
A
Alonso
Carmen
C
San Román
Juan Manuel
JM
González-Sarmiento
Rogelio
R
Miner
Cristina
C
Carracedo
Angel
A
Eugenia Armengod
María
M
Caldés
Trinidad
T
Benítez
Javier
J
Baiget
Montserrat
M
D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D018567:Breast Neoplasms, Male / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D018703:Founder Effect; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics*; D011110:Polymorphism, Genetic; D013030:Spain