Analysis of BRCA1 and BRCA2 in breast and breast/ovarian cancer families shows population substructure in the Iberian peninsula

Abstract

An estimated 5-10 % of all breast and ovarian cancers are due to an inherited predisposition, representing a rather large number of patients. In Spain 1\13-1\14 women will be diagnosed with breast cancer during their lifetime. Two major breast cancer genes, BRCA1 and BRCA2, have been identified. To date, several hundred pathogenic mutations in these two genes have been published or reported to the Breast Cancer Information Core, BIC database (http:\\www.nhgri.nih.gov\ IntramuralIresearchILab transfer\Bic\index.html). In the present study, 30 Spanish breast and breast\ovarian cancer families (29 from Galicia, NW Spain, and 1 from Catalonia, NE Spain) were screened for mutations in the BRCA1 and BRCA2 genes. The analysis of these genes was carried out by SSCP for shorter exons and direct sequencing in the case of longer ones. Mutations were found in 8 of the 30 families studied (26n66 %). It is important to note that all mutations were detected within the BRCA1 gene : 330 A G, 910I913delGTTC, 2121 C T, 3958I3962delCTCAGinsAGGC, and 5530 T A. The BRCA1 330 A G mutation was found in four unrelated families and accounted for 50 % of all identified mutations. Since the identification of the BRCA1 and BRCA2 genes (MIMFs 113705 and 600185), more than nine hundred different mutations have been identified in these genes (BIC Database). BRCA1 maps to chromosome 17q21 (Miki et al. 1994) and predisposes to early-onset hereditary breast and ovarian cancer. BRCA2, located at 13q12-q13 (Wooster et al. 1995), also predisposes to earlyonset breast cancer in women, but confers a higher risk of inherited male breast cancer and a lower risk of familiar ovarian cancer compared to BRCA1. Both genes are characterized for their large size and complex genomic structures :

The Average Cumulative Risks of Breast and Ovarian Cancer for Carriers of Mutations in BRCA1 and BRCA2 Attending Genetic Counseling Units in Spain

“…In contrast, the evidence that the mutation 330A>G in BRCA1 has lower breast cancer penetrance to age 70 years was very consistent. This variant has been shown to be deleterious, causing aberrant splicing of the transcript that leads to a premature stop codon (42), and represents an estimated 50% of all mutations detected in women from Galicia, in the northwest of Spain (43). Although evidence was marginal (P = 0.09) that breast cancer risks varied between carriers of 330A>G and carriers of all other mutations in BRCA1 (including 185delAG) combined, the estimated cumulative risks of breast cancer to age 70 years were strikingly different, being 27% (95% CI, 0-52%) and 66% (95% CI, 34-83%), respectively.…”

Analysis ofBRCA1andBRCA2genes in Spanish breast/ovarian cancer patients: A high proportion of mutations unique to Spain and evidence of founder effects

“…The families had been investigated for a number of reasons, including research, directed screening of case series of female or male breast cancer, or attendance at cancer genetic clinics. Some of these families had been included in earlier works [Díez et al, 1999a;Osorio et al, 2000;Campos et al, 2001;de la Hoya et al, 2001de la Hoya et al, , 2002Vega et al, 2002].…”

“…However, there were some differences due to the geographic origin of the families, with a higher proportion of BRCA1 findings in families from northwest Spain. It has been suggested that the differences found in Galicia [Vega et al, 2002] or Catalonia [Campos et al, 2003], compared with those in other parts of Spain, could be due in part to the presence of founder effects. Alternatively, the lower prevalence of BRCA2 mutations in these families and patients could be due to fewer mutations and to lower penetrance, and/or to later age of onset of BRCA2 breast cancer.…”

Molecular analysis of the eighteen most frequent mutations in the BRCA1 gene in 63 Chilean breast cancer families

“…BRCA1 mutation studies have been reported in different ethnic groups (Panguluri et al, 1999;Ruiz-Flores et al, 2002;Saxena et al, 2002;Zhi et al, 2002;Manguoglu et al, 2003). There have been extensive molecular analyses of the BRCA1 mutations performed in Caucasian populations in countries such as Canada, USA, UK, Sweden, Netherlands, Belgium, Norway, and Spain (Simard et al, 1994;Gayther et al, 1995;Shattuck-Eidens et al, 1995;Johannsson et al, 1996;Peelen et al, 1997;Claes et al, 1999;Borg et al, 1999;Neuhausen., 2000;Osorio et al, 2000;Llort et al, 2002;Vega et al, 2002;de Sanjose et al, 2003;Díez et al, 2003). BRCA1 mutations have been reported in Japanese (Inoue et al, 1995;Matsushima et al, 1995;Katagiri et al, 1996;Miki et al, 1996), Taiwanese (Li et al, 1999), other Asian populations (BIC), and in African Americans (Panguluri et al, 1999).…”