Raquel Salazar

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

Purpose: It is not clear that the published estimates of the breast and ovarian cancer penetrances of mutations in BRCA1 and BRCA2 can be used in genetic counseling in countries such as Spain, where the incidence of breast cancer in the general population is considerably lower, the prevalence of BRCA2 mutations seems to be higher, and a distinct spectrum of recurrent mutations exists for both genes. We aimed to estimate these penetrances for women attending genetic counseling units in Spain. Experimental Design: We collected phenotype and genotype data on 155 BRCA1 and 164 BRCA2 mutation carrier families from 12 centers across the country. Average age-specific cumulative risks of breast cancer and ovarian cancer were estimated using a modified segregation analysis method. Results: The estimated average cumulative risk of breast cancer to age 70 years was estimated to be 52% [95% confidence interval (95% CI), 26-69%] for BRCA1 mutation carriers and 47% (95% CI, 29-60%) for BRCA2 mutation carriers. The corresponding estimates for ovarian cancer were 22% (95% CI, 0-40%) and 18% (95% CI, 0-35%), respectively. There was some evidence (two-sided P = 0.09) that 330A>G (R71G) in BRCA1 may have lower breast cancer penetrance. Conclusions: These results are consistent with those from a recent meta-analysis of practically all previous penetrance studies, suggesting that women with BRCA1 and BRCA2 mutations attending genetic counseling services in Spain have similar risks of breast and ovarian cancer to those published for other Caucasian populations. Carriers should be fully informed of their mutation- and age-specific risks to make appropriate decisions regarding prophylactic interventions such as oophorectomy.

THE VARIANT E233G OF THE RAD51D GENE COULD BE A LOW-PENETRANCE ALLELE IN HIGH-RISK BREAST CANCER FAMILIES WITHOUT BRCA1/2 MUTATIONS

Six SNPs have been detected in the DNA repair genes RAD51C and RAD51D, not previously characterized. The novel variant E233G in RAD51D is more highly represented in high‐risk, site‐specific, familial breast cancer cases that are not associated with the BRCA1/2 genes, with a frequency of 5.74% (n = 174) compared to a control population (n = 567) and another subset of breast cancer patients (n = 765) with a prevalence of around 2% only (comparison to controls, OR = 2.6, 95% CI 1.12–6.03; p < 0.021). We found that the immunohistochemical profile detected in available tumors from these patients differs slightly from those described in non‐BRCA1/2 tumors. Finally, the structural prediction of the putative functional consequence of this change indicates that it can diminish protein stability and structure. This suggests a role for E233G as a low‐penetrance susceptibility gene in the specific subgroup of high‐risk familial breast cancer cases that are not related to BRCA1/2.

Molecular analysis of BRCA1 and BRCA2 genes in Centre West Spanish population

9572 Background: Inherited mutations in BRCA1 and BRCA2 genes predispose to breast and ovarian cancer. The proportion of high risk breast and breast/ovarian cancer families carrying BRCA1/2 germline mutations as well as the mutational spectra are variable and strongly dependant on the population and the types of families analyzed. METHODS DNA from 100 individuals with family history of breast/ovarian cancer was obtained and then analyzed by PCR, conformational sensitive gel electrophoresis (CSGE) and automated sequencing techniques. RESULTS We detected a total of 10 pathogenic mutations (5 for BRCA1 and 5 for BRCA2), 63 missense mutations (28 in BRCA1 and 35 in BRCA2) and 43 polymorphisms. The pathogenic mutations in BRCA1 were two deletions, 589delCT, 2031delG; one nonsense mutation in two unrelated families, C1806T (Q563X) and one missense mutation C5242A (A1708E). The pathogenic mutations in BRCA2 were two deletion, 8873delACCA and 3036delACAA in three unrelated families and one nonsense mutation C2604A (Y792X). 8873delACCA and Y792X mutations have not been previously described and Q563X mutation has not been previously described in Spanish population. The missense mutation H1284R in BRCA1 and H150R, D244N, W395G, K1057R, I2840V in BRCA2 and the polymorphism I785I and T2542T in BRCA2 have not been reported previously. CONCLUSIONS Some variants of the genes appear to be unique to the population studied. The 3036delACAA mutation in BRCA2 gene is the most common in our studied population, the same as in Spanish population. The occurrence in Latin America of founder mutations that originated in Spain will be useful in establishing a cost-effective mutational analysis in such populations. No significant financial relationships to disclose.