Our aim was to estimate the prevalence of mutations in the BRCA1 and BRCA2 genes among unselected incident cases of breast cancer in young women. We identified 158 incident breast cancer cases diagnosed before age 46 years in predefined geographic areas in Girona and Tarragona, Spain, during 1995-1997. Of these, 136 (86%) provided information on family history of cancer and were screened for BRCA1 and BRCA2 mutations. Nine of the 136 (6.6%) were found to carry BRCA deleterious mutations (MUT) (1 BRCA1 and 8 BRCA2), and 20 were detected with rare BRCA variants of unknown significance (UV). Both MUT and US BRCA alterations were more frequent in younger patients: 7 (11.6%) MUT and 12 (19.3%) UV carriers were found in the group of 62 patients younger than 40 years, whereas 2 (2.7%) MUT and 9 (12%) US carriers were identified in the group of 74 patients aged 40 -45. Family history of breast and ovarian cancers suggestive of hereditary condition (at least 2 first-or second-degree relatives affected with breast cancer or at least 1 relative affected with ovarian cancer or early-onset breast cancer) was absent for 5 of 9 MUT carriers. This suggests that BRCA screening policies based on family history of cancer would miss a considerable proportion of BRCA mutations. Mutations in the BRCA1 and BRCA2 genes explain at least 10% of breast cancer cases diagnosed before age 40 years. The contribution of these genes to early-onset breast cancer is likely to be even higher given that certain UV cases might be disease-associated. © 2003 Wiley-Liss, Inc. Key words: BRCA; breast cancer; SpainBreast cancer is the most frequent cancer type among women in the world, affecting up to 12% of all women in Europe and North America. 1 Germline mutations of the BRCA1 and BRCA2 genes substantially increase the lifetime risk of developing breast and ovarian cancers. 2,3 The estimated cumulative risk for breast cancer by age 70 in carriers of these mutations is about 80%. 2-5 Estimates of penetrance and contribution of BRCA1 and BRCA2 to cancer incidence have been mainly based on data from high-risk families and might not reflect the situation in all BRCA1/2 carriers. Several studies on founder mutations in populations like Ashkenazi Jews or Icelanders have provided penetrance estimates that were lower than those obtained in high-risk families. 4,5 The same trend was observed in Australian and UK studies on outbred populationbased series of breast cancers, estimating breast cancer penetrance to be 40 -50% by age 70. 6,7 Several reports estimating the prevalence of BRCA1 and BRCA2 mutations in large population-based samples of breast cancer cases have been published. 6 -11 However, all but the study of Loman et al. 11 confronted the problems of a relatively low proportion of incident cases included in the analysis and limited mutation screening protocols.Our aim was to evaluate in the Spanish population the prevalence of mutations in the BRCA1 and BRCA2 genes among unselected incident cases of breast cancer diagnosed before the age of 46 years....

HPRC can occur in an early onset form. The median age for renal tumor development in these 3 HPRC families was 46 to 63 years. HPRC associated papillary renal tumors may be aggressive and metastasize, leading to mortality. Median survival age was 60 to 70 years. Families with identical germline mutations in MET do not always share a common ancestor. HPRC is characterized by germline mutations in MET and papillary type 1 renal tumor histology.

Heterozygous carriers of ATM (ataxia telangiectasia mutated gene) mutations have increased risk of breast cancer (BC). We have estimated the prevalence of mutations in the ATM gene among Spanish patients with early-onset BC. Forty-three patients diagnosed with BC before the age of 46 years, and negative for BRCA1 and BRCA2 mutations, were analysed for the presence of ATM mutations. A total of 34 ATM sequence variants were detected: 1 deleterious mutation, 10 unclassified variants and 23 polymorphisms. One patient (2.3%) carried the ATM deleterious mutation (3802delG that causes ataxia telangiectasia in the homozygous state) and 13 patients carried the 10 ATM unclassified variants. The truncating mutation 3802delG and eight of the rare variants were not detected in a control group of 150 individuals. Different bioinformatic sequence analysis tools were used to evaluate the effects of the unclassified ATM changes on RNA splicing and function protein. This in silico analysis predicted that the missense variants 7653 T>C and 8156 G>A could alter the splicing by disrupting an exonic splicing enhancer motif and the 3763 T>G, 6314 G>C, and 8156 G>A variants would affect the ATM protein function. These are the initial results concerning the prevalence of germline mutations in the ATM gene among BC cases in a Spanish population, and they suggest that ATM mutations can confer increased susceptibility to early-onset BC.

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