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 from12 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.

We developed a risk score to predict CS in an at-risk population. This score may help to identify at-risk patients in non-endocrinological settings such as primary care, but external validation is warranted.

Purpose: A subset of colorectal cancers (CRC) arises in families that, despite fulfilling clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC), do not show evidence of a mismatch repair (MMR) deficiency. The main objective of this study was to characterize these tumors at the molecular level. Experimental Design: After comprehensive germ line mutation scanning, microsatellite analysis, and MMR protein expressions, we selected a well-defined cohort of 57 colorectal tumors with no evidence of MMR defects. In this group of tumors, we analyzed KRAS, BRAF, and APC somatic mutations, as well as methylguanine methyltransferase (MGMT) and h-catenin expression.We correlated these alterations with clinicopathologic data and explored the relationship between KRAS G > A transitions and lack of MGMTexpression. Results:The mutation profile at the RAS/RAF/MAPK pathway mimics sporadic microsatellitestable CRCs. We found an average age of diagnosis 10 years older in KRAS-mutated patients (P = 0.001). In addition, we show that KRAS G > A transitions are actively selected by tumors, regardless of MGMT status. Similarities with HNPCC high^microsatellite instability tumors are observed when APC data are analyzed. The APC mutation rate was low and small insertions/ deletions accounted for 70% of the alterations. In addition, we found a low frequency of h-catenin nuclear staining. Finally, we did not find evidence of tumors arising in individuals from the same family sharing molecular features. Conclusions: We show evidence that CRC tumors arising in HNPCC families without MMR alterations have distinctive molecular features. Overall, our work shows that systematic analysis of somatic alterations in a well-defined subset of CRCs is a good approach to provide new insights into the mechanisms of colorectal carcinogenesis.Approximately 5% of all colorectal cancers (CRC) are diagnosed in the context of known Mendelian syndromes, principally, hereditary nonpolyposis colon cancer (HNPCC) and familial adenomatous polyposis. When considering HNPCC as a syndrome linked to mismatch repair (MMR) gene mutations, the frequency range is from 0.3% to 3% of the total CRC burden (1). Tumors from patients with MMR mutations frequently show high -microsatellite instability (MSI-H; ref.2). The MSI-H phenotype is also found in 10% to 15% of sporadic CRCs, although these tumors differ from their hereditary counterparts at the molecular level (3, 4). For instance, the MMR deficiency seen in sporadic tumors is mainly due to hMLH1 promoter hypermethylation. Apart from MSI, less wellcharacterized genetic instability phenotypes may contribute to colorectal carcinogenesis. For example, epigenetic silencing of methylguanine methyltransferase (MGMT), leading to an excess of G > A transitions, is a common event (5).Early genetic events in colorectal carcinogenesis involve the deregulation of the WNT and RAS/RAF/MAPK pathways. The mutation profile of a particular tumor is related to the underlying phenotype instability. For example, in MSI...

Colorectal cancer (CRC) risk associated with germline monoallelic MUTYH mutations remains controversial, although a slightly increased risk for this disease has been suggested. MUTYH and MSH6 proteins act in cooperation during the DNA repair process. Based on this interaction, it was hypothesized that the combination of heterozygote germline mutations in both genes could result in an increased CRC risk. To further clarify the interaction between MUTYH and MSH6, we analyzed the prevalence of MSH6 mutations in a cohort of CRC patients and controls previously tested for MUTYH mutations: CRC patients with and without a monoallelic MUTYH mutation (group I, n = 26; group II, n = 50, respectively), and healthy carriers with a monoallelic MUTYH mutation (group III, n = 21). In group I, we found three patients (11.5%) with MSH6 mutations, a missense mutation (p.R635G), a change in the 3'UTR region (c.*4098A > C) and a nonsense mutation (p.Q982X). In group II and III, no mutations were detected. In CRC patients, MSH6 mutations were more frequently found in MUTYH mutation carriers than in noncarriers (11.5% vs. 0%, P = 0.037). CRC patients carrying monoallelic MUTYH mutations harbor more frequently concomitant MSH6 mutations than patients without them, thus suggesting that both genes could act cooperatively and confer together an increased CRC risk.

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