HPC1/RNASEL was recently identified as a candidate gene for hereditary prostate cancer. We identified a novel founder frameshift mutation in RNASEL, 471delAAAG, in Ashkenazi Jews. The mutation frequency in the Ashkenazi population, estimated on the basis of the frequency in 150 healthy young women, was 4% (95% confidence interval [CI] 1.9%-8.4%). Among Ashkenazi Jews, the mutation frequency was higher in patients with prostate cancer (PRCA) than in elderly male control individuals (6.9% vs. 2.4%; odds ratio = 3.0; 95% CI 0.6-15.3; P=.17). 471delAAAG was not detected in the 134 non-Ashkenazi patients with PRCA and control individuals tested. The median age at PRCA diagnosis did not differ significantly between the Ashkenazi carriers and noncarriers included in our study. However, carriers received diagnoses at a significantly earlier age, compared with patients with PRCA who were registered in the Israeli National Cancer Registry (65 vs. 74.4 years, respectively; P<.001). When we examined two brothers with PRCA, we found a heterozygous 471delAAAG mutation in one and a homozygous mutation in the other. Loss of heterozygosity was demonstrated in the tumor of the heterozygous sib. Taken together, these data suggest that the 471delAAAG null mutation is associated with PRCA in Ashkenazi men. However, additional studies are required to determine whether this mutation confers increased risk for PRCA in this population.
Patients with advanced melanoma usually do not benefit from conventional chemotherapy treatment. There is therefore a true need for a new kind of therapy for melanoma. One factor responsible for the poor prognosis of melanoma is the inhibitor of apoptosis protein (IAP) family member Livin. In this study, we applied a novel approach for the treatment of melanoma, using a unique strain of the oncolytic Newcastle disease virus (NDV-HUJ). We found that, unlike chemotherapeutic drugs, NDV-HUJ, a one-cycle replicating virus, overcomes the resistance to apoptosis of melanoma primary cultures that over express the Livin protein. Newcastle disease virus (NDV) is an avian paramyxovirus that has a potential selective oncolytic effect on human tumors (5,7,13,21,25, 26). NDV's natural host is avian, and while mammalian cells bear the sialic acid receptor for NDV and may be infected by the virus, the virus has limited replication capacity in normal mammalian cells (21). We recently reported the development of an attenuated (lentogenic) isolate of NDV (HUJ) that undergoes only one cycle replication in infected mammalian cells (7,25). NDV-HUJ is a single clone derived from the parental strain NDV Hitchner B1, which contains a mixed viral population. The new virus clone is attenuated due to multiple passages in specific-pathogen-free (SPF) eggs, and its intracerebral pathogenicity index (ICPI) value is low (an ICPI of 0.01 versus an ICPI of 0.93 for the parental NDV Hitchner B1). Sequence analysis of NDV-HUJ indicated 156 changes at the nucleotide sequence level and multiple amino acid changes from the parental B1 virus in all six viral genes (see Fig. S1 in the supplemental material). Although NDV-HUJ is an attenuated virus in chicken, it retains a selective cytotoxic potential for cancer cells, as determined in vitro and in vivo, using murine and human lung carcinomas (25). The oncolytic effect of the virus is apoptosis dependent (25).NDV-HUJ has been applied to treat glioblastoma patients in a phase I/II clinical trials and found to be safe and potentially active (7).The inhibitors of apoptosis proteins (IAPs) are receiving increased attention as key players in the initiation of tumors, their progression, and resistance to chemotherapy treatment (17). To date, eight human IAPs have been identified, including Livin. IAPs are characterized by one or more repeats of a highly conserved 70-amino-acid domain termed the baculovirus IAP repeat (BIR) that can bind and inhibit caspases, some IAPs also contain a conserved sequence termed the RING finger. RING finger proteins might function as E3 ubiquitin ligases; however, the exact nature of the E3 ligase activity of IAPs is still largely unclear.IAPs inhibit apoptosis induced by a variety of stimuli, mainly through their ability to bind and inhibit specific caspases (17). Intense study has shown that the role of IAP in apoptosis regulation is highly diverse, with a prominent role in tumorigenesis and resistance to therapy. Among the human IAPs, XIAP is the best characterized and the m...
Variation in the penetrance estimates for BRCA1 and BRCA2 mutation carriers suggests that other genetic polymorphisms may modify the cancer risk in carriers. The RAD51 gene, which participates in homologous recombination double-strand breaks (DSB) repair in the same pathway as the BRCA1 and BRCA2 gene products, is a candidate for such an effect. A single-nucleotide polymorphism (SNP), RAD51-135g-c, in the 5 0 untranslated region of the gene has been found to elevate breast cancer (BC) risk among BRCA2 carriers. We genotyped 309 BRCA1/2 mutation carriers, of which 280 were of Ashkenazi origin, 166 noncarrier BC patients and 152 women unaffected with BC (a control group), for the RAD51-135g-c SNP. Risk analyses were conducted using COX proportional hazard models for the BRCA1/2 carriers and simple logistic regression analysis for the noncarrier case -control population. BRCA2 carriers were also studied using logistic regression and Kaplan -Meier survival analyses. The estimated BC hazard ratio (HR) for RAD51-135c carriers adjusted for origin (Ashkenazi vs non-Ashkenazi) was 1.28 (95% CI 0.85 -1.90, P ¼ 0.23) for BRCA1/2 carriers, and 2.09 (95% CI 1.04 -4.18, P ¼ 0.04) when the analysis was restricted to BRCA2 carriers. The median BC age was younger in BCRA2-RAD51-135c carriers (45 (95% CI 36 -54) vs 52 years (95% CI 48 -56), P ¼ 0.05). In a logistic regression analysis, the odds ratio (OR) was 5.49 (95% CI 0.5 -58.8, P ¼ 0.163). In noncarrier BC cases, carrying RAD51-135c was not associated with BC risk (0.97; 95% CI 0.47 -2.00). These results indicate significantly elevated risk for BC in carriers of BRCA2 mutations who also carry a RAD51-135c allele. In BRCA1 carriers and noncarriers, no effect for this SNP was found.
Carriers of germline mutations in BRCA1 or BRCA2 are at substantially increased risk of both breast (BC) and ovarian cancer (OC). There are, however, significant differences in the penetrance estimates generated by different studies. Studies by the Breast Cancer Linkage Consortium (BCLC) have estimated that cumulative risks of BC and OC, by age 70, are approximately 70% and 40%, respectively, in BRCA1 carriers, and 70% and 27% in BRCA2 carriers (Easton et al, 1995;Ford et al, 1998). In contrast, risk estimates based on relatives of unselected BC and OC patients with mutations have generally been somewhat lower (Streuwing et al, 1997;Thorlacius et al, 1998;Peto et al, 1999). Although some of this difference may be due to differences in risk conferred by different mutations, it is likely that modification of risk by other genes or environmental risk factors clustering in families explain most of this difference. It is also possible that these modifying genes are associated with variation in risk in non-carriers.Two population-based case-control studies, based on 368 BC cases diagnosed below age 40 (Spurdle et al, 1999) and 508 BC cases diagnosed below age 55 (Dunning et al, 1999) respectively, have examined the association between CAG repeat length and BC risk, and neither found any evidence of an interaction. However, a recent study of 304 BRCA1 carriers by Rebbeck et al (1999) found that longer repeat lengths, particularly genotypes with ≥28 repeats, were associated with a higher risk of breast cancer.In an attempt to replicate this latter observation, we have genotyped the AR repeats in a large series of BRCA1/2 carriers, mainly from an Ashkenazi Jewish study in Israel. We also studied an unselected series of Ashkenazi BC cases and controls for comparison. This population has a strong founder effect such that 3 mutations, the 185delAG and 5382insC mutations in BRCA1 and the 617delT mutation in BRCA2, account for almost all the BRCA1/2 carriers in this population and have a combined population frequency of about 2.5% (Struewing et al, 1997). SUBJECTS AND METHODS Study populationTwo populations were studied; BRCA1/2 carriers and non-carrier BC patients and controls. Blood samples from 188 BRCA1/2 carriers were identified through two centres: 142 were collected The Royal Marsden NHS Trust, Sutton, UK Summary Variation in the penetrance estimates for BRCA1 and BRCA2 mutations carriers suggests that other genetic polymorphisms may modify the cancer risk in carriers. A previous study has suggested that BRCA1 carriers with longer lengths of the CAG repeat in the androgen receptor (AR) gene are at increased risk of breast cancer (BC). We genotyped 188 BRCA1/2 carriers (122 affected and 66 unaffected with breast cancer), 158 of them of Ashkenazi origin, 166 BC cases without BRCA1/2 mutations and 156 Ashkenazi control individuals aged over 56 for the AR CAG and GGC repeats. In carriers, risk analyses were conducted using a variant of the log-rank test, assuming two sets of risk estimates in carriers: penetrance estima...
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