The aim of this study is to estimate the frequency of pathologic complete response (pCR) after neoadjuvant treatment with cisplatin chemotherapy in women with breast cancer and a BRCA1 mutation. One hundred and seven women with breast cancer and a BRCA1 mutation, who were diagnosed with stage I to III breast cancer between December 2006 and June 2014, were treated with cisplatin 75 mg/m(2) every 3 weeks for four cycles, followed by mastectomy and conventional chemotherapy. Information was collected on clinical stage, grade, hormone receptor status, and Her2neu status prior to treatment. pCR was determined by review of surgical specimens. One hundred and seven patients were enrolled in the study, including 93 patients who were treated for first primary breast cancer and 14 patients who had previously received treatment for a prior cancer. A pCR was observed in 65 of the 107 patients (61 %). Platinum-based chemotherapy is effective in a high proportion of patients with BRCA1-associated breast cancer.
Background: Germline mutations in the Chek2 kinase gene (CHEK2) have been associated with a range of cancer types. Recently, a large deletion of exons 9 and 10 of CHEK2 was identified in several unrelated patients with breast cancer of Czech or Slovak origin. The geographical and ethnic extent of this founder allele has not yet been determined. Participants and methods: We assayed for the presence of this deletion, and of three other CHEK2 founder mutations, in 1864 patients with prostate cancer and 5496 controls from Poland. Results: The deletion was detected in 24 of 5496 (0.4%) controls from the general population, and is the most common CHEK2 truncating founder allele in Polish patients. The deletion was identified in 15 of 1864 (0.8%) men with unselected prostate cancer (OR 1.9; 95% CI 0.97 to 3.5; p = 0.09) and in 4 of 249 men with familial prostate cancer (OR 3.7; 95% CI 1.3 to 10.8; p = 0.03). These ORs were similar to those associated with the other truncating mutations (IVS2+1GRA, 1100delC). Conclusion: A large deletion of exons 9 and 10 of CHEK2 confers an increased risk of prostate cancer in Polish men. The del5395 founder deletion might be present in other Slavic populations, including Ukraine, Belarus, Russia, Baltic and Balkan countries. It will be of interest to see to what extent this deletion is responsible for the burden of prostate cancer in other populations.
There is increasing evidence that hereditary factors play a greater role in ovarian cancer than in any of the other common cancers of adulthood. This is attributable, to a large extent, to a high frequency of mutations in the BRCA1 or BRCA2 genes. In Poland, 3 common founder mutations in BRCA1 account for the majority of families with identified BRCA mutations. Our study was conducted in order to estimate the prevalence of any of 3 founder BRCA1 mutations (5382insC, C61G and 4153delA) in 364 unselected women with ovarian cancer, and among 177 women with ovarian cancer and a family history of breast or ovarian cancer. A mutation was identified in 49 out of 364 unselected women with ovarian cancer (13.5%) and in 58 of 177 women with familial ovarian cancer (32.8%). The majority of women with ovarian cancer and a BRCA1 mutation have no family history of breast or ovarian cancer. The high frequency of BRCA1 mutations in Polish women with ovarian cancer supports the recommendation that all Polish women with ovarian cancer should be offered testing for genetic susceptibility, and that counseling services be made available to them and to their relatives. It is important that mutation surveys be conducted in other countries prior to the introduction of national genetic screening programs.
Evidence to date that BRCA1 mutation carriers are at an increased risk of prostate cancer is mixed - both positive and negative studies have been published. To establish whether or not inherited variation in BRCA1 influences prostate cancer risk we genotyped 1793 men with prostate cancer in Poland and 4570 controls for three founder mutations (C61G, 4153delA and 5382insC). A BRCA1 mutation was present in 0.45% of the cases and 0.48% of the controls (odds ratio=0.9; P=1.0). The odds ratios varied substantially by mutation. The 5382insC mutation is the most common of the three founder mutations. It was detected only in one case (0.06%), whereas it was seen in 0.37% of controls (P=0.06). In contrast, the 4153delA was more common in prostate cancer cases (0.22%) than in controls (0.04%) (odds ratio=5.1; 95% confidence interval: 0.9-27.9; P=0.1). The C61G mutation was also found in excess in cases (0.17%) compared with controls (0.07%) (odds ratio=2.6; 95% confidence interval: 0.5-12.7; P=0.5). Eight men with prostate cancer carried a mutation. Only one of these carried the 5382insC mutation, compared with 17 of 22 individuals with mutations in the control population (P=0.003). These data suggest that the 5382insC mutation is unlikely to be pathogenic for prostate cancer in the Polish population. The presence of one of the other alleles was associated with an increased risk for prostate cancer (odds ratio=3.6; 95% confidence interval: 1.1-11.3; P=0.045); in particular for familial prostate cancer (odds ratio=12; 95% confidence interval: 2.9-51; P=0.0004). We consider that the risk of prostate cancer in BRCA1 carriers varies with the position of the mutation.
Three di erent novel BRCA1 mutations, ®ve independent cases of the same 12 bp insertion-duplication in intron-20 and two novel rare BRCA1 sequence variants were identi®ed among 122 Polish women with positive, in most cases moderate family history of breast and/or ovarian cancer, 80 controls and 34 unselected breast cancer tissue specimens. All mutations and variants were germline. The 4153 delA frameshift mutation, the Tyr105Cys missense mutation and two cases of the alteration in intron-20 were found in the group of healthy women with positive family history. Two other cases of the intronic insertion were found in unselected controls. Their carriers had no family history of breast or ovarian cancer but other cancers occurred in their families. The 1782 Trp/STOP nonsense mutation and one case of the insertion in intron-20 were ®rst found in tissue specimens of breast cancer patient and breast/ovarian cancer patient, respectively. Their carriers also had no family history of breast or ovarian cancer. The distribution of the insertion in intron-20 in analysed groups and results of RT ± PCR experiments suggest a less prominent role for this variant considered earlier a splicing mutation. This study shows also, that more population-oriented research is needed, involving women with less profound or even no family history of breast and ovarian cancer, to better understand the role and signi®cance of di erent BRCA1 variants and mutations.Keywords: BRCA1; mutations and variants; SSCPheteroduplex analysis; Polish women; positive family history IntroductionApproximately one in ten women in western countries will develop breast cancer during their lifetime . In most cases the disease is sporadic; however, some 5 ± 10% of women with breast cancer inherit increased susceptibility to the disease (Claus et al., 1991). Within this fraction of breast cancer the germline mutations in BRCA1 (Miki et al., 1994) and BRCA2 genes most frequently form a favorable genetic background for the disease. Also at increased risk are the carriers of one abnormal allele of the ataxia telangiectasia gene (Swift et al., 1991), the carriers of rare minisatelite allele at the HRAS1 locus (Krontiris et al., 1993) and the members of Li Fraumeni families with germline mutation in the p53 gene (Srivastava et al., 1990).The BRCA1 gene located on chromosome 17q21 (Hall et al., 1990) is also linked to hereditary ovarian cancer (Narod et al., 1991). More than 400 BRCA1 sequence variants have been identi®ed thus far and deposited in Breast Cancer Information Core Database (Friend et al., 1995) which now contains about 150 di erent cancer predisposing mutations. Most of this knowledge comes from studies of breast and breastovarian cancer families. Therefore the known mutations are probably biased towards those with more severe e ects on phenotype. It is expected that less expressive mutations will be identi®ed when studies expand and include women with less profound family history and women from the general population. It is also very likely that the inciden...
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