RESUMO
It is well known that founder mutations associated with cancer risk have useful implications for molecular diagnostics. We report the presence of a founder mutation in EPCAM involved in the etiology of Lynch syndrome (LS). The mutation extends nearly 8.7 kb (c.858 + 2478_*4507del) and is shared by 8 Polish families. Family members suffered almost exclusively from colorectal cancer; however, pancreatic and gastric cancers were also apparent. Next to mutations c. 2041G>A in MLH1 gene and c.942+3A>T in MSH2, the deletion mutation encompassing EPCAM is one of the most common causative changes responsible for LS in Poland.
Assuntos
Sequência de Bases , Neoplasias Colorretais Hereditárias sem Polipose/genética , Molécula de Adesão da Célula Epitelial/genética , Proteína 2 Homóloga a MutS/genética , Neoplasias Pancreáticas/genética , Deleção de Sequência , Neoplasias Gástricas/genética , Adulto , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Feminino , Efeito Fundador , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patologia , Linhagem , Mutação Puntual , Polônia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologiaRESUMO
The aim of the study is to identify treatments which predict survival for women with a BRCA1 mutation, including oophorectomy and chemotherapy. 476 women with stage I to stage III breast cancer who carried a BRCA1 mutation were followed from diagnosis until April 2015. Information on treatment was obtained from chart review and patient questionnaires. Dates of death were obtained from the Poland vital statistics registry. Survival curves were compared for different subgroups according to treatment received. Predictors of overall survival were determined using the Cox proportional hazards model. The ten-year overall survival was 78.3 % (95 % CI 74.2-82.6 %) and the ten-year breast cancer-specific survival was 84.2 % (95 % CI 80.5-88.0 %). Sixty-two patients died of breast cancer, 14 patients died of ovarian cancer, and 2 patients died of peritoneal cancer. Oophorectomy was associated with a significant reduction in all-cause mortality in the entire cohort (adjusted HR = 0.41; 95 % CI 0.24-0.69; p = 0.0008) and in breast cancer-specific mortality among ER-negative breast cancer patients (HR = 0.44; 95 % CI 0.22-0.89; p = 0.02). Among women with breast cancer and a BRCA1 mutation, survival is greatly improved by oophorectomy due to the prevention of deaths from both breast and ovarian cancer.
Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/mortalidade , Neoplasias Ovarianas/mortalidade , Ovariectomia/métodos , Adulto , Idoso , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Tratamento Farmacológico , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/cirurgia , Modelos de Riscos Proporcionais , Fatores de Risco , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
The purpose of this study is to estimate 10-year survival rates for patients with early onset breast cancer, with and without a CHEK2 mutation and to identify prognostic factors among CHEK2-positive breast cancer patients. 3,592 women with stage I to stage III breast cancer, diagnosed at or below age 50, were tested for four founder mutations in the CHEK2 gene. Information on tumor characteristics and on treatments received was retrieved from medical records. Dates of death were obtained from the Poland Vital Statistics Registry. Survival curves were generated for the mutation-positive and -negative sub-cohorts. Predictors of survival were determined among CHEK2 carriers using the Cox proportional hazards model. 3,592 patients were eligible for the study, of whom 140 (3.9 %) carried a CHEK2-truncating mutation and 347 (9.7 %) carried a missense mutation. The mean follow-up was 8.9 years. The 10-year survival for all CHEK2 mutation carriers was 78.8 % (95 % CI 74.6-83.2 %) and for non-carriers was 80.1 % (95 % CI 78.5-81.8 %). Among women with a CHEK2-positive breast cancer, the adjusted hazard ratio associated with ER-positive status was 0.88 (95 % CI 0.48-1.62). Among women with an ER-positive breast cancer, the adjusted hazard ratio associated with a CHEK2 mutation was 1.31 (95 % CI 0.97-1.77). The survival of women with breast cancer and a CHEK2 mutation is similar to that of patients without a CHEK2 mutation.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Quinase do Ponto de Checagem 2/genética , Mutação , Adulto , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Epidemiologia Molecular , Polônia/epidemiologia , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
To identify characteristic features of breast cancers associated with an NBS1 mutation. To estimate and to compare 10-year survival rates for patients with early-onset breast cancer, with and without an NBS1 mutation. 4,566 women with stage I to stage III breast cancer, diagnosed at or below age 50, were tested for a founder mutation in the NBS1 gene. Information on tumor characteristics and on treatments received was retrieved from medical records. Dates of death were obtained from the Poland vital statistics registry. Survival curves for the mutation-positive and negative sub-cohorts were generated and were compared and the effect of an NBS1 mutation on survival was determined using the Cox proportional hazards model. 4566 patients were enrolled in the study, of whom 53 (1.2 %) carried a NBS1 mutation. Mutation carriers were similar to non-carriers in terms of tumor receptor status, grade, and lymph node status. The 10-year survival for NBS1 mutation carriers was 81.2 % (95 % CI 70.1-94.1 %) and for non-carriers was 79.4 % (95 % CI 78.0-80.9 %). The presence of an NBS1 mutation is not associated with prognosis (HR = 1.21; 95 % 0.67-2.19). The survival of women with breast cancer and a NBS1 mutation is similar to that of patients without a NBS1 mutation.
Assuntos
Neoplasias da Mama/genética , Proteínas de Ciclo Celular/genética , Proteínas Nucleares/genética , Adulto , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Feminino , Efeito Fundador , Estudos de Associação Genética , Humanos , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Risco , Adulto JovemRESUMO
PURPOSE: There have been no studies to date which look at the relative effectiveness of different regimens of chemotherapy in women who have breast cancer and who carry a BRCA1 germ-line mutation. We wished to compare rates of response to neo-adjuvant chemotherapy in BRCA1 mutation carriers and non-carrier controls. EXPERIMENTAL DESIGN: From a registry of 3,479 patients, we identified 44 Polish women who carried a BRCA1 founder mutation and who had been treated with neo-adjuvant chemotherapy for breast cancer, and 41 age- and hospital-matched controls. RESULTS: 35 of the 44 BRCA1 mutation carriers (80%) experienced a partial or complete response to neo-adjuvant chemotherapy, compared to 39 of the 41 (95%) non-carriers (P=0.05). In the hereditary subgroup, response rates differed depending on whether or not a taxane (docetaxel) was given. Six of the 15 BRCA1 carrier women given docetaxel with doxorubicin responded (complete or partial), compared to 29 of 29 given other (DNA-damaging) therapies (P=0.001). Among the non-carriers, the rates of response to the two categories of chemotherapy were similar. CONCLUSIONS: Breast cancers among BRCA1 carriers frequently do not exhibit sensitivity to docetaxel in the neo-adjuvant setting. It is likely that normal BRCA1 is required for clinical response to mitotic spindle poisons.