Établissement d'une cohorte de patientes ayant consulté à l'Institut de Cancérologie de Lorraine et porteuses de la mutation BRCA1-3600del11 : étude descriptive des caractéristiques cliniques et anatomo-pathologiques des cancers du sein et de l'ovaire dans cette cohorte : mise en évidence d'un phénomène d'anticipation génétique dans 38 paires mères-filles atteintes de cancer du sein ou de l'ovaire

Abstract : Introduction: Over 1000 alterations in the BRCA1 gene have been documented. Most of these are frameshifts and ~10% are missense mutations that generate stop codons leading to a truncated and therefore inactive BRCA1 protein. In the French population, prevalence of BRCA1 mutations has been reported in few studies; In a preliminary study of 14 breast and/or ovarian cancer families, a frequent BRCA1 mutation was detected in five unrelated families; the c.3481_3491del11 mutation (BIC: 3600del11), an 11 base-pair deletion in exon 11 leading to a premature stop codon at 1165. In a second study carried out in 2004 involving 27 index cases, the c.3481_3491del11 mutation accounted for 37%. The haplotype analysis of the families carrying the mutation c.3481_3491del11, all originating from Alsace-Lorraine (North-East of France), revealed the presence of a common allele, indicating a founder effect. Purpose: To an attempt to better define the clinical and pathologic characteristics of breast and ovarian cancer related with the 3600del11 BRCA1 mutation, we report our experience with breast and ovarian cancer patients carrying the 3600del11 mutation at the Lorraine Oncology Institute in France. The aim of the current analysis is also to evaluate any differences of breast or ovarian cancer age at diagnosis between mothers and daughters carrying the c.3481_3491del11 mutation in the BRCA1 gene.Patients: Within the population who were referred between 1994 and 2012 to our oncogenetic clinic at the Lorraine oncology institute and who underwent genetic testing for BRCA1 and BRCA2, we identified 404 women carrying a BRCA1 mutation. Interestingly, 45% (180 of 404) of women with detected BRCA1 mutation had the germline 3600del11 mutation. These women were members of 89 different families with breast and or ovarian cancer cases. A study cohort of 38 women carrying the c.3481_3491del11 mutation and affected by first breast or ovarian cancer who reported a first breast or ovarian cancer in their mother carrying the c.3481_3491del11 mutation, was identified in 37 different families including members with breast and/or ovarian cancer at the Oncology Institute of Lorraine. Twelve mothers underwent genetic testing. Twenty five pairs of the 38 mothers-daughters pairs with c.3481_3491del11 mutation were affected by breast cancer and 13 pairs by ovarian cancer.Methods: Clinical and genetic data were collected from medical files and family pedigrees. Analyses were conducted for each cancer type. We investigated an early breast cancer detection effect due to early screening programs and also an increased breast tumor aggression. Since major improvements in breast cancer clinical management and imaging techniques appeared after 1980, we compared the age at breast cancer diagnosis and the age at death in mothers and daughters before and after 1980, first, in the group of women including mothers and daughters taken together and then in mothers and daughters separately. Genetic data were retrieved from familial files and clinical and pathological data from medical files. Descriptive statistics for the study population were calculated using the SPSS software (version 20.0). Results: Ninety one patients (71, 7%) were affected by first breast cancer and 31 (24,4%) by ovarian cancer. Breast tumors were identified in 37.4% of cases aged <40 years. Estrogen receptor status and progesterone receptor status were reported to 67 patients. Hormonal receptors status was positive in 31.4% of breast tumors. A triple-negative subtype was found in 21 cases, which accounts for 65.6% of the 32 patients with 3600del11 mutation for whom HER2 status was available. Ovarian tumors of the serous type, which constitute about 71 percent of all epithelial ovarian carcinomas, predominate among patients with 3600del11 mutation. Eighty six per cent of carriers were diagnosed at advanced stages III/IV [...]
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Rachelle El Tannouri. Établissement d'une cohorte de patientes ayant consulté à l'Institut de Cancérologie de Lorraine et porteuses de la mutation BRCA1-3600del11 : étude descriptive des caractéristiques cliniques et anatomo-pathologiques des cancers du sein et de l'ovaire dans cette cohorte : mise en évidence d'un phénomène d'anticipation génétique dans 38 paires mères-filles atteintes de cancer du sein ou de l'ovaire. Génétique. Université de lorraine, 2017. Français. ⟨NNT : 2017LORR0072⟩. ⟨tel-01759166⟩

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