Breast cancer is the most common cancer in South African women. Approximately 5¬10% of all breast cancer cases are due to an inherited predisposition, resulting from mutations in tumour suppressor genes. The BRCA1 gene on chromosome 17q is one such tumour suppressor gene, that when mutated confers an increased risk of breast/ovarian cancer in carriers. To date, more than 500 different BRCA 1 mutations have been reported worldwide. Some of these mutations are frequently reported and others occur commonly in certain population groups. These population-specific differences in mutations represent founder effects, whereby a single ancestral mutation accounts for the majority of breast cancer cases. This study was undertaken as the nature and frequency of BRCA1 mutations in South African breast/ovarian cancer families is unknown. Fifty-one breast/ovarian cancer families were screened for three commonly occurring mutations (185deIAG, 4184del4 and 5382insC) using polymerase chain reaction (PCR) and allele-specific oligonucleotide (ASO) hybridisation. The protein truncation test (PTT) was utilised to detect truncating mutations in the large exon 11, and the remaining coding exons were screened for mutations using exon-by-exon PCR single strand conformation polymorphism/heteroduplex analysis (SSCP/HA). Seven disease-causing mutations were identified in 15 families, consisting of five different frameshift mutations and two different nonsense mutations. Four Ashkenazi Jewish families were found to harbour the 185delAG mutation; the 5382insC mutation was identified in two Afrikaner families and one Ashkenazi Jewish family. Haplotype analysis revealed that the four Ashkenazi families share the common Ashkenazi Jewish haplotype, suggesting a common ancestor for these families. Similarly, the two Afrikaner families share the same haplotype as families of north and east European ancestry with the 5382insC mutation. The haplotype of the Ashkenazi Jewish family with this mutation was however different to the linked haplotype, indicating a recombination event or an independent mutation. Both these mutations are thought to have occurred in or before the medieval period. Furthermore, four Afrikaner families were found to carry the novel E881X nonsense mutation, which has not been previously described. Haplotype analysis of these families suggested that these patients share a common ancestor, and genealogic studies have identified the founding couple for this mutation, who both arrived in the Cape from France in the late 1600s. Four additional families were found to harbour BRCA1 mutations by SSCP/HA. Three of these mutations have not been previously reported - the S451X nonsense mutation (identified in a family of Scottish origin), the 1493delC mutation identified in an Afrikaner family, and the 4957insC mutation identified in an Indian family. The 448insA mutation was identified in a family of German origin, where the patient had cancer of the fallopian tubes. A number of different described polymorphisms and variants of unknown functional significance were also identified. This is the first study to show that BRCA1 is involved in South African breast/ovarian cancer families, to the extent that 29.4% (15/51) of families have BRCA1 mutations. Furthermore, minor founder effects in the Afrikaner population have been demonstrated. These results enable improved genetic counselling and clinical management of mutation positive families as well as subsequent testing of family members. / Dissertation (MSc (Human Genetics))--University of Pretoria, 2005. / Genetics / unrestricted

Contexte: La grande majorité des mutations délétères identifiées sur le gène BRCA1 sont des mutations « privées ». Cependant, certaines d’entre elles proviennent d’un ancêtre commun, à l’origine d’un effet fondateur. Ainsi, la mutation BRCA1-3600del11 (c.3481_3491del11, p.Glu1161Phefs*3) est localisée en France pour 82% des familles porteuses et 85% d’entre elles sont originaires du quart Nord-Est. En 2006, cette mutation représentait respectivement 51,5% et 42,0% de toutes les mutations du gène BRCA1 identifiées dans les familles lorraines et alsaciennes atteintes d’un cancer du sein et/ou de l’ovaire. En 2004, parmi les 27 cas-index ayant consulté en Alsace et présentant une mutation de BRCA1, 37% sont porteurs de cette mutation, tous issus de familles originaires des Vosges, suggérant l’existence d’un effet fondateur. L’identification d’un haplotype commun est venue confirmer l’existence de cette hypothèse. Une équipe alsacienne a mentionné dans deux publications en 2000 et 2004 sur la mise en évidence de la mutation 3600del11 que les caractéristiques des cancers associés à cette mutation, ne plaidaient pas en faveur d’une relation génotype-phénotype. Or, les caractéristiques anatomo-pathologiques des cancers associés à cette mutation n’ont pas été abordées par ces deux publications. Nous nous sommes alors posés la question de caractéristiques anatomo-pathologiques particulières des cancers du sein et des cancers de l’ovaire diagnostiqués chez les femmes porteuses de cette mutation dans notre région. Nous nous sommes également posés la question de l’existence d’un phénomène d’anticipation génétique dans ces familles. L’anticipation génétique est la survenue plus précoce d’une pathologie et/ou l’aggravation de ses signes cliniques lors de la transmission d’une mutation d’une génération à la suivante au sein d’une même famille. Très peu d’études ont cherché à mettre en évidence ce phénomène d’anticipation dans des cohortes issues de familles de syndrome sein-ovaire associées à une mutation de BRCA1 ou BRCA2. Les études publiées présentaient des biais de sélection du fait de l’inclusion de patients non testés dans leur analyse. Les études publiées sur des cohortes issues de familles présentant une mutation sur le gène BRCA1/2 suggéraient que le dépistage ciblé et l’excès de surveillance pourraient avoir une influence sur l’âge au diagnostic d’un cancer du sein chez les jeunes femmes incluses.Les améliorations majeures au niveau de la mammographie et du traitement du cancer du sein, de même que le programme de dépistage organisé pour les femmes de 50 ans et plus sont apparues en France, après 1980. A notre connaissance, à ce jour, aucune étude n’a été réalisée en France visant à identifier un phénomène d’anticipation génétique dans les familles associées à une mutation sur BRCA1ou BRCA2 et à analyser ce phénomène.Objectif: Notre premier objectif est de constituer une première cohorte lorraine de patientes porteuses de la mutation 3600del11 et d’analyser les caractéristiques anatomo-pathologiques des cancers du sein et de l’ovaire liés à cette mutation. Notre deuxième objectif rechercher l’existence d’une anticipation génétique dans des familles présentant la mutation fondatrice BRCA1-3600del11.Patientes: Quatre cent quatre patientes sont porteuses d’une mutation BRCA1 à l’Institut de Cancérologie de Lorraine (ICL) sur la période s’étendant de 1994 à 2012, parmi elles, nous avons identifié les patientes porteuses de la mutation BRCA1-3600del11. Nous avons identifié à l’Institut de Cancérologie de Lorraine, 38 paires mères-filles atteintes d’un cancer du sein ou de l’ovaire issues de 37 familles présentant le syndrome sein-ovaire associé à cette mutation dont 25 paires mères-filles atteintes d’un cancer du sein et 13 paires mères-filles atteintes d’un cancer de l’ovaire [...] / 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 [...]

Apie 5–10 proc. visų krūties navikų atvejų sudaro paveldimas vėžys. BRCA1 ir BRCA2 genai yra patys svarbiausi polinkį susirgti krūties vėžiu sąlygojantys genai. Kiti reikšmingai su padidėjusia krūties navikų išsivystymo rizika susiję – CHEK2 ir NBS1 genai. Šiame darbe ištirtos paveldimos dažniausiai Europos regione nustatomos šių genų mutacijos. Nustatytas BRCA1 ir CHEK2 genų mutacijų dažnis tarp jaunų krūties vėžiu susirgusių moterų, ištyrinėtos jų sąsajos su pacientės amžiumi, naviko klinikinėmis ir morfologinėmis savybėmis. Išanalizuota šeiminės anamnezės prognozinė vertė nustatant paveldimus BRCA1 ir CHEK2 genų pokyčius. Pirmą kartą Lietuvoje įsisavintas CHEK2 bei NBS1 genų tyrimas, nustatyta, kokios CHEK2 geno mutacijos dažniausios. Nors NBS1 geno mutacijų nerasta, bet įsisavinta metodika, kuri bus panaudota ateities tyrimams. Sukurtas kompleksinis BRCA1 bei CHEK2 genų mutacijų radimo prognozavimo modelis. Šiandien klinikinėje praktikoje panašūs modeliai naudojami įvertinti BRCA1/2 genų mutacijų tikimybę. Jų pritaikomumas ir specifiškumas skirtingose etninėse grupėse gali skirtis. Naudojant tirtų pacienčių charakteristikas, įtraukiant ne tik šeiminę anamnezę, pacientės ypatybes, bet ir klinikinius bei molekulinius navikų požymius, sukurti mūsų regionui pritaikyti modeliai bei nustatyti kriterijai, kurie padės atrinkti pacientes genetiniam konsultavimui dėl BRCA1 bei CHEK2 genų mutacijų. Šis naujas požiūris turi didžiulę praktinę naudą. / Approximately 5–10% of all breast cancer cases are considered to be hereditary. BRCA1 and BRCA2 genes are the most important breast cancer predisposing genes. Other genes significantly linked with an increased risk of breast tumors are CHEK2 and NBS1 gene. In this scientific work were studied the most prevalent in European region mutations of these genes. The rate of BRCA1 and CHEK2 gene mutations in young women with breast cancer was evaluated and the relationships between these mutations and patient's age, clinical and morphological tumor features are examined. The prognostic value of family history was analyzed when forecasting hereditary BRCA1 and CHEK2 gene mutations. For the first time in Lithuania the CHEK2, NBS1 genes tests were applied and the evaluation of which CHEK2 gene mutations are most prevalent was obtained. Although NBS1 gene mutations were not found, but applied test technique will be used in future research. There was created a prognostic model for determination of BRCA1 and CHEK2 gene mutations. In today's clinical practice similar models are used to assess the likelihood of the BRCA1/2 mutation. Their applicability and specificity in different ethnic groups may vary. Applying the studied data there was created a model adapted to our region. Testing patients, there were considered not only family medical history and personal characteristics, but also the clinical and molecular features of tumors. The criteria have been found which will help in selecting... [to full text]