The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations

International audienceBACKGROUND:Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers.METHODS:Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort.RESULTS:For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc = 0.79, 95% CI = 0.69 to 0.91; HRc = 0.70, 95% CI = 0.59 to 0.82; HRc = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively, P trend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort P trend = .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] = 1.69, 95% CI = 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc = 0.72, 95% CI = 0.54 to 0.98).CONCLUSIONS:These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers

Correction to: Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers.

After publication of the original article [1], we were notified that columns in Table 2 were erroneously displayed

Non contribution de la délétion CTT de la région 3'UTR du gène MLH1 au déterminisme génétique du Syndrome de Lynch

Le syndrome de Lynch ou syndrome HNPCC (Hereditary Non Polyposis Colorectal Cancer) est la forme la plus fréquente de cancer colorectal héréditaire. De transmission autosomique dominante, il est lié à une mutation constitutionnelle de l'un des 4 gènes du système MMR de réparation de l'ADN : MLH1, MSH2, MSH6 et PMS2. La première anomalie de la région 3'UTR d'un gène MMR, avec conséquence fonctionnelle démontrée a été identifiée en 2008 et posait d'emblée la question de son implication dans le syndrome de Lynch. Nous avons donc recherché cette délétion de 3 paires de base (CTT) de la région 3'UTR du gène MLH1 [NM_000249.2:c.*35_*37del (p?)] chez 527 patients sélectionnés sur leur histoire clinique, répondant aux critères d'Amsterdam ou associée à un phénotype d'instabilité microsatellitaire au niveau tumoral, le criblage a été réalisé par la méthode de QMPSF, Quantitative Multiplex PCR of Short Fluorescent fragment. Trois éléments de notre étude permettent clairement de montrer que la délétion CTT de la région 3'UTR du gène MLH1 ne suffit pas à induire un syndrome de Lynch : (i) la fréquence allélique de cette variation chez ces patients n'est pas supérieure à celle observée dans une population témoin dont la fréquence allélique correspond aux données de la littérature, (ii) nous avons mis en évidence cette variation à l'état homozygote chez une patiente dont le tableau clinique correspondait à un syndrome de Lynch et non aux atteintes décrites dans les cas d'ihactivation biallélique des gènes du système MMR (hémopathies, tumeurs cérébrales et colorectales chez l'enfant), (iii) nous avons identifié cette délétion de 3 paires de base du 3'UTR du gène MLH1 associée à une mutation délétère du gène MSH2 chez une patiente dont la tumeur présentait une extinction somatique de la protéine MSH2. Ainsi notre étude permet clairement de réfuter le rôle causal de l'altération du 3'UTR du gène MLH1 dans le syndrome de Lynch. En revanche nous ne pouvons exclure que cette variation dont la fréquence allélique est de 3.5 % dans la population générale soit un facteur modificateur chez des patients présentant une mutation délétère d'un gène MMR ou corresponde à un facteur de risque accru de cancer colorectal dans la population générale. Ces 2 hypothèses pourraient être testées en étudiant d'une part l'impact de cette variation sur un paramètre simple (âge d'apparition des tumeurs) chez les porteurs d'une mutation des gènes MMR et, d'autre part, par des études d'association sur de grandes séries de patients présentant un cancer colorectal sporadique versus une population contrôle appariée au niveau de l'âge et du fonds génétique.ST ETIENNE-BU Médecine (422182102) / SudocSudocFranceF

The UMD-APC Database, a Model of Nation-Wide Knowledge Base: Update with Data from 3,581 Variations

International audienceFamilial adenomatous polyposis (FAP) is a rare autosomal-inherited disease that highly predisposes to colorectal cancer, characterized by a diffuse duodenal and colorectal polyposis associated with various extradigestive tumors and linked to germline mutations within the APC gene. A French consortium of laboratories involved in APC mutation screening has progressively improved the description of the variation spectrum, inferred functional significance of nontruncating variations, and delineated phenotypic characteristics of the disease. The current version of the UMD-APC database is described here. The total number of variations has risen to 5,453 representing 1,473 distinct variations. The published records initially registered into the database were extended with 3,581 germline variations found through genetic testing performed by the eight licensed laboratories belonging to the French APC network. Sixty six of 149 variations of previously unknown significance have now been classified as (likely) causal or neutral. The database is available on the Internet (http://www.umd.be/APC/) and updated twice per year according to the consensus rules of the network. The UMD-APC database is thus expected to facilitate functional classification of rare synonymous, nonsynonymous, and intronic mutations and consequently improve genetic counseling and medical care in FAP families

Diversity of the clinical presentation of the MMR gene biallelic mutations

International audienceConstitutional mismatch repair-deficiency, due to biallelic mutations of MMR genes, results in a tumour spectrum characterized by leukaemias, lymphomas, brain tumours and adenocarcinomas of the gastro-intestinal tract, occurring mostly in childhood. We report here two families illustrating the phenotypic diversity associated with biallelic MMR mutations. In the first family, two siblings developed six malignancies including glioblastoma, lymphoblastic T cell lymphoma, rectal and small bowel adenocarcinoma with onset as early as 6 years of age. We showed that this dramatic clinical presentation was due to the presence of two complex genomic PMS2 deletions in each patient predicted to result into complete PMS2 inactivation. In the second family, the index case presented with an early form of Lynch syndrome with colorectal adenocarcinomas at ages 17 and 20 years, and urinary tract tumours at the age of 25 years. We identified in this patient two MSH6 mutations corresponding to a frameshift deletion and an in frame deletion. The latter was not predicted to result into complete inactivation of MSH6. These reports show that the clinical expression of biallelic MMR mutations depends on the biological impact of the second MMR mutation and that, in clinical practice, the presence of a second MMR mutation located in trans should also be considered in patients suspected to present a Lynch syndrome with an unusual early-onset of tumours

Variation in breast cancer risk associated with factors related to pregnancies according to truncating mutation location, in the French National BRCA1/2 carrier cohort (GENEPSO).

International audienceABSTRACT: INTRODUCTION: Mutations in BRCA1 and BRCA2 confer a high risk of breast cancer (BC), but the magnitude of this risk seems to vary according to the study and various factors. Although controversial, there are data to support the hypothesis of allelic risk heterogeneity. METHODS: We assessed variation in BC risk according to factors related to pregnancies by location of mutation in homogeneous risk region of BRCA1 and BRCA2 in 990 women of the French study GENEPSO by using a weighted Cox regression model. RESULTS: Our results confirm the existence of a protective effect of an increasing number of full-term pregnancies (FTPs) toward BC among BRCA1 and BRCA2 mutation carriers ([greater than or equal to]3 vs. 0 FTPs: HR=0.51, 95% CI=0.33-0.81). Additionally, hazard ratio (HR) show an association between incomplete pregnancies and a higher BC risk, which reached 2.39 (95% CI=1.28-4.45) among women who had at least three incomplete pregnancies when compared with women with zero incomplete pregnancies. This increased risk appeared to be restricted to incomplete pregnancies occurring before the first FTP (HR=1.77, 95% CI=1.19-2.63). We defined the TMAP score (defined as the Time of breast Mitotic Activity during Pregnancies) to take into account simultaneously the opposite effect of full-term and interrupted pregnancies. Compared with women with a TMAP score of less than 0.35, an increasing TMAP score was associated with a statistically significant increase in the risk of BC (P trend=0.02) which reached 1.97 (95% CI=1.19-3.29) for a TMAP score > 0.5 (vs. TMAP less than or equal to 0.35). All these results appeared to be similar in BRCA1 and BRCA2. Nevertheless, our results suggest a variation in BC risk associated with parity according to the location of the mutation in BRCA1. Indeed, parity seems to be associated with a significantly decreased risk of BC only among women with a mutation in the central region of BRCA1 (low-risk region) (greater than or equal to 1 vs. 0 FTP: HR=0.27, 95% CI=0.13-0.55) (pinteraction <10-3). CONCLUSION: Our findings show that, taking into account environmental and lifestyle modifiers, mutation position might be important for the clinical management of BRCA1 and BRCA2 mutation carriers and could also be helpful in understanding how BRCA1 and BRCA2 genes are involved in BC