Molecular apocrine differentiation is a common feature of breast cancer in patients with germline PTEN mutations

International audienceINTRODUCTION: Breast carcinoma is the main malignant tumor occurring in patients with Cowden disease, a cancer-prone syndrome caused by germline mutation of the tumor suppressor gene PTEN characterized by the occurrence throughout life of hyperplastic, hamartomatous and malignant growths affecting various organs. The absence of known histological features for breast cancer arising in a PTEN-mutant background prompted us to explore them for potential new markers. METHODS: We first performed a microarray study of three tumors from patients with Cowden disease in the context of a transcriptomic study of 74 familial breast cancers. A subsequent histological and immunohistochemical study including 12 additional cases of Cowden disease breast carcinomas was performed to confirm the microarray data. RESULTS: Unsupervised clustering of the 74 familial tumors followed the intrinsic gene classification of breast cancer except for a group of five tumors that included the three Cowden tumors. The gene expression profile of the Cowden tumors shows considerable overlap with that of a breast cancer subgroup known as molecular apocrine breast carcinoma, which is suspected to have increased androgenic signaling and shows frequent ERBB2 amplification in sporadic tumors. The histological and immunohistochemical study showed that several cases had apocrine histological features and expressed GGT1, which is a potential new marker for apocrine breast carcinoma. CONCLUSIONS: These data suggest that activation of the ERBB2-PI3K-AKT pathway by loss of PTEN at early stages of tumorigenesis promotes the formation of breast tumors with apocrine features

Increasing involvement of CAPN1 variants in spastic ataxias and phenotype-genotype correlations

Spastic ataxias are rare neurogenetic disorders involving spinocerebellar and pyramidal tracts. Many genes are involved. Among them, CAPN1, when mutated, is responsible for a complex inherited form of spastic paraplegia (SPG76). We report the largest published series of 21 novel patients with nine new CAPN1 disease-causing variants and their clinical characteristics from two European university hospitals (Paris and Stockholm). After a formal clinical examination, causative variants were identified by next-generation sequencing and confirmed by Sanger sequencing. CAPN1 variants are a rare cause (~ 1.4%) of young-adult-onset spastic ataxia; however, together with all published cases, they allowed us to better describe the clinical and genetic spectra of this form. Truncating variants are the most frequent, and missense variants lead to earlier age at onset in favor of an additional deleterious effect. Cerebellar ataxia with cerebellar atrophy, dysarthria and lower limb weakness are often associated with spasticity. We also suggest that cognitive impairment and depression should be assessed specifically in the follow-up of SPG76 cases.Identification of new causative genes in spinocerebellar degenerations by combination of whole genome scan, next-generation sequencing and biological validation in vitro and in vivoInfrastructure de Recherche Translationnelle pour les Biothérapies en NeurosciencesEuropean Union’s Horizon 2020 research and innovation programm

Genomic study of familial breast cancer

La découverte des gènes BRCA1 et BRCA2, ainsi que leurs altérations constitutionnelles dans les formes familiales de cancer du sein, a conduit à la prise en compte en pratique médicale des syndromes de prédisposition héréditaire de ce cancer (5% des cas). Cependant, une altération délétère de l’un de ces gènes n’est détectée que dans 30 % des cas environ. Plus de la moitié des suspicions cliniques de prédisposition héréditaire au cancer du sein reste aujourd’hui inexpliquée sur le plan mutationnel, même si de nombreux autres gènes ont été impliqués dans la majoration du risque de survenue du cancer du sein (TP53, PTEN, FGFR2), témoignant d’une importante hétérogénéité génétique. Récemment, des profils transcriptionnels ou génomiques ont été testés pour prédire l’implication de BRCA1 ou BRCA2 avec une certaine efficacité. Il est donc possible que d’autres gènes de prédisposition au cancer du sein, dénommés BRCAx, occasionnent la survenue de tumeurs au profil génomique et/ou transcriptionnel spécifique, caractérisant ainsi autant d’endophénotypes tumoraux. Notre projet consiste en l’étude par CGH-array et puces d’expression de 103 échantillons tumoraux avec une forte suspicion familiale. L’analyse de nos résultats suggère l’existence de sous-groupes tumoraux aux profils génomiques bien différenciés. De plus, nous avons pu établir une signature des tumeurs BRCA1, des tumeurs BRCA2, et des cancers du sein intervenant dans le cadre d’un syndrome de la maladie de Cowden.The discovery of the BRCA1 and BRCA2 genes, along with their germline alterations in familial forms of breast cancer, led to the recognition of hereditary cancer predisposition syndromes in clinical practice (5% of cases). However, a deleterious alteration in one of these genes is not detected in approximately 30% of cases. To date, the underlying genetic cause of more than half of clinically suspected hereditary breast cancer predisposition remains unidentified despite the fact that several other genes have been associated with an increased risk of breast cancer (TP53, PTEN, FGFR2), demonstrating that there is significant genetic heterogeneity in this form of cancer. Transcriptomic and genomic profiles linked to BRCA1 or BRCA2 alterations have recently been identified and were used to predict (with a certain efficacy) if these genes are implicated in other breast cancers. It is therefore possible that other breast cancer predisposition genes (named BRCAx) could associate with breast cancer risk in transcriptomic and/or genomic profiles and characterise novel tumour endophenotypes. The project consists of a CGH-array and microarray study of 103 tumour samples from patients with clinically diagnosed familial breast cancer. Our results provide evidence of the existence of tumour subgroups with significantly different genomic profiles. In addition, we were able to establish a signature for BRCA1 tumours, another for BRCA2 tumours and a third signature for breast cancers resulting from Cowden syndrome

Genomic study of familial breast cancer

La découverte des gènes BRCA1 et BRCA2, ainsi que leurs altérations constitutionnelles dans les formes familiales de cancer du sein, a conduit à la prise en compte en pratique médicale des syndromes de prédisposition héréditaire de ce cancer (5% des cas). Cependant, une altération délétère de l’un de ces gènes n’est détectée que dans 30 % des cas environ. Plus de la moitié des suspicions cliniques de prédisposition héréditaire au cancer du sein reste aujourd’hui inexpliquée sur le plan mutationnel, même si de nombreux autres gènes ont été impliqués dans la majoration du risque de survenue du cancer du sein (TP53, PTEN, FGFR2), témoignant d’une importante hétérogénéité génétique. Récemment, des profils transcriptionnels ou génomiques ont été testés pour prédire l’implication de BRCA1 ou BRCA2 avec une certaine efficacité. Il est donc possible que d’autres gènes de prédisposition au cancer du sein, dénommés BRCAx, occasionnent la survenue de tumeurs au profil génomique et/ou transcriptionnel spécifique, caractérisant ainsi autant d’endophénotypes tumoraux. Notre projet consiste en l’étude par CGH-array et puces d’expression de 103 échantillons tumoraux avec une forte suspicion familiale. L’analyse de nos résultats suggère l’existence de sous-groupes tumoraux aux profils génomiques bien différenciés. De plus, nous avons pu établir une signature des tumeurs BRCA1, des tumeurs BRCA2, et des cancers du sein intervenant dans le cadre d’un syndrome de la maladie de Cowden.The discovery of the BRCA1 and BRCA2 genes, along with their germline alterations in familial forms of breast cancer, led to the recognition of hereditary cancer predisposition syndromes in clinical practice (5% of cases). However, a deleterious alteration in one of these genes is not detected in approximately 30% of cases. To date, the underlying genetic cause of more than half of clinically suspected hereditary breast cancer predisposition remains unidentified despite the fact that several other genes have been associated with an increased risk of breast cancer (TP53, PTEN, FGFR2), demonstrating that there is significant genetic heterogeneity in this form of cancer. Transcriptomic and genomic profiles linked to BRCA1 or BRCA2 alterations have recently been identified and were used to predict (with a certain efficacy) if these genes are implicated in other breast cancers. It is therefore possible that other breast cancer predisposition genes (named BRCAx) could associate with breast cancer risk in transcriptomic and/or genomic profiles and characterise novel tumour endophenotypes. The project consists of a CGH-array and microarray study of 103 tumour samples from patients with clinically diagnosed familial breast cancer. Our results provide evidence of the existence of tumour subgroups with significantly different genomic profiles. In addition, we were able to establish a signature for BRCA1 tumours, another for BRCA2 tumours and a third signature for breast cancers resulting from Cowden syndrome

Genomic study of familial breast cancer

La découverte des gènes BRCA1 et BRCA2, ainsi que leurs altérations constitutionnelles dans les formes familiales de cancer du sein, a conduit à la prise en compte en pratique médicale des syndromes de prédisposition héréditaire de ce cancer (5% des cas). Cependant, une altération délétère de l’un de ces gènes n’est détectée que dans 30 % des cas environ. Plus de la moitié des suspicions cliniques de prédisposition héréditaire au cancer du sein reste aujourd’hui inexpliquée sur le plan mutationnel, même si de nombreux autres gènes ont été impliqués dans la majoration du risque de survenue du cancer du sein (TP53, PTEN, FGFR2), témoignant d’une importante hétérogénéité génétique. Récemment, des profils transcriptionnels ou génomiques ont été testés pour prédire l’implication de BRCA1 ou BRCA2 avec une certaine efficacité. Il est donc possible que d’autres gènes de prédisposition au cancer du sein, dénommés BRCAx, occasionnent la survenue de tumeurs au profil génomique et/ou transcriptionnel spécifique, caractérisant ainsi autant d’endophénotypes tumoraux. Notre projet consiste en l’étude par CGH-array et puces d’expression de 103 échantillons tumoraux avec une forte suspicion familiale. L’analyse de nos résultats suggère l’existence de sous-groupes tumoraux aux profils génomiques bien différenciés. De plus, nous avons pu établir une signature des tumeurs BRCA1, des tumeurs BRCA2, et des cancers du sein intervenant dans le cadre d’un syndrome de la maladie de Cowden.The discovery of the BRCA1 and BRCA2 genes, along with their germline alterations in familial forms of breast cancer, led to the recognition of hereditary cancer predisposition syndromes in clinical practice (5% of cases). However, a deleterious alteration in one of these genes is not detected in approximately 30% of cases. To date, the underlying genetic cause of more than half of clinically suspected hereditary breast cancer predisposition remains unidentified despite the fact that several other genes have been associated with an increased risk of breast cancer (TP53, PTEN, FGFR2), demonstrating that there is significant genetic heterogeneity in this form of cancer. Transcriptomic and genomic profiles linked to BRCA1 or BRCA2 alterations have recently been identified and were used to predict (with a certain efficacy) if these genes are implicated in other breast cancers. It is therefore possible that other breast cancer predisposition genes (named BRCAx) could associate with breast cancer risk in transcriptomic and/or genomic profiles and characterise novel tumour endophenotypes. The project consists of a CGH-array and microarray study of 103 tumour samples from patients with clinically diagnosed familial breast cancer. Our results provide evidence of the existence of tumour subgroups with significantly different genomic profiles. In addition, we were able to establish a signature for BRCA1 tumours, another for BRCA2 tumours and a third signature for breast cancers resulting from Cowden syndrome

Étude génomique des formes familiales de cancer du sein

La découverte des gènes BRCA1 et BRCA2, ainsi que leurs altérations constitutionnelles dans les formes familiales de cancer du sein, a conduit à la prise en compte en pratique médicale des syndromes de prédisposition héréditaire de ce cancer (5% des cas). Cependant, une altération délétère de l un de ces gènes n est détectée que dans 30 % des cas environ. Plus de la moitié des suspicions cliniques de prédisposition héréditaire au cancer du sein reste aujourd hui inexpliquée sur le plan mutationnel, même si de nombreux autres gènes ont été impliqués dans la majoration du risque de survenue du cancer du sein (TP53, PTEN, FGFR2), témoignant d une importante hétérogénéité génétique. Récemment, des profils transcriptionnels ou génomiques ont été testés pour prédire l implication de BRCA1 ou BRCA2 avec une certaine efficacité. Il est donc possible que d autres gènes de prédisposition au cancer du sein, dénommés BRCAx, occasionnent la survenue de tumeurs au profil génomique et/ou transcriptionnel spécifique, caractérisant ainsi autant d endophénotypes tumoraux. Notre projet consiste en l étude par CGH-array et puces d expression de 103 échantillons tumoraux avec une forte suspicion familiale. L analyse de nos résultats suggère l existence de sous-groupes tumoraux aux profils génomiques bien différenciés. De plus, nous avons pu établir une signature des tumeurs BRCA1, des tumeurs BRCA2, et des cancers du sein intervenant dans le cadre d un syndrome de la maladie de Cowden.The discovery of the BRCA1 and BRCA2 genes, along with their germline alterations in familial forms of breast cancer, led to the recognition of hereditary cancer predisposition syndromes in clinical practice (5% of cases). However, a deleterious alteration in one of these genes is not detected in approximately 30% of cases. To date, the underlying genetic cause of more than half of clinically suspected hereditary breast cancer predisposition remains unidentified despite the fact that several other genes have been associated with an increased risk of breast cancer (TP53, PTEN, FGFR2), demonstrating that there is significant genetic heterogeneity in this form of cancer. Transcriptomic and genomic profiles linked to BRCA1 or BRCA2 alterations have recently been identified and were used to predict (with a certain efficacy) if these genes are implicated in other breast cancers. It is therefore possible that other breast cancer predisposition genes (named BRCAx) could associate with breast cancer risk in transcriptomic and/or genomic profiles and characterise novel tumour endophenotypes. The project consists of a CGH-array and microarray study of 103 tumour samples from patients with clinically diagnosed familial breast cancer. Our results provide evidence of the existence of tumour subgroups with significantly different genomic profiles. In addition, we were able to establish a signature for BRCA1 tumours, another for BRCA2 tumours and a third signature for breast cancers resulting from Cowden syndrome.BORDEAUX2-Bib. électronique (335229905) / SudocSudocFranceF

Phenoconversion from Spastic Paraplegia to ALS/FTD Associated with CYP7B1 Compound Heterozygous Mutations

International audienceBiallelic mutations in the CYP7B1 gene lead to spastic paraplegia-5 (SPG5). We report herein the case of a patient whose clinical symptoms began with progressive lower limb spasticity during childhood, and who secondly developed amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) at the age of 67 years. Hereditary spastic paraplegia (HSP) gene analysis identified the compound heterozygous mutations c.825T>A (pTyr275*) and c.1193C>T (pPro398Leu) in CYP7B1 gene. No other pathogenic variant in frequent ALS/FTD causative genes was found. The CYP7B1 gene seems, therefore, to be the third gene associated with the phenoconversion from HSP to ALS, after the recently described UBQLN2 and ERLIN2 genes. We therefore expand the phenotype associated with CYP7B1 biallelic mutations and make an assumption about a link between cholesterol dyshomeostasis and ALS/FTD

RNF170-related hereditary spastic paraplegia: confirmation by a novel mutation

International audienc

Deletion of chromosomes 13q and 14q is a common feature of tumors with BRCA2 mutations.

INTRODUCTION: Germline BRCA1 or BRCA2 mutations account for 20-30% of familial clustering of breast cancer. The main indication for BRCA2 screening is currently the family history but the yield of mutations identified in patients selected this way is low. METHODS: To develop more efficient approaches to screening we have compared the gene expression and genomic profiles of BRCA2-mutant breast tumors with those of breast tumors lacking BRCA1 or BRCA2 mutations. RESULTS: We identified a group of 66 genes showing differential expression in our training set of 7 BRCA2-mutant tumors and in an independent validation set of 19 BRCA2-mutant tumors. The differentially expressed genes include a prominent cluster of genes from chromosomes 13 and 14 whose expression is reduced. Gene set enrichment analysis confirmed that genes in specific bands on 13q and 14q showed significantly reduced expression, suggesting that the affected bands may be preferentially deleted in BRCA2-mutant tumors. Genomic profiling showed that the BRCA2-mutant tumors indeed harbor deletions on chromosomes 13q and 14q. To exploit this information we have created a simple fluorescence in situ hybridization (FISH) test and shown that it detects tumors with deletions on chromosomes 13q and 14q. CONCLUSION: Together with previous reports, this establishes that deletions on chromosomes 13q and 14q are a hallmark of BRCA2-mutant tumors. We propose that FISH to detect these deletions would be an efficient and cost-effective first screening step to identify potential BRCA2-mutation carriers among breast cancer patients without a family history of breast cancer