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Genomic and transcriptomic heterogeneity in metaplastic carcinomas of the breast

Le Centre de Ressources Biologiques de l'Institut Curie a été initié en 1989 par le Dr Xavier SASTRE-GARAU, avec la constitution d'une banque de tissus tumoraux cryopréservés, puis, au cours des années,il s'est enrichi par une collection de sérums-plasmas et une banque de produits dérivés de la tumorothèque (ADN, ARN et protéines extraits de tissus tumoraux complété par une collection d'ADN constitutionnels). Le CRB assure ses missions avec un double objectif : un objectif médical où la conservation des échantillons permet de les rendre disponibles pour des investigations diagnostiques complémentaires plusieurs années après le diagnostic initial, et un objectif de recherche scientifique ou une partie des échantillons conservés au sein du CRB est mise a la disposition des chercheurs qui désirent conduire des programmes de recherche sur le cancer afin de mieux caractériser les différents types de tumeurs, d'adapter au mieux les traitements ou de développer de nouvelles cibles thérapeutiques.

Breast cancer affects 54,000 women in France each year. Institut Curie is a key center for the treatment of this pathology. The breast cancer medico-scientific program has been reinforced with Prof. Martine Piccart, MD-PhD, an oncologist renowned worldwide.

The breast cancer medico-scientific program priority is to step up efforts on “triple negative” cancers and to rely more on the basic research of the Research Center in this field. Innovation is at the heart of breast cancer treatment.

Dr Anne Vincent-Salomon, Pathologist and Researcher associated to the INSERM U934 (Pr HEARD),  Head of the Department of Médecine Diagnostique et Théranostique, published in collaboration with Pr Jorge Reis-Filho and Dr Britta Weigelt at Memorial Sloan Kettering in New York in the prestigious npj Breast Cancer journal. Together, the two teams worked on defining whether histologically distinct subgroups of High grade metaplastic breast cancers would be underpinned by distinct genomic and/or transcriptomic alterations. Their results highlight the molecular heterogeneity of High grade Metaplastic Breast Carcinomas. In addition, their results may open up the path for new therapeutic strategies targeting the PIK3CA pathway in this rare form of triple-negative breast carcinomas.

Abstract
« Metaplastic breast cancer (MBC) is a rare special histologic type of triple-negative breast cancer, characterized by the presence of neoplastic cells showing differentiation towards squamous epithelium and/or mesenchymal elements. Here we sought to define whether histologically distinct subgroups of MBCs would be underpinned by distinct genomic and/or transcriptomic alterations. Microarray-based copy number profiling identified limited but significant differences between the distinct MBC subtypes studied here, despite the limited sample size (n = 17). In particular, we found that, compared to MBCs with chondroid or squamous cell metaplasia, MBCs with spindle cell differentiation less frequently harbored gain of 7q11.22-23 encompassing CLDN3 and CLDN4, consistent with their lower expression of claudins and their association with the claudin-low molecular classification. Microarray-based and RNA-sequencing-based gene expression profiling revealed that MBCs with spindle cell differentiation differ from MBCs with chondroid or squamous cell metaplasia on the expression of epithelial-to-mesenchymal transition-related genes, including down-regulation of CDH1 and EPCAM. In addition, RNA-sequencing revealed that the histologic patterns observed in MBCs are unlikely to be underpinned by a highly recurrent expressed fusion gene or a pathognomonic expressed mutation in cancer genes. Loss of PTEN expression or mutations affecting PIK3CA or TSC2 observed in 8/17 MBCs support the contention that PI3K pathway activation plays a role in the development of MBCs. Our data demonstrate that despite harboring largely similar patterns of gene copy number alterations, MBCs with spindle cell, chondroid and squamous differentiation are distinct at the transcriptomic level but are unlikely to be defined by specific pathognomonic genetic alterations. »

Genomic and transcriptomic heterogeneity in metaplastic carcinomas of the breast
Salvatore Piscuoglio, Charlotte K. Y. Ng, Felipe C. Geyer, Kathleen A. Burke, Catherine F. Cowell, Luciano G. Martelotto, Rachael Natrajan, Tatiana Popova, Christopher A. Maher, Raymond S. Lim, Ino de Bruijn, Odette Mariani, Larry Norton, Anne Vincent-Salomon, Britta Weigelt & Jorge S. Reis-Filho