GRCh38 · COSMIC v98


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The Landscape of Somatic Genetic Alterations in Metaplastic Breast Carcinomas.
Paper ID
Ng CK, Piscuoglio S, Geyer FC, Burke KA, Pareja F, Eberle C, Lim R, Natrajan R, Riaz N, Mariani O, Norton L, Vincent-Salomon A, Wen YH, Weigelt B and Reis-Filho JS
Institute of Pathology, University Hospital Basel.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2017
ISSN: 1078-0432
PMID: 28153863 (view at PubMed or Europe PMC)
Purpose: Metaplastic breast carcinoma (MBC) is a rare and aggressive histologic type of breast cancer predominantly of triple-negative phenotype, and characterized by the presence of malignant cells showing squamous and/or mesenchymal differentiation. We sought to define the repertoire of somatic genetic alterations and the mutational signatures of MBCs.Whole-exome sequencing was performed in 35 MBCs, with 16, ten and nine classified as harboring chondroid, spindle and squamous metaplasia as the predominant metaplastic component. The genomic landscape of MBCs was compared to that of triple-negative invasive ductal carcinomas of no special type (IDC-NSTs) from The Cancer Genome Atlas. Wnt pathway activity was assessed using a quantitative PCR assay.Results: MBCs harbored complex genomes with frequent TP53 (69%) mutations. In contrast to triple-negative IDC-NSTs, MBCs more frequently harbored mutations in PIK3CA (29%), PIK3R1 (11%), ARID1A (11%), FAT1 (11%) and PTEN (11%). PIK3CA mutations were not found in MBCs with chondroid metaplasia. Compared to triple-negative IDC-NSTs, MBCs significantly more frequently harbored mutations in PI3K/AKT/mTOR pathway-related (57% vs 22%) and canonical Wnt pathway-related (51% vs 28%) genes. MBCs with somatic mutations in PI3K/AKT/mTOR or Wnt pathway-related genes displayed increased activity of the respective pathway.Conclusion: MBCs are genetically complex and heterogeneous, and are driven by a repertoire of somatic mutations distinct from that of triple-negative IDC-NSTs. Our study highlights the genetic basis and the importance of PI3K/AKT/mTOR and Wnt pathway dysregulation in MBCs, and provides a rationale for the metaplastic phenotype and the reported responses to PI3K/AKT/mTOR inhibitors in these tumors.
Paper Status