Synapse - The Landscape of Somatic Genetic Alterations in Metaplastic Breast Carcinomas

The Landscape of Somatic Genetic Alterations in Metaplastic Breast Carcinomas Journal Article

Authors:	Ng, C. K. Y.; Piscuoglio, S.; Geyer, F. C.; Burke, K. A.; Pareja, F.; Eberle, C. A.; Lim, R. S.; Natrajan, R.; Riaz, N.; Mariani, O.; Norton, L.; Vincent-Salomon, A.; Wen, Y. H.; Weigelt, B.; Reis, J. S.
Article Title:	The Landscape of Somatic Genetic Alterations in Metaplastic Breast Carcinomas
Abstract:	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. Experimental Design: Whole-exome sequencing was performed in 35 MBCs, with 16, 10, and 9 classified as harboring chondroid, spindle, and squamous metaplasia as the predominant metaplastic component. The genomic landscape of MBCs was compared with that of triple-negative invasive ductal carcinomas of no special type (IDC-NST) from The Cancer Genome Atlas. Wnt and PI3K/AKT/mTOR pathway activity was assessed using a qPCR 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 with 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. Conclusions: 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. (C) 2017 AACR.
Keywords:	tumors; recommendations; growth; pathway; heterogeneity; clinical; inactivation; mutational processes; practice guideline update; oncology/college; cancer american society
Journal Title:	Clinical Cancer Research
Volume:	23
Issue:	14
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2017-07-15
Start Page:	3859
End Page:	3870
Language:	English
ACCESSION:	WOS:000405678400041
DOI:	10.1158/1078-0432.ccr-16-2857
PROVIDER:	wos
PMCID:	PMC5511565
PUBMED:	28153863
Notes:	Article -- Source: Wos