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
PMCID: PMC5511565
PUBMED: 28153863
Notes: Article -- Source: Wos
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MSK Authors
  1. Larry Norton
    558 Norton
  2. Nadeem Riaz
    210 Riaz
  3. Yong Hannah Wen
    118 Wen
  4. Carey Eberle
    17 Eberle
  5. Britta Weigelt
    260 Weigelt
  6. Jorge Sergio Reis
    283 Reis
  7. Kiu Yan Charlotte Ng
    152 Ng
  8. Raymond Sear Lim
    54 Lim
  9. Kathleen   Burke
    55 Burke