The Landscape of Somatic Genetic Alterations in Metaplastic Breast Carcinomas.
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 frequentTP53(69%) mutations. In contrast to triple-negative IDC-NSTs, MBCs more frequently harbored mutations inPIK3CA(29%),PIK3R1(11%),ARID1A(11%),FAT1(11%), andPTEN(11%).PIK3CAmutations 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.Clin Cancer Res; 23(14); 3859-70. ©2017 AACR.
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.|Institute of Pathology, University Hospital Basel, Basel, Switzerland.
Charlotte K Y
CKY
Ng
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.|Institute of Pathology, University Hospital Basel, Basel, Switzerland.
Salvatore
S
Piscuoglio
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Pathology, Hospital Israelita Albert Einstein, Instituto Israelita de Ensino e Pesquisa, São Paulo, Brazil.
Felipe C
FC
Geyer
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
Kathleen A
KA
Burke
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
Fresia
F
Pareja
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
Carey A
CA
Eberle
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
Raymond S
RS
Lim
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom.
Rachael
R
Natrajan
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
Nadeem
N
Riaz
Department of Pathology, Institut Curie, Paris, France.
Odette
O
Mariani
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Larry
L
Norton
Department of Pathology, Institut Curie, Paris, France.
Anne
A
Vincent-Salomon
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
Y Hannah
YH
Wen
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. reisfilj@mskcc.org weigeltb@mskcc.org.
Britta
B
Weigelt
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. reisfilj@mskcc.org weigeltb@mskcc.org.|Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Jorge S
JS
Reis-Filho
D014408:Biomarkers, Tumor / Q000235:genetics; D015820:Cadherins / Q000235:genetics; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008679:Metaplasia / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000073359:Exome Sequencing; D060449:Wnt Signaling Pathway / Q000235:genetics
D014408:Biomarkers, Tumor; D015820:Cadherins; D058534:Class I Phosphatidylinositol 3-Kinases; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C112476:ARID1A protein, human; C502403:FAT1 protein, human; C495901:TP53 protein, human; C546842:MTOR protein, human; C484760:PIK3CA protein, human; C494929:PTEN protein, human