Genomic amplification of 9p24.1 targeting JAK2, PD-L1, and PD-L2 is enriched in high-risk triple negative breast cancer
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Michael T. Barrett1, Karen S. Anderson2, Elizabeth Lenkiewicz1, Mariacarla Andreozzi1, Heather E. Cunliffe3, Christine L. Klassen4, Amylou C. Dueck5, Ann E. McCullough6, Srikanth K. Reddy7, Ramesh K. Ramanathan8, Donald W. Northfelt8, Barbara A. Pockaj4
1Department of Research, Mayo Clinic in Arizona, Scottsdale, Arizona, United States of America
2Biodesign Institute, Arizona State University, Tempe, Arizona, United States of America
3Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
4Division of General Surgery, Section of Surgical Oncology, Mayo Clinic in Arizona, Phoenix, Arizona, United States of America
5Section of Biostatistics, Mayo Clinic in Arizona, Scottsdale, Arizona, United States of America
6Department of Pathology and Laboratory Medicine, Mayo Clinic in Arizona, Scottsdale, Arizona, United States of America
7Vanderbilt University, Nashville, Tennessee, United States of America
8Division of Hematology-Oncology, Mayo Clinic in Arizona, Scottsdale, Arizona, United States of America
Michael T. Barrett, e-mail: [email protected]
Keywords: 9p24.1 amplicon, flow sorting, triple negative breast cancer, JAK2, PD-L1
Received: May 05, 2015 Accepted: June 22, 2015 Published: July 03, 2015
We used DNA content flow cytometry followed by oligonucleotide array based comparative genomic hybridization to survey the genomes of 326 tumors, including 41 untreated surgically resected triple negative breast cancers (TNBC). A high level (log2ratio ≥1) 9p24 amplicon was found in TNBC (12/41), glioblastomas (2/44), and colon carcinomas (2/68). The shortest region of overlap for the amplicon targets 9p24.1 and includes the loci for PD-L1, PD-L2, and JAK2 (PDJ amplicon). In contrast this amplicon was absent in ER+ (0/8) and HER2+ (0/15) breast tumors, and in pancreatic ductal adenocarcinomas (0/150). The PDJ amplicon in TNBCs was correlated with clinical outcomes in group comparisons by two-sample t-tests for continuous variables and chi-squared tests for categorical variables. TNBC patients with the PDJ amplicon had a worse outcome with worse disease-free and overall survival. Quantitative RT-PCR confirmed that the PDJ amplicon in TNBC is associated with elevated expression of JAK2 and of the PD-1 ligands. These initial findings demonstrate that the PDJ amplicon is enriched in TNBC, targets signaling pathways that activate the PD-1 mediated immune checkpoint, and identifies patients with a poor prognosis.
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