TY - JOUR
T1 - Genomic amplification of 9p24.1 targeting JAK2, PD-L1, and PD-L2 is enriched in high-risk triple negative breast cancer
AU - Barrett, Michael T.
AU - Anderson, Karen
AU - Lenkiewicz, Elizabeth
AU - Andreozzi, Mariacarla
AU - Cunliffe, Heather E.
AU - Klassen, Christine L.
AU - Dueck, Amylou C.
AU - McCullough, Ann E.
AU - Reddy, Srikanth K.
AU - Ramanathan, Ramesh K.
AU - Northfelt, Donald W.
AU - Pockaj, Barbara A.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - 9p24.1 amplicon
KW - Flow sorting
KW - JAK2
KW - PD-L1
KW - Triple negative breast cancer
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U2 - 10.18632/oncotarget.4494
DO - 10.18632/oncotarget.4494
M3 - Article
C2 - 26317899
AN - SCOPUS:84944455351
SN - 1949-2553
VL - 6
SP - 26483
EP - 26493
JO - Oncotarget
JF - Oncotarget
IS - 28
ER -