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Comparative Study
. 2015 Sep 22;6(28):26483-93.
doi: 10.18632/oncotarget.4494.

Genomic amplification of 9p24.1 targeting JAK2, PD-L1, and PD-L2 is enriched in high-risk triple negative breast cancer

Michael T Barrett  1 , Karen S Anderson  2 , Elizabeth Lenkiewicz  1 , Mariacarla Andreozzi  1 , Heather E Cunliffe  3 , Christine L Klassen  4 , Amylou C Dueck  5 , Ann E McCullough  6 , Srikanth K Reddy  7 , Ramesh K Ramanathan  8 , Donald W Northfelt  8 , Barbara A Pockaj  4
Affiliations
Comparative Study

Genomic amplification of 9p24.1 targeting JAK2, PD-L1, and PD-L2 is enriched in high-risk triple negative breast cancer

Michael T Barrett et al. Oncotarget. .

Abstract

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.

Keywords: 9p24.1 amplicon; JAK2; PD-L1; flow sorting; triple negative breast cancer.

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Conflict of interest statement

CONFLICTS OF INTEREST

None.

Figures

Figure 1
Figure 1. Whole genome and chromosome 9 aCGH plots of flow sorted tumor populations
A. Colorectal (CRC) and B–C. triple negative breast cancers (TNBC) with high level 9p24.1 amplicon. Amplicons were scored according to log2ratios >1. Blue arrows denote JAK2 locus.
Figure 2
Figure 2. The 9p24 amplicon in a triple negative breast cancer genome
A. Flow histogram of sorted 3.2N TNBC population from FFPE tissue. B. Chromosome 9 CGH plot and detection of 9p24 amplicon. C. Gene specific view of amplicon. Red shaded area denotes ADM2 defined copy number aberrant region. D. Gene expression of JAK2, PD-L1, and PD-L2 in TNBC. Comparisons and correlations between the expression levels of PD-L1, PD-L2, and JAK2 genes and copy number status of chromosome 9p24.1 were performed using an unpaired t test and variation among and between groups were calculated using an ANOVA test (GraphPad Prism 6).
Figure 3
Figure 3. Clinical outcomes for TNBC patients with or without PDJ amplicon
A. Progression free survival. Lower disease-free survival at 5 years 25.0% vs. 66.0%, p = 0.005. B. Overall survival. Lower overall survival at 5 years 25.0% vs. 69.0%, p = 0.004. Median follow up is 4.7 years (range 0.9–12.0 years).
Figure 4
Figure 4. PTEN homozygous deletion in PDJ+ triple negative breast cancer genome
A. Flow histogram of sorted 5.0N TNBC population from FFPE tissue. B–C. Chromosome 10 and chromosome 9 CGH plots. D. Gene specific view of PTEN homozygous deletion. Blue shaded area denotes ADM2 defined copy number aberrant region.
See this image and copyright information in PMC

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