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

Barrett, Michael T.; Anderson, Karen S.; Lenkiewicz, Elizabeth; Andreozzi, Mariacarla; Cunliffe, Heather E.; Klassen, Christine; Dueck, Amylou C.; McCullough, Ann E.; Reddy, Shabashini; Ramanathan, Ramesh K.; Northfelt, Donald W.; Pockaj, Barbara A.

doi:10.18632/oncotarget.4494

Cited by 125 publications

(140 citation statements)

References 42 publications

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“…In addition, others have demonstrated that oncogenic alterations can induce PD-L1 expression. [48][49][50] The correlations we report between lymphocyte infiltration (in particular CD3 and CD8 C ) and distribution (immunotype) with PD-L1 expression, and the lack of any association with BRAF mutational status, suggest that PD-L1 expression by human melanoma cells can be explained predominantly by adaptive resistance. We only found a single case where PD-L1 expression was observed in greater than 5% of the tumor cells in the absence of any CD8 C T cells, a result consistent to Taube and colleagues' finding.…”

Section: Discussionmentioning

confidence: 73%

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

et al. 2016

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Therapeutic blockade of PD-1/PD-L1 can have dramatic therapeutic benefit in some patients; however, the prognostic associations of PD-1 and its ligands, in the absence of therapeutic blockade have not been definitively addressed. In particular, associations of PD-L2 with immune infiltrates and with outcome have yet to be explored. We hypothesized that surface expression of both PD-L1 and PD-L2 by melanoma cells would be associated with immune cell infiltration and with overall patient survival, independent of checkpoint blockade therapy. We also characterized the heterogeneity of their distribution within a tumor and within tumors of the same patient. Tissue microarrays of metastatic melanoma samples from 147 patients were quantified for CD8 C , CD45, CD4 C , CD3, CD163, CD20, CD138, FoxP3, PD-1, PD-L1 and PD-L2 markers by immunohistochemistry. Relationships between the proportions of PD-L1 and PD-L2 expressing tumor cells with the immune cell count, distribution (immunotype) and patient survival were studied. Expressions of both PD-L1 and PD-L2 correlated significantly with increasing densities of immune cells in the tumor specimens and with immunotype. Positive PD-L2 expression was associated with improved overall survival and the simultaneous positive expression of both PD-1 ligands showed a higher association with survival. Significant heterogeneity of PD-L1 and PD-L2 expressions within tumors were observed, however, they were less pronounced with PD-L2. In conclusion, both are markers of immune infiltration and PD-L2, alone or in combination with PD-L1, is a marker for prognosis in metastatic melanoma patients. Larger tumor samples yield more reliable assessments of PD-L1/L2 expression.

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Section: Discussionmentioning

confidence: 73%

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

et al. 2016

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“…For certain subtypes of Hodgkin's lymphoma as well as triple negative breast cancer, gene amplification of the PD-L1 locus (Chr.9 p24.1) has been described. 32,34 Clinical studies with PD-1 inhibitors for these entities are ongoing. 35 In lymphoma, the amplified region may encompass the adjacent genes PD-L2 and JAK2.…”

Section: Pd-l1 Expression (Tumor Cells)mentioning

confidence: 99%

PD-L1 expression in non-small cell lung cancer: Correlations with genetic alterations

et al. 2016

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Inhibition of the PD-1/PD-L1 pathway may induce anticancer immune responses in non-small cell lung cancer (NSCLC). Two PD-L1 immunohistochemistry (IHC) assays have been approved as companion diagnostic tests for therapeutic anti-PD-1 antibodies. However, many aspects of PD-L1 prevalence and association with genetically defined subtypes have not been addressed systematically. Here, we analyzed PD-L1 expression in 436 genetically annotated NSCLC specimens enriched for early stages using PD-L1 antibody 5H1. Expression of PD-L1 was detected in the tumor cells (TC) (34% of cases) and in associated immune cells (IC) (49%) across all stages of NSCLC, either alone or in combination. PD-L1 IHC-positive TC, but not IC showed significantly higher PD-L1 RNA expression levels. Expression in TC was associated with TP53, KRAS and STK11 mutational status in adenocarcinomas (AD) and with NFE2L2 mutations in squamous cell carcinomas (SQ). No correlations with histological subtype, clinical characteristics and overall survival were found. The presence of PD-L1-positive IC was significantly associated with patients' smoking status in AD. The findings are in agreement with the emerging concept that tumors with high mutational burden are more likely to benefit from immunotherapy, since TP53 and KRAS mutations are linked to smoking, increased numbers of somatic mutations and expression of neoantigens. Current clinical studies focus on stage IIIB and IV NSCLC; however, PD-L1 expression occurs in earlier stages and might be a predictive biomarker in clinical trials testing (neo-) adjuvant strategies.

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“…The locus of PD-L1 and PD-L2 at human chromosome 9p24 was found to be amplified in 12 of 41 (29%) triplenegative breast carcinomas, but not in any of the 23 ERpositive or Her2-positive carcinomas examined (19). The amplicon, which included also the locus of the JAK2 kinase gene, was confirmed to be translated producing higher levels of mRNA than those observed in non-amplified patients.…”

Section: Ctla-4mentioning

confidence: 81%

Immune Blockade Inhibition in Breast Cancer

Voutsadakis

2016

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

Cited by 125 publications

References 42 publications

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

PD-L1 expression in non-small cell lung cancer: Correlations with genetic alterations

Immune Blockade Inhibition in Breast Cancer

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