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• W2043682473 abstract "Janus-kinase 2 (JAK2) is a receptor-coupled tyrosine kinase which transmits cytokine-mediated signals to the STAT pathway to drive signals of proliferation and differentiation. JAK2/STAT signaling has been shown to play a role in promoting breast cancer ‘stem-ness’ and driving the proliferation of CD44+/CD24- basal-like breast cancer cells. We performed targeted next-generation sequencing (tNGS) using HiSeq2000 at a CLIA-certified laboratory on 68 residual TNBCs after neoadjuvant chemotherapy (NAC), which are putatively enriched for drug-resistant cells. JAK2 amplifications were identified in 7/68 (10.2%) post-NAC tumors. Gene copy estimation in amplified cases ranged from 7-10 copies. All cases were confirmed by a novel JAK2-FISH assay that we developed using BAC-derived probes targeting the JAK2 locus on chromosome 9, using CEN9 as a normalization factor. Using JAK2-FISH, we identified only one amplified tumor in an independent cohort of 30 untreated TNBCs (3%). Rates of JAK2 amplification in post-NAC residual cancers in this study were also higher than those reported by TCGA ( JAK2 amplifications in the post-NAC residual cancer were associated with poor RFS (median: 7 mo. vs 17 mo; HR: 3.36; p = 0.006) and OS (median: 11.3 mo. vs 27.6 mo; HR: 4.16; p = 0.002), and were significantly associated with higher gene expression of IL6, CXCR1 and SNAI1, among others. The coexistence of these alterations suggests an association of amplified JAK2 with an epithelial-to-mesenchymal transition and cancer-stem cell programs. To explore the clonal evolution of JAK2 lesions in breast cancer, we sequenced sequential samples (diagnostic biopsy, post-NAC residual disease and metastatic recurrence) of two TNBCs where JAK2 amplifications were detected in the residual disease. In each of these, JAK2 gain was noted at levels below the amplification threshold at diagnosis, but was focally amplified in both the residual tumor at the time of definitive surgery as well as in the subsequent metastatic recurrence. To our knowledge, this is the first report of JAK2 gene amplification in breast cancer. These data suggest a role for JAK2 amplifications in driving chemotherapeutic resistance and disease progression. We hypothesize these lesions are therapeutically targetable with currently approved JAK2 or pan-JAK inhibitors. Additional data to be presented will include analysis of tumor-infiltrating lymphocytes in JAK2-amplified tumors and molecular studies of the role of JAK2 overexpression in breast cancer cell lines as well as their sensitivity to JAK2 inhibitors in clinical development. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S6-01." @default.
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• W2043682473 date "2013-12-15" @default.
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• W2043682473 title "Abstract S6-01: JAK2 amplifications are enriched in triple negative breast cancers (TNBCs) after neoadjuvant chemotherapy and predict poor prognosis" @default.
• W2043682473 doi "https://doi.org/10.1158/0008-5472.sabcs13-s6-01" @default.
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