PTPRT and PTPRD Deleterious Mutations and Deletion Predict Bevacizumab Resistance in Metastatic Colorectal Cancer Patients.
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ABSTRACT: BACKGROUND:Bevacizumab-based regimens are used as standard treatments for colorectal cancer. Unfortunately, there are no established predictive markers for bevacizumab response. METHODS:Tumor samples from 36 metastatic colorectal cancer patients treated with bevacizumab plus chemotherapy were analyzed by next-generation sequencing of all coding exons of more than 400 genes. Single gene and signaling pathway analyses were performed to correlate genomic data with response. RESULTS:Among the genes most frequently mutated in our cohort, only mutations in PTPRT, a phosphatase involved in JAK/STAT signaling, were associated with response status, with deleterious mutations being enriched in non-responders. Pathway analysis revealed that deleterious mutations in genes of the JAK/STAT pathway, namely in PTPRT and the related gene PTPRD, correlated with resistance. Mutations in RTK/PI3K/RAS, Wnt and TGF? pathways did not associate with response. Lack of response was observed in all patients with deleterious mutations or copy number loss of PTPRT/PTPRD (n = 10), compared to only 30.8% (n = 8) of patients without such alterations (relative risk, 3.25; 95% CI, 1.83?5.79, p = 0.0003). Similarly, PTPRT/PTPRD deleterious alterations were associated with shorter progression-free survival, an association that was retained in multivariate analysis (HR, 3.33; 95% CI, 1.47?7.54; p = 0.0038). CONCLUSION:Deleterious alterations in PTPRT/PTPRD are potential biomarkers for bevacizumab resistance.
SUBMITTER: Hsu HC
PROVIDER: S-EPMC6162606 | biostudies-literature | 2018 Sep
REPOSITORIES: biostudies-literature
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