ANKRD36 mutation as a negative predictor for melanoma immunotherapy.

Abstract

e21517 Background: Melanoma is one of the most aggressive and immunogenic tumors. Current immunotherapies using immune checkpoint inhibitors such as CTLA4 and PD1 to stimulate T cell-mediated tumor killing significantly improved the overall survival of patients with metastatic melanoma. However, the clinical predictors of response to these therapies are still not fully characterized. Previous studies have shown that the high gene expression of Ankyrin repeat domain 36 (ANKRD36) can lead to the occurrence and poor prognosis of colon cancer and kidney cancer. In this study, we aimed to explore the role of ANKRD36 mutation in the prognosis of melanoma immune checkpoint inhibitors (ICIs). Methods: Public data of patients treated with ICIs(ipilimumab) from Van Allen (n = 110) cohort were obtained and analyzed. In survival analysis, Kaplan-Meier curves were compared by log-rank test, and the hazard ratio (HR) was determined through a multivariable Cox regression model. The potential mechanism was subsequently explored through RNA expression data from The Cancer Genome Atlas (TCGA). Results: The frequency of ANKRD36 mutation in the Van Allen cohort and TCGA cohort was 7.2% (8 in 110) and 1.56% (7 in 448) respectively. We further analyzed the Kaplan Meier curve and multiple Cox regression model of the Allen cohort and found that the survival of the mutant type in immunotherapy was significantly shorter than that of the wild-type group (PFS: HR = 3.09 [95% CI: 1.47, 6.51], p = 0.002; OS: HR = 2.33 [95% CI: 1.12, 4.86], p = 0.02). Both mutant type and tumor metastasis would have negative effects on immunotherapy(PFS: HR = 3.66 [95% CI: 1.71, 7.85], p < 0.001***; OS: HR = 3.16 [95% CI: 1.47, 6.82], p = 0.003**). Analysis of the transcriptome data from the TCGA database found that resting CD4 memory T cells is highly expressed in ANKRD36 mutant patients (p = 0.032), which may indicate that the patient's immune system did not activate the anti-tumor immune mechanism. Conclusions: In our study, the frequency of ANKRD36 mutations was investigated in clinical and TCGA cohorts, which may provide useful information for guiding patient treatment. ANKRD36 mutation may be a negative predictor of ICIs in patients with melanoma and play a role in prognosis.

Investigations on Clinical Validation of mutated ANKRD36 as a Novel Molecular Biomarker for Monitoring Early Progression and Timely Therapeutic Interventions in Blast Crisis CML

“…According to the information obtained from the transcriptome analysis of the TCGA database, the expression of resting CD4 memory T cells is significantly elevated in patients with the ANKRD36 mutation (p = 0.032). Based on this finding, the authors of the study proposed that it is possible that the immune system of the patients with ANKRD36 mutations did not activate the immunological mechanism that is responsible for fighting tumors (29). We think that this could be one of the possible mechanisms through which ANKRD36 mutation might lead to CML progression.…”