Comprehensive characterization of PTPRT expression in colorectal cancer (CRC).
Authors: Battaglin Francesca , Xiu Joanne , Brodskiy Pavel , Algaze Sandra , Jayachandran Priya , Arai Hiroyuki , Soni Shivani , Zhang Wu , Weinberg Benjamin Adam , Lou Emil , Shields Anthony Frank , Goldberg Richard M. , Marshall John , Korn Wolfgang Michael , Lenz Heinz-Josef 
Published: June 2022

3538

Background: PTPRT is a protein coding gene involved in signal transduction and cellular adhesion. It acts as a tumor suppressor gene and mutated PTPRT has been implicated in the early metastasis of CRC. PTPRT mutations have been reported as independent potential biomarkers for bevacizumab resistance in metastatic CRC and linked to improved response and survival of patients treated with checkpoint inhibitors in several tumors. Here we characterized the molecular features and clinical outcomes associated with PTPRT gene expression in CRC. Methods: 15025 CRC tested with NextGen Sequencing on DNA (592 genes or WES) and RNA (WTS) by Caris Life Sciences (Phoenix, AZ) were analyzed. Top quartile transcripts per million for PTPRT expression were considered high (H) and bottom quartile low (L). Cell infiltration in the tumor microenvironment (TME) was estimated by QuantiSEQ. X2, Fisher-Exact, Mann-Whitney tests were used and significance determined as P-value adjusted for multiple comparisons ( Q <.05). Real world survival was obtained from insurance claims data and Kaplan-Meier estimates were calculated for molecularly defined patients. Results: PTPRT expression was higher in left- than right-sided CRC and in metastases than primary/local tumors; it was highest in CMS4 and lowest in CMS1 (all Q <.05). PTPRT mutants had lower expression than wild type (0.037 vs 0.064, Q <.05). Overall, PTPRT-H had a lower rate of TMB-H (5% vs 17%), deficient mismatch repair (dMMR) (3% vs 13%) and PD-L1 (2% vs 6%) (H vs L, all Q <.05). In the proficient MMR (pMMR) cohort, PTPRT-H remained inversely correlated with TMB and PD-L1, was negatively associated with rates of mutated KRAS, PIK3CA, SMAD4, FBXW7, and positively associated with mutated TP53 and CDX2 amplification (all Q <.05). Expression of immune related genes was higher in PTPRT-H CRC, including CD274, CD80, CD86, CTLA4, HAVCR2, IDO1, IFNG, LAG3, PDCD1, and PDCD1LG2, regardless of MMR status (all Q <.05). PTPRT-H was associated with higher immune cell infiltration in the TME including B cells, M2 macrophages, neutrophils, NK, Tregs, CD4+ and CD8+ T cells, and myeloid dendritic cells (fold change/FC: 1.21-7.1), but lower M1 macrophages (FC: 0.76), regardless of MMR status (all Q <.05) with the only exception of CD8+ T cells in dMMR. PTPRT expression above median was associated with better OS (overall: HR 0.69, 95% CI [0.64-0.74]; pMMR: HR 0.67 [0.63-0.73]), longer time on treatment of bevacizumab (overall: HR 0.80 [0.74-0.87], pMMR: HR 0.80 [0.74-0.87]), and shorter time on immunotherapy treatment in the dMMR cohort (HR 2.13 [1.33-3.45]). Conclusions: Our data show a strong association between PTPRT expression and distinct molecular features (including CMS and immune biomarkers), TME cell infiltration and targeted treatment outcomes in CRC. These findings support PTPRT as a candidate prognostic and predictive biomarker for bevacizumab and immunotherapy treatment, and as a potential target in CRC.