Csig-05. Clinicogenomic Landscape and Functional Implications of Ptpn11 (Shp2) Alterations in Glioblastoma

BACKGROUND PTPN11 encodes SHP2, a non-receptor protein tyrosine phosphatase that facilitates RAS/MAPK signaling via relief of autoinhibition. While germline mutations in PTPN11 are described in developmental ‘RASopathy’ syndromes (Noonan/NSML), somatic alterations are also observed in malignancies—notably leukemias. SHP2 signaling is implicated as a central node in glioblastoma, but the prevalence, oncogenic role, and therapeutic significance of PTPN11 alterations in glioblastoma and other solid cancers remains largely unexplored. METHODS We evaluated PTPN11 alterations across 206,768 patient tumors (2,985 PTPN11 mutant tumor samples) from AACR GENIEv17.0, with a focused analysis on IDH-wildtype GBM (n=293). Functional annotation of PTPN11 variants was performed using OncoKB, ClinVar, and AlphaMissense scoring. Co-mutation patterns and patient outcomes were analyzed. An independent clinical cohort with RNA sequencing was used to validate co-mutations and identify MAPK pathway dependence. RESULTS PTPN11 mutations were enriched in GBM, with clustering in the N-SH2 and phosphatase (PTP) domains, implicated in dysregulating autoinhibition and phosphatase activity respectively. In GBM, 76% of PTPN11-alterations were found to be oncogenic or likely oncogenic. Using AlphaMissense, nearly all PTPN11 alterations were predicted to be likely pathogenic, suggesting OncoKB and ClinVar could underestimate the number of pathogenic or oncogenic alterations. Among the 5,704 GBM samples, PTPN11 alterations co-occurred with NF1, PIK3CA, and loss of CDKN2A, but were mutually exclusive with EGFR alterations. Interestingly, when compared across the most-frequently altered cancer types (GBM, leukemia, melanoma, NSCLC, colorectal cancer, endometrial cancer) PTPN11 alterations also commonly co-occurred with NF1. Kaplan-Meier analysis indicated a trend toward poorer survival in patients with PTPN11-altered GBM. CONCLUSIONS Oncogenic PTPN11 alterations occur in a biologically distinct subset of GBM characterized by clinically inferior prognosis and co-mutations suggesting altered MAPK signaling. These findings may have implications for clinical management, including the use of targeted therapy and sensitivity to SHP2 inhibitors.