Abstract 868: Splicing factor mutant lung cancers: A comprehensive molecular and clinicopathologic characterization

Abstract

Abstract Background: Splicing factor mutations can drive oncogenesis in different cancer types. More importantly, strategies to target splicing-dependent cancers have been developed, including PRMT5 inhibition which regulates alternative splicing and targets posttranslational modification; PRMT5 inhibitors are in ongoing phase I clinical trials. The characterization of splicing alterations in non-small cell lung cancer (NSCLC) has not been extensively studied and represents an unmet need. Methods: Based on previously known genes associated with splicing alterations, genomic and clinicopathologic data from NSCLC patients with hotspot or loss of function mutations identified by next-generation sequencing in the splicing factors SF3B1, SRSF2, U2AF1, ZRSR2, RBM10, and FUBP1 were explored. Results: Among 626 NSCLC patients with at least one splicing mutation, 85% (529/626) also harbored a co-occurring oncogenic driver, such as alterations involving KRAS (60%; 319/529), EGFR (25%;132/529), MET (5%; 27/529), BRAF(4%; 24/529), and ERBB2 (3%; 17/529). After excluding patients with concurrent drivers, 97 splicing-factor-mutant NSCLCs were identified, with 80 (82%) adenocarcinomas and 6 (6%) squamous cell carcinomas. The median age was 71 years (43-89). Forty-nine patients (51%) were female. Sixty patients (62%) were diagnosed with stage I-III disease. Eleven (11%) were never smokers, while 86 (89%) were former/current smokers, with a median of pack years of 30. The median tumor mutational burden was 7.9 mut/Mb (0.9-90.4). Regarding splicing factor mutations, sixty-two patients (64%) had nonsense or splice-site RBM10 mutations, 17 (17%) had missense hotspot SF3B1 mutations, 16 (16%) had hotspot missense U2AF1 mutations, and 7 (7%) had nonsense, splice-site, or hotspot missense FUBP1 mutation. No patients with ZRSR2 or SRSF2 were identified. Only three patients presented concurrent splicing mutations: one with two SF3B1 mutations; one with RBM10 and SF3B1 mutations; and one with U2AF1 and SF3B1 mutations. Conclusion: Most patients with splicing factor mutant NSCLCs are smokers whose cancers commonly harbor RBM10 mutations and higher TMB compared to other driver-positive cancers. The characterization of this profile is key to identifying appropriate patients for ongoing targeted therapy trials for this population. Citation Format: Guilherme Harada, Christina J. Falcon, Fernando C. Santini, Jason C. Chang, Soo R. Yang, Maria E. Arcila, Natasha Rekhtman, Alexander Drilon. Splicing factor mutant lung cancers: A comprehensive molecular and clinicopathologic characterization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 868.