P2.02-006 Targeted Next Generation Sequencing Reveals Prognostic Recurrent Somatic Mutations in the GNAQ Oncogene in NSCLC

Abstract

GNAQ is a stimulatory αq subunit of heterotrimeric G-proteins that is highly mutated in human melanoma and currently has no targeted treatment. GNAQ protein is similar to the RAS protein, in which activating mutations occurring within the catalytic (GTPase) domain confer constitutive signaling activity of the RAS pathway. However, GNAQ mutations have not been documented in Non-Small Cell Lung Cancer (NSCLC). Therefore, the aim of this study was to examine genomic alterations in GNAQ and correlate its mutation status with clinical characteristics of NSCLC patients. A cohort of 53 patients treated at the Thoracic Oncology Unit of the Instituto Nacional de Cancerologia (INCan) of Mexico were screened in a mutation analysis of the GNAQ oncogene by targeted next generation sequencing (NGS). All information from the patients was recorded in a database containing clinicopathological characteristics. Patients characteristics included a median age of 66 years (36-82 years), with 77% of females, 39% of smokers, 51% with wood smoke exposure and the predominant histology was adenocarcinoma (86%) with intermediate grade (acinar-papillary) in 65% of cases. In this study, recurrent somatic mutations in GNAQ were found in 37/53 patients (70%) with a mutant allele (QNAQmut) frequency over 1%. GNAQ mutations were more frequently found in adenocarcinoma and stage IV (p=0.054 and p=0.098 respectively). The GNAQmut allele was associated with metastasis to the Central Nervous System (CNS) and bones (p < 0.001). This mutation was associated with a decrease in overall survival (69 vs. 12 months, p = 0.047). Additionally, two of these GNAQ-mutated patients having co-occurring oncogenic mutations in GNAS and GNA11 exhibited faster disease progression and a poorer overall survival of only two months. There was no association between GNAQ and frequently mutated genes like EGFR, KRAS or MET. This is the first report of the presence of recurrent somatic mutations in GNAQ, GNA11 and GNAS oncogenes in NSCLC based on targeted NGS. We found a correlation between these genomic alterations and the patients response measured as disease progression and overall survival.