GNAS mutations in primary mucinous and non-mucinous lung adenocarcinomas

GNAS mutations have been described in mucinous and non-mucinous epithelial neoplasms of the appendix, pancreas, and colon, with hotspot GNAS mutations found in up to two-thirds of pancreatic intraductal papillary mucinous neoplasms. Additionally, many GNAS-mutated tumors have concurrent mutations in the Ras/Raf pathway. The clinicopathologic features of GNAS-mutated lung carcinomas, however, have not yet been characterized. Primary lung carcinomas from Brigham and Women's Hospital (n=1282) or Massachusetts General Hospital (n=1070) were genotyped on a targeted massively parallel sequencing panel of oncogenes and tumor suppressor genes including GNAS. Clinical and pathological features were reviewed, and TTF-1 immunohistochemistry was performed when material was available. Nineteen lung adenocarcinomas with hotspot GNAS mutations were identified (19/2352, 0.8%) including 14 at codon 201 and 5 at codon 227. GNAS-mutated lung adenocarcinomas occurred predominantly in female patients (16/19, 84%). Ten (10) were classified as invasive mucinous adenocarcinomas (IMA), and nine (9) were non-mucinous adenocarcinomas. All IMAs had GNAS codon 201 mutations and concurrent Ras/Raf pathway mutations (9 KRAS, 1 BRAF). No tumors with GNAS codon 227 mutations had mucinous histological features. 86% of GNAS-mutated non-mucinous adenocarcinomas (6/7) were positive for TTF-1 immunohistochemistry, while only 25% of GNAS-mutated IMAs (1/4) were positive for TTF-1. Patients with GNAS-mutated non-mucinous adenocarcinomas were more likely to have a history of smoking (9/9, 100%) compared to patients with GNAS-mutated IMAs (2/10, 20%) (P<0.001). Hotspot GNAS mutations can occur in primary lung adenocarcinomas. When associated with concurrent mutations in the Ras/Raf pathway, these neoplasms often present as IMAs. GNAS mutations are not specific to neoplasms of the gastrointestinal tract, and clinicopathologic correlation is necessary in GNAS-mutated adenocarcinomas in the lung to determine the primary site of origin.