Joined Analysis of Sarcomatoid Carcinoma (SC) Mutational Profiles: Comparison of Lung Versus Head and Neck Cancer

Background: SC is a rare tumor of lung and head and neck. In a previous study, lung SC (LSC) have been classified in 2 molecular clusters (C) based on mutational signatures and oncogenic drivers: C1 marked by tobacco-associated signature 4 and C2 marked by homologous repair deficiency signature 3 and APOBEC-associated signatures 2 and 13. We aimed to assign this classification to head and neck SC (HNSC). Methods: Whole exome sequencing was performed in 15 LSC and 6 HNSC. Mutations have been called using Mutect2 (GATK v4.0). In addition, 10 LSC published by Liu et al. were included. Mutational signatures described by Alexandrov et al. have been called using DeconstructSigs. Oncogenic mutations were reported in known cancer-associated genes. Unsupervised clustering based on mutational signatures was performed using NMF. Results: Clinical characteristics of LSC were male (10/15), smokers (15/15), aged <60yrs (4/10) and pleomorphic carcinomas (n = 14/15). HNSC were male (6/6), smokers (6/6), aged <60yrs (4/6) and pleomorphic carcinomas (n = 5/6). Heavy alcohol consumption was reported for HNSC (3/6). Samples clustering based on mutational signatures confirmed the 2 previously described clusters plus one additional cluster: C1 (n = 13) associated with Signatures 4 and 8; C2 (n = 18) associated with Signatures 1, 2, 3 and 13; C3 associated with Signature 16 (unknown factor). Thirteen, 9 and 3 LSC versus 0, 2 and 4 HNSC were classified in C1, C2 and C3, respectively (p-value < 0.01). The 3 patients with high alcohol consumption HNSC were C3. C1 LSC had KRAS (n = 8), NRAS (n = 1), RRAS (n = 1) mutations. C2 LSC had MET (n = 2), KRAS (n = 2), BRCA2 (n = 2), BRCA1 (n = 1), EGFR (n = 1) and IDH1 (n = 1) mutations. C3 LSC had MET (n = 2) and MAP2K1 (n = 1). By contrast, C2 and C3 HNSC had FAT1 (n = 3) and HRAS (n = 1) mutations, which are frequent in head and neck squamous cell carcinomas. Conclusions: Joined analysis of SC identified a group C3 associated with signature 16, which has been associated with liver cancers and a putatively link with DNA damage of alcohol metabolites. Although sharing similar histology, these results suggest that HNSC differs from LSC regarding mutational processes and oncogenic events: C1 limited to LSC, C2 found in LSC and HNSC and C3 more associated with HNSC. Legal entity responsible for the study: Marie Wislez. Funding: Legs Poix La Chancellerie des Universités de Paris - La Ligue Contre le Cancer - Comite de Paris. Disclosure: N. Pecuchet: Employee: Dassault Systemes. H. Blons: Speaker honoraria: AstraZeneca, Boehringer Ingelheim, Pfizer; Travel funding: AstraZeneca. A. Lemoine: Honoraria: AstraZeneca, Boehringer Ingelheim, Roche. M. Wislez: Consulting/advisory role: AstraZeneca, Roche, BMS, MSD, Novartis, Boehringer Ingelheim; Research funding: BMS, Boehringer Ingelheim; Travel, accommodations, expenses: Roche, BMS, Novartis, Pfizer. All other authors have declared no conflicts of interest.