Genomic origin and immune-related status of pulmonary sarcomatoid carcinoma.

Abstract

e13500 Background: Pulmonary sarcomatoid carcinoma (PSC), composed of sarcomatous component (SaC) and carcinomatous component (CaC), is a rare and generally aggressive subtype of non-small-cell lung cancer (NSCLC). Little is known about the genetic origin, TMB, and PD-L1 status of PSC. Methods: 31 immunohistochemically (IHC) confirmed PSCs were enrolled and tumor samples were subjected to microdissection to obtain SaC and CaC. Different components were subjected to targeted sequencing with a 1021-gene-panel. Somatic mutations were used to assess TMB and construct phylogenetic tree. PD-L1 expression level was determined by IHC. Independent cohorts of 90 lung adenocarcinomas (LUAD) from the Geneplus database and 167 sarcomas from TCGA were used for genomic comparison. Results: 87% of patients (pts) were male, with a median age of 57.0 years. 52% were smokers. The most recurrently mutated genes were TP53 (80%), MET (24%), NF1 (21%), EGFR (21%), and KRAS (21%) in CaC, while TP53 (76%), MAP3K1 (21%), NF1 (21%), MET (21%), and KRAS (21%) in SaC. 55.4% of the variations (SNV, small indels, SV, and CNV) were shared within SaC and CaC. TP53, MET, NF1, and EGFR were mostly frequently found in shared mutations. Overwhelming majority of PSCs (29/30) had common mutations between SaC and CaC implying a monoclonal origin. EGFR were mutated significantly less in adenocarcinoma components (AdC) than LUAD (Fisher Exact test, 4/24 vs 52/90, p < 0.001). High-frequency mutated driver genes in SaC, MET, EGFR, NF1, and ALK, were rarely detected in leiomyosarcomas and uterine sarcomas. The median of TMB in SaC and CaC were both 12.9 mutations/Mb (range, SaC 2.88-33.1, CaC 2.88-47.5), with high correlation between the two components (p < 0.001). PD-L1 expression levels in the two components also had high correlation (p < 0.001). More pts showed high PD-L1 expression ( > = 50%) in SaC rather than CaC (8 versus 3). Conclusions: A majority of PSCs share a monoclonal origin. PSCs with AdC exhibited lower mutated frequency of EGFR than LUAD. SaC and CaC had similar higher TMB status than LUAD. SaC and CaC had similar level of PD-L1expression.