KMT2C mutation associated with tumor mutational burden in small cell lung cancer.

Abstract

e20098 Background: Immune checkpoint inhibitors are used to treat small cell lung cancer (SCLC). Tumor mutational burden (TMB) emerges as a promising predictor of immunotherapy efficacy, but the relationship between TMB and genetic features of SCLC remains unclear. In this study, we explored the correlation between genetic profiles and TMB in SCLC. Methods: FFPE tumor and matched blood samples were collected from 119 SCLC patients for panel targeted based next-generation sequencing. Genomic alterations (GAs) including single nucleotide variations, short and long insertions/deletions, copy number variations and gene rearrangements were assessed. Results: This study enrolled 114 SCLC and 5 mixed SCLC patients (91 males and 28 females) with a median age of 59 years. Median TMB was 9.3 muts/Mb (25% quantile: 6.3 muts/Mb, 75% quantile: 13.2 muts/Mb). For all patients, 31 (26%) had low TMB (≤6.3 muts/Mb), 55 (46%) had intermediate TMB (6.4-13.1 muts/Mb), and 33 (28%) had high TMB (≥13.2 muts/Mb). KMT2D mutations (mut), included substitution/indel (6/25) and truncation (19/25). KMT2D exhibited substitution/indel (6/25) and truncation (19/25) mutations in 19% of SCLC tumors while KMT2C exhibited substitution/indel (11/17), gene homozygous deletion (1/17) and truncation (5/17) mutations in 12% of SCLC tumors. Tumors with KMT family gene mut (KMT2C and KMT2D) (n = 33) had higher TMB (11.7 vs. 8.5 muts/Mb, p = 0.009). KMT2C mut tumors had higher TMB than KMT2C wildtype (wt) tumors (15.2 vs. 9.2 muts/Mb, p = 0.0036). TP53 mut occurred in 86% of KMT2C mut tumors and KMT2C/TP53 co-mutated tumors had higher TMB than KMT2C wt/TP53 mut tumors (17.8 vs. 9.3 muts/Mb, p = 0.0035) or KMT2C wt/TP53 wt tumors (17.8 vs. 5.4 muts/Mb, p = 0.027). Conclusions: Our data indicates that KMT family genes were frequently mutated in SCLC. KMT2C mut positively correlated with higher TMB and KMT2C co-mutated with TP53 or FAT1 may have a synergic effect on TMB. Our study explored a novel relationship between GAs and TMB that may greatly improve immunotherapeutic strategies for SCLC.