Distinct patterns of somatic genomic alterations and mutational signatures in central and peripheral-type small-cell lung cancer

Abstract

Background: Generally, small-cell lung cancer (SCLC) can be classified into central and peripheral-type. Genomic landscape and genetic heterogeneity between central and peripheral-type SCLCs is scarce. Methods: We conducted whole-exome sequencing (WES) of 41 tumor/control pairs of SCLC samples. In all cases, 8,186 genes with non-synonymous mutations were identified, as well as significantly mutated genes (SMGs), tumor mutation burden (TMB), weighted genome instability index (wGII) and somatic copy number alteration (SCNA), the driver recurrent SCNA, and mutational signatures between central and peripheral-type SCLCs. Results: TMB of peripheral-type SCLCs were higher than central-type. Smoking patients had significantly higher wGII and CNA burden than the non-smokers in SCLCs, these alterations were more obviously in central-types. Furthermore, the driver SCNA regions of central and peripheral-type SCLCs were different. Central and peripheral-type SCLCs had no common recurrent amplification (AMP) cytobands or genes, but had collective recurrent deletion (DEL) including four cytobands and five genes. Interestingly, the AMP 12q24.31 was negative correlated with overall survival (OS) in central but not peripheral-type SCLCs. Moreover, a de novo mutational signature A was found significantly higher in peripheral than central-type SCLCs. In parallel, signature D was predictive of poor outcome, which was mainly in peripheral SCLC patients. COSMIC signatures analysis revealed that the association with signature D and OS was similar to the positive relationship between signature 13 and outcome. Conclusions: Central and peripheral-type SCLCs were different in immunotherapy response, genome instability, the driver SCNAs and mutational signatures, which leaded to differences of prognosis.