Distinct Patterns of Somatic Genomic Alterations and Mutational Signatures in Central and Peripheral-Type Small-Cell Lung Cancer

Abstract

Background: Only a few studies have mentioned the differences in survival between patients with central and peripheral-type small-cell lung cancer (SCLC). Genomic landscape and genetic heterogeneity between central and peripheral-type SCLC is scarce. Methods: A total of 41 tumor/control pairs were to move forward for whole-exome sequencing. Distinct patterns of somatic genomic alterations and mutational signatures in central and peripheral-type SCLCs were analyzed. Findings: Tumor mutation burden (TMB) of peripheral-type SCLCs were higher than central-type. And smoking patients had significantly higher weighted genome instability index (wGII) and copy number alteration (CNA) burden than the non-smokers in SCLCs, these alterations were more obviosly in central-types. Furthermore, the driver recurrent somatic CNA (SCNA) regions of central and peripheral-type SCLCs were different. Central and peripheral-type SCLCs had no common recurrent amplification cytobands or genes, but had common recurrent deletion inculding 4 cytobands and 5 genes. Interestingly, the recurrent amplification 12q24.31 was negative correlation with overall survival (OS) in central but not peripheral-type. Moreover, a de novo 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. Interpretation: Although central and peripheral-type SCLCs had similar significantly mutated genes (SMGs), immunotherapy response, genome instability, the driver SCNAs and mutational signatures may be largely distinct. These mutations leaded to different prognosis between central and peripheral-type SCLCs. Funding Statement: None Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: Experimental plans and protocols for this study (NO K18-203Y) were approved by the ethics/licensing committee of the Shanghai Pulmonary Hospital for review and confirmation. Written informed consent was obtained from all patients participating in the study.