Genomic features of Chinese small cell lung cancer

Abstract

Background: Small cell lung cancer (SCLC) is an aggressive disease with poor survival. Although molecular and clinical characteristics have been established for SCLC in western patients, limited investigation has been performed for Chinese SCLC patients.

Objective: In this study, we investigated the genomic features of Chinese SCLC patients.

Methods: A total of 75 SCLC patients were enrolled. Genomic alterations in 618 selected genes were analyzed by targeted next-generation sequencing.

Results: Here, we showed that TP53 (77.30%) and RB1 (30.70%) were the most prevalent genes alterations, followed by KMT2D, ALK, LRP1B, EGFR, NOTCH3, AR, CREBBP, ROS1, and BRCA2. And the most common genetic alterations were enriched in the cell cycle signaling pathway (84.00%) of Chinese SCLC patients. DNA damage repair (DDR) pathway analysis showed that the most frequently enriched DDR pathways were fanconi anaemia (FA, 29.41%) and homology recombination (HR, 21.57%). Notably, 9.33% SCLC patients in our cohort had pathogenic or likely pathogenic germline gene variants. Compared with the U Cologne cohort, a higher prevalence in EGFR, AR, BRCA2, TSC1, ATXN3, MET, MSH2, ERBB3 and FOXA1 were found in our cohort; while compared to the data from the Johns Hopkins cohort, a higher mutated frequency in TP53, KMT2D, ALK, and EGFR were found in our cohort. Moreover, a significant association was found between high tumor mutation burden (TMB) and mutations involved in TP53, CREBBP, EPHA3, KMT2D, ALK and RB1. Approximately 33.33% of patients with SCLC harbored at least one actionable alteration annotated by OncoKB, of which one patient had alterations of level 1; seventeen patients had level 3; fifteen patients possessed level 4.

Conclusion: Our data might provide an insightful meaning in targeted therapy for Chinese SCLC patients.

Keywords: Actionable alterations; DNA damage repair; Germline; Small cell lung cancer; TMB.

Fig. 1

The landscape of mutated genes in a series of 75 SCLC patients. A Oncoprint of the 30 most frequently mutated genes in our cohort. B Summary of the mutation information with statistical calculations. C, D Classification of mutation types according to different categories, in which missense mutation accounts for the most fraction, SNP showed more frequency than insertion or deletion, and C > T was the most common of SNV; E, F) Tumor mutation burden in specific samples. G The top 10 mutated genes in SCLC. H The prevalence of total and oncogenic alterations in specified signaling pathways in SCLC. SNV: single nucleotide variation

Fig. 2

Genetic alterations in DNA damage repair pathway. A The distribution of known or likely deleterious somatic DDR gene mutations. B Frequency of altered pathway for DDR

Fig. 3

A Comparisons of the gene prevalence identified in our cohort (red bars) and U Cologne cohort (green bars). B Comparisons of the gene prevalence identified in our cohort and in Johns Hopkins cohort. Two-sided Fisher’s tests were conducted to compare the different frequency between two cohorts. ***p $\le$ 0.001, **p $\le$ 0.01, *p $\le$ 0.05

Fig. 4

Comparisons of median TMB in Chinese SCLC patients with certain specific gene mutations. DDRmt: DDR mutant; DDRwt: DDR wildtype

Fig. 5

A Samples were assigned to the highest level of actionable alterations. B Distribution of levels of actionable alterations