Characteristics of genomic alterations of lung adenocarcinoma in young never-smokers

Abstract

Non-small-cell lung cancer (NSCLC) has been recognized as a highly heterogeneous disease with phenotypic and genotypic diversity in each subgroup. While never-smoker patients with NSCLC have been well studied through next generation sequencing, we have yet to recognize the potentially unique molecular features of young never-smoker patients with NSCLC. In this study, we conducted whole genome sequencing (WGS) to characterize the genomic alterations of 36 never-smoker Chinese patients, who were diagnosed with lung adenocarcinoma (LUAD) at 45 years or younger. Besides the well-known gene mutations (e.g., TP53 and EGFR), our study identified several potential lung cancer-associated gene mutations that were rarely reported (e.g., HOXA4 and MST1). The lung cancer-related copy number variations (e.g., EGFR and CDKN2A) were enriched in our cohort (41.7%, 15/36) and the lung cancer-related structural variations (e.g., EML4-ALK and KIF5B-RET) were commonly observed (22.2%, 8/36). Notably, new fusion partners of ALK (SMG6-ALK) and RET (JMJD1C-RET) were found. Furthermore, we observed a high prevalence (63.9%, 23/36) of potentially targetable genomic alterations in our cohort. Finally, we identified germline mutations in BPIFB1 (rs6141383, p.V284M), CHD4 (rs74790047, p.D140E), PARP1 (rs3219145, p.K940R), NUDT1 (rs4866, p.V83M), RAD52 (rs4987207, p.S346*), and MFI2 (rs17129219, p.A559T) were significantly enriched in the young never-smoker patients with LUAD when compared with the in-house noncancer database (p < 0.05). Our study provides a detailed mutational portrait of LUAD occurring in young never-smokers and gives insights into the molecular pathogenesis of this distinct subgroup of NSCLC.

Keywords: genetic predisposition; genomics; lung adenocarcinoma; next generation sequencing; young age.

Figure 1

Mutation landscape of lung adenocarcinoma in young never‐smoker patients. (a) Nonsynonynous mutation rates (number of mutations per Mb) in 36 tumor samples. (b) Genes predicted to be significantly mutated by MuSiC. Asterisk indicated that the genes were noted by both MuSiC and MutSigCV. Genes were sorted by significant FDR value (right panel); the frequency was indicated by the number of mutated samples (left panel). (c) Focal CNVs in known lung cancer genes in 36 tumor samples. (d) SVs previously implicated in lung cancer in 36 tumor samples. (e) Percentage of six types of single nucleotide substitutions in each tumor sample. The samples were ordered on the horizontal axis based on the clustering of their mutated genes. The colors denoted different types of somatic events. [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 2

Mutations of noncoding regions in lung adenocarcinoma occurring in young never‐smoker patients. (a) The log10 of number of SNVs per Kb in the six noncoding regions and protein‐coding genes, and the number of mutational genes displayed in the parentheses behind every gene types. Items with different letters were significantly different (LSD test, p < 0.01). (b) The mutation frequency heatmap of the top 10 genes with highest mutation frequency in 36 tumor samples. The legend showed the meaning of the heatmap color; the depth of the color represented the size of the log10 (number of SNVs per kb). (c) RP11–774D14.1 and RP11–435B5.4 mutations in each tumor. The x‐axis indicated the absolute position of the gene and the dotted line showed the recurrent mutations, which had a high mutation percentage (>10% in all samples). And the mutation percentage of the recurrent mutations was showed in the upper of the figure. [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 3

Somatically altered pathways in lung adenocarcinoma in young never‐smoker patients. Components and inferred functions of p53 signaling/cell cycle process, RTK/Ras/PI3K pathway and histone/chromatin modification were summarized in the main text. Percentage presented alteration frequencies in 36 tumor samples. Pathway alterations including somatic SNVs, CNVs and SVs were shown. Activated and inactivated pathways/genes and activating or inhibitory symbols were based on predicted effects of genome alterations and/or pathway function. [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 4

Therapeutic targets in young never‐smoker patients with lung adenocarcinoma. Missense mutations, in‐frame indel, copy number amplifications and gene fusions that were regarded as potential targets of specific kinase inhibitors or antibodies were investigated thoroughly. Tumors with at least one alteration were shown. [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 5

Pathogenic and likely pathogenic germline alterations classified by ACMG. Genes were categorized into “lung cancer genes” (top) and “other type cancer genes” (below). The square frame indicated genes related to DNA reparation. The color denoted different tiers of germline events. Patients with assumable predisposition of cancer were indicated by * (multiple primary cancers) or # (immediate family member diagnosed with cancer). [Color figure can be viewed at http://wileyonlinelibrary.com]