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.

Germline mutations in young non-smoking women with lung adenocarcinoma

“…Its role in the carcinogenic process in our patient remains elusive, however. During the review process of this manuscript, a study on the mutational profile of 36 young LUAD patients was published [54]. Besides characterizing unique somatic mutational features of this patient subgroup, potential predisposing mutations were also identified.…”

NUDT1-Knockdown Inhibits Proliferation, Invasion and Migration of CAL27

“…Therefore, the gene mutation caused by 8-oxo-dGTP was inhibited by overexpressed NUDT1 and the cancer cell apoptosis could not be activated [21]. Recent study indicated that the NUDT is a potential gene associated with germline mutation of non-small cell lung cancer [22]. Another research also found that the NUDT1 is quite associated with the progression of non-small cell lung cancer [23].…”

High kinesin family member 18A expression correlates with poor prognosis in primary lung adenocarcinoma

“…Lung cancer is the leading cause of cancer‐related death worldwide, accounting for one million deaths per year . Non‐small‐cell lung cancer (NSCLC) is the most common type of lung cancer, with two main histological subtypes: adenocarcinoma and squamous cell carcinoma.…”

“…Lung cancer is the leading cause of cancer-related death worldwide, accounting for one million deaths per year. 1 Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer, with two main histological subtypes: adenocarcinoma and squamous cell carcinoma. As a common histological subtype of NSCLC, most clinical treatments of lung adenocarcinoma are decided based on the Union for International Cancer Control and American Joint Committee on Cancer (UICC/AJCC) staging system.…”

“…During tumor progression, cellular division is unregulated, and aberrant mechanisms drive chromosome congregation. 4 To date, human kinesin superfamily proteins (KIFs) have been identified and classified into 14 families (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) according to the standardized nomenclature for kinesins. 5 A number of KIFs are known to be involved in diseases, especially tumorigenesis and carcinogenesis.…”