Abstract
ObjectivesMultiple primary lung cancers (MPLCs) are an increasingly well-known clinical phenomenon, but there is a lack of high-level evidence for their optimal clinical diagnosis and therapeutic approaches. Thus, we analysed genetic variation to determine the intertumoural heterogeneity and branch evolution of synchronous multiple primary lung adenocarcinomas.MethodsWe performed multiplex mutational sequencing on 93 synchronous multiple primary lung adenocarcinoma lesions from 42 patients who underwent surgical resection.ResultsThe high discordance rate of mutation was 92.9% (n=39) between tumours in individual patients. EGFR, TP53 and KRAS mutations were detected in 57 (61.3%), 19 (20.4%) and 11 (11.8%) of the 93 tumours, respectively. 16 cases of multiple primary lung adenocarcinomas simultaneously harboured EGFR mutations and TP53 mutations. Matching mutations between paired tumours were observed in 1 (2.4%) patient for P20. The genotypes were all EGFR L858R mutations, but the pathological type of P20T1 was lepidic predominant, and P20T2 was adenocarcinoma in situ. In the phylogenetic tree, genetic variations were divided into trunk, shared and branch subtypes. Branch mutations accounted for 91.09% of variations in sMPLA, while the ratio of trunk (4.95%) and shared (3.96%) variations was significantly lower.ConclusionsRemarkable intertumoural heterogeneity and frequent branch mutations were found in synchronous multiple primary lung adenocarcinomas.
Highlights
Lung cancer remains the leading cause of cancer incidence and mortality in most countries [1]
Branch mutations accounted for 91.09% of variations in synchronous multiple primary lung adenocarcinoma (sMPLA), while the ratio of trunk (4.95%) and shared (3.96%) variations was significantly lower
Remarkable intertumoural heterogeneity and frequent branch mutations were found in synchronous multiple primary lung adenocarcinomas
Summary
Lung cancer remains the leading cause of cancer incidence and mortality in most countries [1]. Martini and Melamed established the first multiple primary lung cancer (MPLC) diagnostic criteria in 1975 and proposed that tumours were ‘synchronous’ when they were detected or resected simultaneously [3], which was later revised by the American College of Chest Physicians (ACCP) [4, 5]. Chen et al demonstrated that adenocarcinoma-adenocarcinoma was the most common pathological type in multiple primary lung cancers [6]. Multiple primary lung cancers with different molecular characteristics are heterogeneous diseases [7]. As a potential cause of drug resistance in targeted therapy, lung cancer heterogeneity may promote tumour evolution and adaptation and decrease sensitivity to individualized treatment [9]
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