Utility of whole exome sequencing analysis in differentiating intrapulmonary metastatic multiple ground-glass nodules (GGNs) from multiple primary GGNs

Dong Zhou,Quan-Xing Liu,Gui-Xue Yang,Xiao Lu,Ji-Gang Dai,Bin Hou,Li Jiang,Man-Yuan Li,Hong Zheng

doi:10.1007/s10147-022-02134-8

Dong Zhou, Quan-Xing Liu + Show 7 more

Open Access

https://doi.org/10.1007/s10147-022-02134-8

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Abstract

PurposeClinical evidence of metastasis with ground-glass nodules (GGNs) has been reported, including pulmonary metastasis and distant metastasis. However, the clonal relationships of multiple GGNs at the genetic level remain unclear.Experimental designSixty tissue specimens were obtained from 19 patients with multiple GGN lung cancer who underwent surgery in 2019. Whole exome sequencing (WES) was performed on tissue samples, and genomic profiling and clone evolution analysis were conducted to investigate the genetic characteristics and clonality of multiple GGNs.ResultsA total of 15,435 nonsynonymous mutations were identified by WES, and GGNs with shared nonsynonymous mutations were observed in seven patients. Copy number variant (CNV) analysis showed that GGNs in ten patients had at least one shared arm-level CNV. Mutational spectrum analysis showed that GGNs in three patients had similar six substitution profiles and GGNs in fou patients had similar 96 substitution profiles. According to the clone evolution analysis, we found that GGNs in five patients had shared clonal driver gene mutations. Taken together, we identified that 5 patients may have multiple primary GGNs without any similar genetic features, 2 patients may have intrapulmonary metastatic GGNs with ≥ 3 similar genetic features, and the other 12 patients cannot be determined due to insufficient evidences in our cohort.ConclusionsOur findings suggest that the intrapulmonary metastasis exist in multiple GGNs, but the number of GGNs was not associated with the probability of metastasis. Application of genomic profiling may prove to be important to precise management of patients with multiple GGNs.

Highlights

Whole exome sequencingWith the widespread use of low-dose chest computed tomography (CT) and lung cancer screening, more patients with early-stage lung cancer were found, including groundglass nodules (GGNs)
We collected 60 ground-glass nodules (GGNs) from 19 patients with lung cancer to explore the evolutionary relationship between GGNs in these patients
Histological examination revealed that 78.3% (47/60) of GGNs were minimally invasive adenocarcinoma (MIA) and 18.3% (11/60) were adenocarcinoma in situ (AIS) (Table S1)

Summary

Introduction

Whole exome sequencingWith the widespread use of low-dose chest computed tomography (CT) and lung cancer screening, more patients with early-stage lung cancer were found, including groundglass nodules (GGNs). GGNs are traditionally considered as multiple primary lung cancers and at the early stage of tumorigenesis [4,5,6]. A few studies have been focused on whether multiple GGNs were multiple primaries or intrapulmonary metastasis [15,16,17,18], most of which were based on the targeted genes [15,16,17], and only one study was based on genomics [18]. The targeted gene based studies did not find any evidence of intrapulmonary metastasis. The genomics based study was the first report of GGNs with intrapulmonary metastasis at the genetic level, only two patients were included

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