Genomic characterisation of pulmonary subsolid nodules: mutational landscape and radiological features

Abstract

BackgroundLung adenocarcinomas (LUADs) that display radiologically as subsolid nodules (SSNs) exhibit more indolent biological behaviour than solid LUADs. SSNs, commonly encompassing pre-invasive and invasive yet early-stage adenocarcinomas, can be categorised as pure ground-glass nodules and part-solid nodules. The genomic characteristics of SSNs remain poorly understood.MethodsWe subjected 154 SSN samples from 120 treatment-naïve Chinese patients to whole-exome sequencing. Clinical parameters and radiological features of these SSNs were collected. The genomic landscape of SSNs and differences from that of advanced-stage LUADs were defined. In addition, we investigated the intratumour heterogeneity and clonal relationship of multifocal SSNs and conducted radiogenomic analysis to link imaging and molecular characteristics of SSNs. Fisher's exact and Wilcoxon rank sum tests were used in the statistical analysis.ResultsThe median somatic mutation rate across the SSN cohort was 1.12 mutations per Mb. Mutations in EGFR were the most prominent and significant variation, followed by those in RBM10, TP53, STK11 and KRAS. The differences between SSNs and advanced-stage LUADs at a genomic level were unravelled. Branched evolution and remarkable genomic heterogeneity were demonstrated in SSNs. Although multicentric origin was predominant, we also detected early metastatic events among multifocal SSNs. Using radiogenomic analysis, we found that higher ratios of solid components in SSNs were accompanied by significantly higher mutation frequencies in EGFR, TP53, RBM10 and ARID1B, suggesting that these genes play roles in the progression of LUADs.ConclusionsOur study provides the first comprehensive description of the mutational landscape and radiogenomic mapping of SSNs.

Application of large-scale targeted sequencing to distinguish multiple lung primary tumors from intrapulmonary metastases

“…1 ). The result was similar to the previous reports in which RBM10 was found with a high mutation rate (16%) in radiological subsolid nodules 25 , and a high mutation rate (21%) in preinvasive and early-stage lung adenocarcinomas 26 . In addition, several oncogenes (such as EGFR , SPTA , and RB1 ) had different mutations in the same or different tumors on the same patient (Fig.…”

“…It is generally accepted that multiple GGNs in patients come out from different lineages, meaning that hematogenous metastasis do not happen to GGNs 5 , 30 , 31 , 33 . However, the possibility that a small number of GGNs come from the same ancestor cannot be excluded, which can be explained by the air space theory 25 , 34 – 36 . In our cohort, the definite IM case (a pGGN and a solid nodule) shared multiple mutations, providing evidence that a small portion of GGNs might be the result of early metastasis.…”

Decoding the multicellular ecosystem of lung adenocarcinoma manifested as pulmonary subsolid nodules by single-cell RNA sequencing

“…Much effort has been devoted to decoding the indolent nature of SSN. Our team has found that the genome of SSN has a relatively low mutation burden and few copy number alterations (11). The tumor lesion is a complex ecosystem composed of malignant cells, various types of immune cells, and stromal cells (12).…”

<p>Predicting Lung Cancer Risk of Incidental Solid and Subsolid Pulmonary Nodules in Different Sizes</p>

“…20 Histologically, solid components of SSNs were usually related to histologic subtypes like papillary, acinar, solid, or invasive mucinous adenocarcinoma. 3 Radiogenomically, Li et al 28 found that higher ratios of solid components in SSNs were accompanied by significantly higher mutation frequencies in EGFR, TP53, RBM10, and ARID1B, suggesting that these genes play roles in the progression of lung adenocarcinomas. Anyway, proper management of SSNs is critical.…”