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Genetics and Genomics

Stepwise evolutionary genomics of early-stage lung adenocarcinoma manifesting as pure, heterogeneous and part-solid ground-glass nodules

British Journal of Cancer volume 127, pages 747–756 (2022)Cite this article

Subjects

Abstract

Background

This study was designed to unravel the genomic landscape and evolution of early-stage subsolid lung adenocarcinomas (SSN-LUADs) manifesting as pure ground-glass nodules (pGGNs), heterogeneous ground-glass nodules (HGGNs) and part-solid nodules (PSNs).

Methods

Samples subjected to either broad-panel next-generation sequencing (NGS) or whole-exome sequencing (WES) were included. Clinicopathologic and genomic features were compared among pGGN, HGGN and PSN, while tumour evolutionary trajectories and mutational signatures were evaluated in the entire cohort.

Results

In total, 247 SSN-LUAD samples subjected to broad-panel NGS and 125 to WES were identified. Compared with PSNs, HGGNs had significantly lower tumour mutation count (P < 0.001), genomic alteration count (P < 0.001), and intra-tumour heterogeneity (P = 0.005). Statistically significant upward trends were observed in alterations involving driver mutations and oncogenic pathways from pGGNs to HGGNs to PSNs. EGFR mutation was proved to be a key early event in the progression of SSN-LUADs, with subsequently two evolutionary trajectories involving either RBM10 or TP53 mutation in the cancer-evolution models.

Conclusions

This study provided evidence for unravelling the previously unknown genomic underpinnings associated with SSN-LUAD evolution from pGGN to HGGN to PSN, proving that HGGN was an intermediate SSN form between pGGN and PSN genetically.

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Fig. 1: Association between radiological subtype and genomic features in the broad-panel NGS cohort.
Fig. 2: Analyses of driver genes detected by dNdScv algorithm in the broad-panel NGS cohort.
Fig. 3: Oncogenic pathway and therapeutic actionability analyses in the broad-panel NGS cohort.
Fig. 4: Cancer-evolution models of early-stage SSN-LUADs.
Fig. 5: Mutational signature analyses in the WES cohort.

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Data availability

All data are available from the authors upon reasonable request.

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Funding

This work was financially supported by the National Natural Science Foundation of China (grant 82002410, HL), the Major Research Plan of National Natural Science of China (grant 92059203, JW) and Peking University People’s Hospital Scientific Research Development Funds (grant RDY2020-02, HL).

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Author notes

  1. These authors contributed equally: Hao Li, Zewen Sun, Rongxin Xiao, Qingyi Qi.

Authors and Affiliations

  1. Department of Thoracic Surgery, Peking University People’s Hospital, Beijing, China

    Hao Li, Zewen Sun, Rongxin Xiao, Xiao Li, Jian Zhou, Zhenfan Wang, Fan Yang & Jun Wang

  2. Department of Radiology, Peking University People’s Hospital, Beijing, China

    Qingyi Qi & Ping Yin

  3. Berry Oncology Corporation, No. 4 Science Park Road, Changping District, Beijing, China

    Haiyan Huang & Ke Liu

  4. Department of Cardiac Surgery, Peking University People’s Hospital, Beijing, China

    Xuan Wang

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  1. Hao Li
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Contributions

HL: conceptualisation, project administration, formal analysis and writing—original draft; ZS: methodology, software, formal analysis and writing—original draft; RX: formal analysis and writing—original draft; QQ: resources, investigation and data curation; XL: project administration and supervision; HH: methodology, software, formal analysis and visualisation; XW: investigation; JZ: investigation; ZW: investigation; PY: investigation; FY: project administration and supervision; JW: project administration and supervision.

Corresponding authors

Correspondence to Xiao Li or Jun Wang.

Ethics declarations

Competing interests

HH and KL were employed by the company Berry Oncology, Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethics approval and consent to participate

This study was approved by the Institutional Review Board at Peking University People’s Hospital (2020PHB363-01). The study was performed in accordance with the Declaration of Helsinki.

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No individual person’s data is presented in this manuscript.

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Li, H., Sun, Z., Xiao, R. et al. Stepwise evolutionary genomics of early-stage lung adenocarcinoma manifesting as pure, heterogeneous and part-solid ground-glass nodules. Br J Cancer 127, 747–756 (2022). https://doi.org/10.1038/s41416-022-01821-7

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