Cancer Res Treat.  2020 Oct;52(4):1120-1134. 10.4143/crt.2020.307.

Genetic Alterations in Preinvasive Lung Synchronous Lesions

• Ahn S
• Lim J
• Park SY
• Kim H
• Kwon HJ
• Han YB
• Lee CT
• Cho S
• Chung JH

• KMID: 2507938
• DOI: http://doi.org/10.4143/crt.2020.307

Abstract

Purpose
Despite advances in treatment, lung cancer remains the leading cause of cancer mortality. This study aimed to characterise genome-wide tumorigenesis events and to understand the hypothesis of the multistep carcinogenesis of lung adenocarcinoma (LUAD)
Materials and Methods
We conducted multiregion whole-exome sequencing of LUAD with synchronous atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ, or minimally invasive adenocarcinoma of 19 samples from three patients to characterize genome-wide tumorigenesis events and validate the hypothesis of the multistep carcinogenesis of LUAD. We identified potential pathogenic mutations preserved in preinvasive lesions and supplemented the finding by allelic variant level from RNA sequencing.
Results
Overall, independent mutational profiles were observed per patient and between patients. Some shared mutations including epidermal growth factor receptor (EGFR , p.L858R) were present across synchronous lesions.
Conclusion
Here, we show that there are driver gene mutations in AAH, and they may exacerbate as a sequence in a histological continuum, supporting the Darwinian evolution model of cancer genome. The intertumoral and intratumoral heterogeneity of synchronous LUAD implies that multi-biomarker strategies might be necessary for appropriate treatment.

Keyword

Adenocarcinoma of lung; Atypical adenomatous hyperplasia; Mutation; Clonal evolution; Whole exome sequencing

Figure

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  Fig. 1. Multiregional variant allele frequency. Blue and red colours denote the heatmap of variant allele frequency (VAF) of the genome and the transcriptome, respectively. The upper panel shows the private mutations, while the lower panel shows gene mutations found in at least two patients. (A) Atypical adenomatous hyperplasia (AAH). (B) Adenocarcinoma in situ (AIS). (D) Adenocarcinoma (ADC). ADC-N, non-invasive portion of ADC.

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  Fig. 2. Inferred clone status. For each patient, two variant allele frequency (VAF) and read-depth matrices [(no. of mutations)×(no. lesions)] were decomposed into a genotype matrix [(no. of mutations)×(no. of clones)] and a clone frequency matrix [(no. of clone)×(no. lesions)]. C1-C3 represents inferred clones. Clone frequencies (i.e., the proportion of a clone in each lesion) are shown in parenthesis. Colours matched to the legions where the mutation occurred (orange, atypical adenomatous hyperplasia [AAH]; green, adenocarcinoma in situ [AIS]; blue, minimally invasive adenocarcinoma [MIA]; purple, adenocarcinoma [ADC]; red, all lesions). For example, C3 clone in P1 occupied 3% of AAH2 and AAH3, 44% of ADC1, and 42% of ADC2.

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  Fig. 3. Mutation signature analysis. Somatic mutational signatures were generated and compared to the 30 known mutational signatures in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. AAH, atypical adenomatous hyperplasia; AIS, adenocarcinoma in situ; MIA, minimally invasive adenocarcinoma; ADC, adenocarcinoma.

Reference

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