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

Genetic Alterations in Preinvasive Lung Synchronous Lesions

Affiliations
  • 1Division of Statistics, Medical Research Collaborating Center, Seoul National University Bundang Hospital, Seongnam, Korea
  • 2Department of Pathology and Translational Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
  • 3Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
  • 4Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Seongnam, Korea

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

  • 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.

  • 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.

  • 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

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018; 68:7–30.
Article
2. Pakkala S, Ramalingam SS. Personalized therapy for lung cancer: striking a moving target. JCI Insight. 2018; 3:e120858.
Article
3. Choi CM, Kim HC, Jung CY, Cho DG, Jeon JH, Lee JE, et al. Report of the Korean Association of Lung Cancer Registry (KALC-R), 2014. Cancer Res Treat. 2019; 51:1400–10.
Article
4. Zhang J, Fujimoto J, Zhang J, Wedge DC, Song X, Zhang J, et al. Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. Science. 2014; 346:256–9.
Article
5. Travis WD, Nicholson AG. WHO classification of tumours of the lung, pleura, thymus and heart. Lyon: International Agency for Research on Cancer;2015.
6. Inamura K. Clinicopathological characteristics and mutations driving development of early lung adenocarcinoma: tumor initiation and progression. Int J Mol Sci. 2018; 19:1259.
Article
7. Izumchenko E, Chang X, Brait M, Fertig E, Kagohara LT, Bedi A, et al. Targeted sequencing reveals clonal genetic changes in the progression of early lung neoplasms and paired circulating DNA. Nat Commun. 2015; 6:8258.
Article
8. Sivakumar S, Lucas FA, McDowell TL, Lang W, Xu L, Fujimoto J, et al. Genomic landscape of atypical adenomatous hyperplasia reveals divergent modes to lung adenocarcinoma. Cancer Res. 2017; 77:6119–30.
Article
9. Park E, Ahn S, Kim H, Park SY, Lim J, Kwon HJ, et al. Targeted sequencing analysis of pulmonary adenocarcinoma with multiple synchronous ground-glass/lepidic nodules. J Thorac Oncol. 2018; 13:1776–83.
Article
10. Noguchi M. Stepwise progression of pulmonary adenocarcinoma: clinical and molecular implications. Cancer Metastasis Rev. 2010; 29:15–21.
11. Tamborero D, Rubio-Perez C, Deu-Pons J, Schroeder MP, Vivancos A, Rovira A, et al. Cancer Genome Interpreter annotates the biological and clinical relevance of tumor alterations. Genome Med. 2018; 10:25.
Article
12. Alves JM, Prieto T, Posada D. Multiregional tumor trees are not phylogenies. Trends Cancer. 2017; 3:546–50.
Article
13. Bailey MH, Tokheim C, Porta-Pardo E, Sengupta S, Bertrand D, Weerasinghe A, et al. Comprehensive characterization of cancer driver genes and mutations. Cell. 2018; 173:371–85.
14. Rhee JK, Lee S, Park WY, Kim YH, Kim TM. Allelic imbalance of somatic mutations in cancer genomes and transcriptomes. Sci Rep. 2017; 7:1653.
Article
15. Govindan R, Ding L, Griffith M, Subramanian J, Dees ND, Kanchi KL, et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell. 2012; 150:1121–34.
Article
16. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014; 511:543–50.
17. Labbe C, Cabanero M, Korpanty GJ, Tomasini P, Doherty MK, Mascaux C, et al. Prognostic and predictive effects of TP53 co-mutation in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Lung Cancer. 2017; 111:23–9.
18. Schmid K, Oehl N, Wrba F, Pirker R, Pirker C, Filipits M. EGFR/KRAS/BRAF mutations in primary lung adenocarcinomas and corresponding locoregional lymph node metastases. Clin Cancer Res. 2009; 15:4554–60.
Article
19. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013; 500:415–21.
20. Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TB, Veeriah S, et al. Tracking the evolution of non-small-cell lung cancer. N Engl J Med. 2017; 376:2109–21.
21. Valero V 3rd, Pawlik TM, Anders RA. Emerging role of Hpo signaling and YAP in hepatocellular carcinoma. J Hepatocell Carcinoma. 2015; 2:69–78.
22. Zheng W, Jiang C, Li R. Integrin and gene network analysis reveals that ITGA5 and ITGB1 are prognostic in non-small-cell lung cancer. Onco Targets Ther. 2016; 9:2317–27.
Article
23. Pirinen R, Leinonen T, Bohm J, Johansson R, Ropponen K, Kumpulainen E, et al. Versican in nonsmall cell lung cancer: relation to hyaluronan, clinicopathologic factors, and prognosis. Hum Pathol. 2005; 36:44–50.
Article
24. Ma P, Fu Y, Cai MC, Yan Y, Jing Y, Zhang S, et al. Simultaneous evolutionary expansion and constraint of genomic heterogeneity in multifocal lung cancer. Nat Commun. 2017; 8:823.
Article
25. He XP, Song FJ, Liu XY, Wang Z, Li XX, Liu FY, et al. The relationship between KRAS gene mutations and HLA class I antigen downregulation in the metastasis of non-small cell lung cancer. J Int Med Res. 2013; 41:1473–83.
Article
26. Blakely CM, Watkins TB, Wu W, Gini B, Chabon JJ, McCoach CE, et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat Genet. 2017; 49:1693–704.
Article
27. Hakimi AA, Pham CG, Hsieh JJ. A clear picture of renal cell carcinoma. Nat Genet. 2013; 45:849–50.
Article
28. Ahn JW, Kim HS, Yoon JK, Jang H, Han SM, Eun S, et al. Identification of somatic mutations in EGFR/KRAS/ALK-negative lung adenocarcinoma in never-smokers. Genome Med. 2014; 6:18.
Article
29. Park IY, Powell RT, Tripathi DN, Dere R, Ho TH, Blasius TL, et al. Dual chromatin and cytoskeletal remodeling by SETD2. Cell. 2016; 166:950–62.
Article
30. Sottoriva A, Kang H, Ma Z, Graham TA, Salomon MP, Zhao J, et al. A Big Bang model of human colorectal tumor growth. Nat Genet. 2015; 47:209–16.
Article
31. Venkatesan S, Birkbak NJ, Swanton C. Constraints in cancer evolution. Biochem Soc Trans. 2017; 45:1–13.
Article
32. Shin HT, Choi YL, Yun JW, Kim NK, Kim SY, Jeon HJ, et al. Prevalence and detection of low-allele-fraction variants in clinical cancer samples. Nat Commun. 2017; 8:1377.
Article
Full Text Links
  • CRT
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr