Abstract
The Mesenchymal Epithelial Transition factor gene (MET) is a crucial proto-oncogene implicated in cancer initiation and metastasis. Copy number amplification is a primary form of MET aberration, commonly occurring as focal amplification and polysomy. Despite NGS techniques being capable of identifying MET gene amplification, accurately quantifying its absolute copy number remains challenging. Specifically, NGS-based detection often exhibits lower concordance with the gold-standard Fluorescence in Situ Hybridization and lacks the ability to distinguish between amplification types. This paper presents a novel NGS-based approach designed to accurately quantify the copy number of MET gene amplification by incorporating tumor purity and variant classification considerations, thereby enhancing reliability. Our approach includes evaluating tumor cell content, converting observed MET gene copy numbers to absolute gene copy numbers (GCN), and differentiating between focal amplification and polysomy forms of MET amplification. The proposed approach has been evaluated on the real sequencing dataset. The results indicate that our approach significantly improves the precision of MET amplification status estimation via NGS, making it more consistent with FISH benchmark results.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Kawakami, H., Okamoto, I., Okamoto, W., Tanizaki, J., Nakagawa, K., Nishio, K.: Targeting MET amplification as a new oncogenic driver. Cancers 6(3), 1540–1552 (2014)
Guo, R., Luo, J., Chang, J., Rekhtman, N., Arcila, M., Drilon, A.: MET-dependent solid tumours - molecular diagnosis and targeted therapy. Nat. Rev. Clin. Oncol. 17(9), 569–587 (2020)
Camidge, D.R., et al.: Crizotinib in patients with MET-Amplified NSCLC. J. Thorac. Oncol. 16(6), 1017–1029 (2021)
Wolf, J., et al.: Capmatinib in MET Exon 14-mutated or MET-amplified non-small-cell lung cancer. N. Engl. J. Med. 383(10), 944–957 (2020)
Camidge, D.R., Davies, K.D.: MET copy number as a secondary driver of epidermal growth factor receptor tyrosine kinase inhibitor resistance in EGFR-mutant non-small-cell lung cancer. J. Clin. Oncol. 37(11), 855–857 (2019)
Westover, D., Zugazagoitia, J., Cho, B.C., Lovly, C.M., Paz-Ares, L., Mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors. Ann. Oncol. 29(suppl_1), i10–i19 (2018)
Matikas, A., Mistriotis, D., Georgoulias, V., Kotsakis, A.: Current and future approaches in the management of non-small-cell lung cancer patients with resistance to EGFR TKIs. Clin. Lung Cancer 16(4), 252–261 (2015)
Leonetti, A., Sharma, S., Minari, R., Perego, P., Giovannetti, E., Tiseo, M.: Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br. J. Cancer 121(9), 725–737 (2019)
Dagogo-Jack, I., et al.: MET alterations are a recurring and actionable resistance mechanism in ALK-positive lung cancer. Clin. Cancer Res. 26(11), 2535–2545 (2020)
Sequist, L.V., et al.: Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study. Lancet Oncol. 21(3), 373–386 (2020)
Wu, Y.L., et al.: Phase Ib/II study of Capmatinib (INC280) plus gefitinib after failure of epidermal growth factor receptor (EGFR) inhibitor therapy in patients with EGFR-Mutated, MET factor-dysregulated non-small-cell lung cancer. J. Clin. Oncol. 36(31), 3101–3109 (2018)
Recondo, G., Che, J., Jänne, P.A., Awad, M.M.: Targeting MET dysregulation in cancer. Cancer Discov. 10(7), 922–934 (2020)
Sun, B., et al.: Detection of MET Polysomy by next-generation sequencing and its clinical relevance for MET inhibitors. Cancer Res. Commun. 3(4), 532–539 (2023)
Drilon, A., Cappuzzo, F., Ou, S.H.I., Camidge, D.R.: Targeting MET in lung cancer: will expectations finally be MET? J. Thorac. Oncol. 12(1), 15–26 (2017)
Yuan, X., et al.: Accurate inference of tumor purity and absolute copy numbers from high-throughput sequencing data. Front. Genet. 11, 458 (2020)
Carter, S.L., et al.: Absolute quantification of somatic DNA alterations in human cancer. Nat. Biotechnol. 30(5), 413–421 (2012)
Olshen, A.B., Venkatraman, E.S., Lucito, R., Wigler, M.: Circular binary segmentation for the analysis of array-based DNA copy number data. Biostatistics 5(4), 557–572 (2004)
Peng, L.X., et al.: MET amplification identified by next-generation sequencing and its clinical relevance for MET inhibitors. Exp. Hematol. Oncol. 10(1), 52 (2021)
Acknowledgments
We thank all faculty members and graduate students who discussed the mathematical and statistical issues in seminars.
Author information
Authors and Affiliations
Corresponding authors
Editor information
Editors and Affiliations
Ethics declarations
Author M.C. and Z.C. are employed by Nanjing Geneseeq Technology Inc. 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.
Rights and permissions
Copyright information
© 2024 The Author(s), under exclusive license to Springer Nature Switzerland AG
About this paper
Cite this paper
Zhao, M., Wang, J., Chang, Z., Liu, Y. (2024). Enhancing MET Copy Number Estimation by Factoring in Tumor Purity and Variant Types. In: Rojas, I., Ortuño, F., Rojas, F., Herrera, L.J., Valenzuela, O. (eds) Bioinformatics and Biomedical Engineering. IWBBIO 2024. Lecture Notes in Computer Science(), vol 14849. Springer, Cham. https://doi.org/10.1007/978-3-031-64636-2_21
Download citation
DOI: https://doi.org/10.1007/978-3-031-64636-2_21
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-64635-5
Online ISBN: 978-3-031-64636-2
eBook Packages: Computer ScienceComputer Science (R0)