Genetic instability and recurrent MYC amplification in ALK‐translocated NSCLC: a central role of TP53 mutations
Open accessAbstract
The anaplastic lymphoma kinase (ALK) rearrangement defines a distinct molecular subtype of non‐small cell lung cancer (NSCLC). Despite the excellent initial efficacy of ALK inhibitors in patients with ALK+ lung cancer, resistance occurs almost inevitably. To date, there is no reliable biomarker allowing the identification of patients at higher risk of relapse. Here, we analysed a subset of 53 ALK+ tumours with and without TP53 mutation and ALK+ NSCLC cell lines by NanoString nCounter technology. We found that the co‐occurrence of early TP53 mutations in ALK+ NSCLC can lead to chromosomal instability: 24% of TP53‐mutated patients showed amplifications of known cancer genes such as MYC (14%), CCND1 (10%), TERT (5%), BIRC2 (5%), ORAOV1 (5%), and YAP1 (5%). MYC‐overexpressing ALK+ TP53‐mutated cells had a proliferative advantage compared to wild‐type cells. ChIP‐Seq data revealed MYC‐binding sites within the promoter region of EML4, and MYC overexpression in ALK+ TP53‐mutated cells resulted in an upregulation of EML4–ALK, indicating a potential MYC‐dependent resistance mechanism in patients with increased MYC copy number. Our study reveals that ALK+ NSCLC represents a more heterogeneous subgroup of tumours than initially thought, and that TP53 mutations in that particular cancer type define a subset of tumours that harbour chromosomal instability, leading to the co‐occurrence of pathogenic aberrations. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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TP53 co-mutations promote genomic instability in ALK-rearranged LUAD.
“TP53 co-mutations promote genomic instability”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [130]
TP53 co-mutations are an independent negative prognostic factor in ALK-rearranged LUAD regardless of systemic therapy type.
“are an independent negative prognostic factor in ALK-re-arrangement-positive LUAD, regardless of the type of systemic therapy used128–130.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [130]
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Cites
Fast and accurate short read alignment with Burrows-Wheeler transform
Li, H., & Durbin, R. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp324 · Cited by 58,607 · see citing works
Global cancer statistics, 2012
Torre, L. A., Bray, F., Siegel, R. L., Ferlay, J., Lortet‐Tieulent, J., & Jemal, A. (2015) · CA A Cancer Journal for Clinicians · doi:10.3322/caac.21262 · Cited by 26,858 · see citing works
ggplot2: Elegant Graphics for Data Analysis
Wickham, H. (2009) · doi:10.1007/978-0-387-98141-3 · Cited by 14,447 · see citing works
Vogelstein, B., Lane, D., & Levine, A. J. (2000) · Nature · doi:10.1038/35042675 · Cited by 6,607 · see citing works
Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer
Soda, M., Choi, Y. L., Enomoto, M., Takada, S., Yamashita, Y., Ishikawa, S., Fujiwara, S.-I., Watanabe, H., Kurashina, K., Hatanaka, H., et al. (2007) · Nature · doi:10.1038/nature05945 · Cited by 5,439 · see citing works
The landscape of somatic copy-number alteration across human cancers
Beroukhim, R., Mermel, C. H., Porter, D., Wei, G., Raychaudhuri, S., Donovan, J., Barretina, J., Boehm, J. S., Dobson, J., Urashima, M., et al. (2010) · Nature · doi:10.1038/nature08822 · Cited by 4,017 · see citing works
Robust Tests for the Equality of Variances
Brown, M. B., & Forsythe, A. B. (1974) · Journal of the American Statistical Association · doi:10.1080/01621459.1974.10482955 · Cited by 3,216 · see citing works
Reshaping Data with the reshape Package
Wickham, H. (2007) · Journal of Statistical Software · doi:10.18637/jss.v021.i12 · Cited by 3,167 · see citing works
The Split-Apply-Combine Strategy for Data Analysis
Wickham, H. (2011) · Journal of Statistical Software · doi:10.18637/jss.v040.i01 · Cited by 2,901 · see citing works
Alectinib versus Crizotinib in Untreated <i>ALK</i> -Positive Non–Small-Cell Lung Cancer
Peters, S., Camidge, D. R., Shaw, A. T., Gadgeel, S., Ahn, J. S., Kim, D.-W., Ou, S.-H. I., Pérol, M., Dziadziuszko, R., Rosell, R., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1704795 · Cited by 2,527 · see citing works
Travis, W. D., Brambilla, E. M., BURKE, A. P., Marx, A., & Nicholson, A. G. (2015) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000663 · Cited by 1,910 · see citing works
WHO classification of tumours of the lung, pleura, thymus and heart
Travis, W. D. (2015) · International Agency for Research on Cancer eBooks · Cited by 1,672 · see citing works
Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer
Peifer, M., Fernandez‐Cuesta, L., Sos, M. L., George, J., Seidel, D., Kasper, L. H., Plenker, D., Leenders, F., Sun, R., Zander, T., et al. (2012) · Nature Genetics · doi:10.1038/ng.2396 · Cited by 1,390 · see citing works
Self-citationMechanisms of Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancers
Katayama, R., Shaw, A. T., Khan, T. M., Mino-Kenudson, M. A., Solomon, B., Halmos, B., Jessop, N. A., Wain, J. C., Yeo, A. T., Benes, C. H., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003316 · Cited by 1,316 · see citing works
Gainor, J. F., Dardaei, L., Yoda, S., Friboulet, L., Leshchiner, I., Katayama, R., Dagogo‐Jack, I., Gadgeel, S. M., Schultz, K. R., Singh, M., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0596 · Cited by 1,158 · see citing works
Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice
Artandi, S. E., Chang, S., Lee, S.-L., Alson, S., Gottlieb, G. J., Chin, L., & DePinho, R. A. (2000) · Nature · doi:10.1038/35020592 · Cited by 1,085 · see citing works
Doebele, R. C., Pilling, A. B., Aisner, D. L., Kutateladze, T. G., Le, A. T., Weickhardt, A. J., Kondo, K. L., Linderman, D. J., Heasley, L. E., Franklin, W. A., et al. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-2906 · Cited by 1,064 · see citing works
c-Myc Is a Universal Amplifier of Expressed Genes in Lymphocytes and Embryonic Stem Cells
Nie, Z., Hu, G., Wei, G., Cui, K., Yamane, A., Resch, W., Wang, R., Green, D. R., Tessarollo, L., Casellas, R. C., et al. (2012) · Cell · doi:10.1016/j.cell.2012.08.033 · Cited by 1,063 · see citing works
Peters, S., Adjei, A. A., Gridelli, C., Reck, M., Kerr, K. M., & Felip, E. (2012) · Annals of Oncology · doi:10.1093/annonc/mds226 · Cited by 930 · see citing works
Telomeres in cancer: tumour suppression and genome instability
Maciejowski, J., & de Lange, T. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.171 · Cited by 745 · see citing works
Reck, M., Popat, S., Reinmuth, N., Ruysscher, D. D., Kerr, K. M., & Peters, S. (2014) · Annals of Oncology · doi:10.1093/annonc/mdu199 · Cited by 679 · see citing works
Gainor, J. F., Varghese, A. M., Ou, S. I., Kabraji, S. K., Awad, M. M., Katayama, R., Pawlak, A. C., Mino-Kenudson, M. A., Yeap, B. Y., Riely, G. J., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-0318 · Cited by 609 · see citing works
The Genomic Landscape of Response to EGFR Blockade in Colorectal Cancer
Bertotti, A., Papp, E., Jones, S., Adleff, V., Anagnostou, V., Lupo, B., Sausen, M., Phallen, J., Hruban, C. A., Tokheim, C., et al. (2015) · Nature · doi:10.1038/nature14969 · Cited by 479 · see citing works
Xiang, Y., Zheng, Q., Jia, B., Huang, G., Xie, C., Pan, J., & Wang, J. (2006) · Cell Biology International · doi:10.1016/j.cellbi.2006.11.012 · Cited by 429 · see citing works
Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer
Lovly, C. M., McDonald, N. T., Chen, H., Ortiz-Cuaran, S., Heukamp, L. C., Yan, Y., Florin, A., Ozretić, L., Lim, D., Wang, L., et al. (2014) · Nature Medicine · doi:10.1038/nm.3667 · Cited by 268 · see citing works
Self-citationDirect Repression of FLIP Expression by c-myc Is a Major Determinant of TRAIL Sensitivity
Ricci, M., Jin, Z., Dews, M., Yu, D., Thomas‐Tikhonenko, A., Dicker, D. T., & El‐Deiry, W. S. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.19.8541-8555.2004 · Cited by 241 · see citing works
Treating ALK-positive lung cancer—early successes and future challenges
Camidge, D. R., & Doebele, R. C. (2012) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2012.43 · Cited by 236 · see citing works
Aisner, D. L., Sholl, L. M., Berry, L. D., Rossi, M. R., Chen, H., Fujimoto, J., Moreira, A. L., Ramalingam, S. S., Villaruz, L. C., Otterson, G. A., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-2289 · Cited by 206 · see citing works
Myc proteins as therapeutic targets
Gustafson, W. C., & Weiss, W. A. (2010) · Oncogene · doi:10.1038/onc.2009.512 · Cited by 199 · see citing works
The Evolution of Therapies in Non-Small Cell Lung Cancer
Boolell, V., Alamgeer, M., Watkins, D. N., & Ganju, V. (2015) · Cancers · doi:10.3390/cancers7030864 · Cited by 126 · see citing works
The genomics and genetics of endometrial cancer
Bell, D. W., & Ohara (2012) · Advances in Genomics and Genetics · doi:10.2147/agg.s28953 · Cited by 126 · see citing works
Kim, H. R., Kim, W. S., Choi, Y. J., Choi, C., Rho, J. K., & Lee, J. C. (2013) · Molecular Oncology · doi:10.1016/j.molonc.2013.08.001 · Cited by 114 · see citing works
Schultheis, A., Bos, M., Schmitz, K., Wilsberg, L., Binot, E., Wolf, J., Büttner, R., & Schildhaus, H. (2014) · Modern Pathology · doi:10.1038/modpathol.2013.141 · Cited by 99 · see citing works
Self-citationc-Myc overexpression and endocrine resistance in breast cancer
McNeil, C. M., Sergio, C. M., Anderson, L. R., Inman, C. K., Eggleton, S. A., Murphy, N., Millar, E. K. A., Crea, P., Kench, J. G., Alles, M. C., et al. (2006) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2006.09.028 · Cited by 85 · see citing works
Versatile functions of p53 protein in multicellular organisms
Chumakov, P. M. (2007) · Biochemistry (Moscow) · doi:10.1134/s0006297907130019 · Cited by 84 · see citing works
Clinicopathologic and prognostic significance of c-MYC copy number gain in lung adenocarcinomas
Seo, A. N., Yang, J. M., Kim, H., Jheon, S., Kim, K., Ct, L., Jin, Y., Yun, S., Chung, J.-H., & Paik, J. H. (2014) · British Journal of Cancer · doi:10.1038/bjc.2014.218 · Cited by 81 · see citing works
Induction of autophagy contributes to crizotinib resistance in ALK-positive lung cancer
Ji, C., Zhang, L., Cheng, Y., Patel, R., Wu, H., Zhang, Y., Wang, M., Ji, S., Belani, C. P., Yang, J., et al. (2014) · Cancer Biology & Therapy · doi:10.4161/cbt.28162 · Cited by 77 · see citing works
Raetz, E. A., Perkins, S. L., Carlson, M. A., et al. (2002) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64248-4 · Cited by 45 · see citing works
Tumour cells surviving in vivo cisplatin chemotherapy display elevated c-myc expression
Walker, T., White, J. D., Esdale, W., et al. (1996) · British Journal of Cancer · doi:10.1038/bjc.1996.105 · Cited by 44 · see citing works
Schildhaus, H., Deml, K.-F., Schmitz, K., et al. (2013) · Modern Pathology · doi:10.1038/modpathol.2013.95 · Cited by 37 · see citing works
Heydt, C., Kostenko, A. V., Merkelbach‐Bruse, S., Wolf, J. M., & Büttner, R. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw303 · Cited by 29 · see citing works
Self-citationEstimating the order of mutations during tumorigenesis from tumor genome sequencing data
Youn, A., & Simon, R. M. (2012) · Bioinformatics · doi:10.1093/bioinformatics/bts168 · Cited by 25 · see citing works
Kim, S. T., Lee, S. J., Park, S. H., et al. (2016) · Journal of Cancer · doi:10.7150/jca.14815 · Cited by 18 · see citing works
Wajchenberg (2000) · doi:10.1002/(sici)1097-0142(20000215)88:4
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Research works printed but not linked: 1
- [9]Lax SF, Kendall B, Tashiro H, et al The frequency of p53, K‐ras mutations, and microsatellite instability differs in uterine endometrioid and serous carcinoma: evidence of distinct molecular genetic pathways. Cancer 2000; 88: 814– 824. 10679651
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Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy
Skoulidis, F., & Heymach, J. V. (2019) · Nature Reviews Cancer · doi:10.1038/s41568-019-0179-8 · Cited by 1,019 · see citing works
Kron, A., Alidousty, C., Scheffler, M., Merkelbach-Bruse, S., Seidel, D., Riedel, R., Ihle, M. A., Michels, S., Nogova, L., Fassunke, J., et al. (2018) · Annals of Oncology · doi:10.1093/annonc/mdy333 · Cited by 197 · see citing works
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- Authors
- Alidousty, C., Baar, T., Martelotto, L. G., Heydt, C., Wagener, S., Fassunke, J., Duerbaum, N., Scheel, A. H., Frank, S., Holz, B., Binot, E., Kron, A., Merkelbach‐Bruse, S., Ihle, M. A., Wolf, J., Buettner, R., & Schultheis, A. M.
- Affiliations
- University Hospital Cologne (DE)
- University of Cologne (DE)
- Monash Health (AU)
- University Hospital Cologne, Institute of Pathology Cologne Germany
- Network Genomic Medicine Cologne Germany
- Corresponding author
- Schultheis, Anne Maria
- ORCID
- Venue
- The Journal of Pathology
- Publisher
- Wiley
- Published
- 2018-07-31
- Volume
- 246
- Issue
- 1
- Pages
- 67-76
- ISSN
- 0022-3417 (ISSN-L)
- 1096-9896
- PMC
- PMC6120547
- OpenAlex
- W2805911662
- Cited by
- 69
- References
- 44
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 7 · 2022: 14 · 2021: 10 · 2020: 20 · 2019: 8 · 2018: 3
- FWCI
- 7.72
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Pathology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Roche and Koelner Krebsstiftung
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- TP53 mutation, MYC amplification, chromosomal instability, EML4-ALK fusion, ALK inhibitors, drug resistance, CCND1 amplification, TERT amplification, cIAP1, tumor heterogeneity, prognostic factors
- MeSH terms
- Anaplastic Lymphoma Kinase, Adult, Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung, Female, Gene Amplification, Humans, Lung Neoplasms, Male, Microtubule-Associated Proteins, Middle Aged, Mutation, Phenotype, Serine Endopeptidases, Translocation, Genetic, Biomarkers, Tumor, Signal Transduction, Oncogene Proteins, Fusion, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-myc, Cell Cycle Proteins, Genetic Predisposition to Disease, Genomic Instability, Cell Line, Tumor, Cell Proliferation
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