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Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer
Open accessAbstract
Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor prognosis. We sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4 ± 1 protein-changing mutations per million base pairs. Therefore, we conducted integrated analyses of the various data sets to identify pathogenetically relevant mutated genes. In all cases, we found evidence for inactivation of TP53 and RB1 and identified recurrent mutations in the CREBBP, EP300 and MLL genes that encode histone modifiers. Furthermore, we observed mutations in PTEN, SLIT2 and EPHA7, as well as focal amplifications of the FGFR1 tyrosine kinase gene. Finally, we detected many of the alterations found in humans in SCLC tumors from Tp53 and Rb1 double knockout mice. Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genomic alterations and provides a generalizable framework for the identification of biologically relevant genes in the context of high mutational background.
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“The TP53 mutation rate exceeds 70% in certain subtypes of cancers, including squamous esophageal cancer, small-cell lung cancer, squamous cell lung cancer, and complex karyotype acute myeloid leukemia (AML), and is lower in partial tumors such as lymphoma, melanoma, and overall AML.8–11”
From p53: from understanding its structure to advances in therapeutic targeting (2026) · doi:10.1038/s41392-025-02549-5 · cites this paper as [9]
In the citing paper
“The TP53 mutation rate exceeds 70% in certain subtypes of cancers, including squamous esophageal cancer, small-cell lung cancer, squamous cell lung cancer, and complex karyotype acute myeloid leukemia (AML), and is lower in partial tumors such as lymphoma, melanoma, and overall AML.8–11”
From p53: from understanding its structure to advances in therapeutic targeting (2026) · doi:10.1038/s41392-025-02549-5 · cites this paper as [9]
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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
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EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy
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Self-citationIdentification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer
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Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors
Sequist, L. V., Waltman, B. A., Dias-Santagata, D., Digumarthy, S., Turke, A. B., Fidias, P., Bergethon, K., Shaw, A. T., Gettinger, S., Cosper, A. K., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002003 · Cited by 3,499
Somatic mutations affect key pathways in lung adenocarcinoma
Ding, L., Getz, G., Wheeler, D. A., Mardis, E. R., McLellan, M. D., Cibulskis, K., Sougnez, C., Greulich, H., Muzny, D. M., Morgan, M. B., et al. (2008) · Nature · doi:10.1038/nature07423 · Cited by 2,681
Self-citationA comprehensive catalogue of somatic mutations from a human cancer genome
Pleasance, E. D., Cheetham, R. K., Stephens, P. J., McBride, D. J., Humphray, S. J., Greenman, C. D., Varela, I., Lin, M.-L., Ordóñez, G. R., Bignell, G. R., et al. (2010) · Nature · doi:10.1038/nature08658 · Cited by 1,696
Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma
Morin, R. D., Mendez-Lago, M., Mungall, A. J., Goya, R., Mungall, K. L., Corbett, R. D., Johnson, N. A., Severson, T. M., Chiu, R., Field, M., et al. (2011) · Nature · doi:10.1038/nature10351 · Cited by 1,614
Kruse, J.-P., & Gu, W. (2009) · Cell · doi:10.1016/j.cell.2009.04.050 · Cited by 1,610
ROS1 Rearrangements Define a Unique Molecular Class of Lung Cancers
Bergethon, K., Shaw, A. T., Ignatius Ou, S.-H., Katayama, R., Lovly, C. M., McDonald, N. T., Massion, P. P., Siwak-Tapp, C., Gonzalez, A., Fang, R., et al. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2011.35.6345 · Cited by 1,555
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Signatures of mutational processes in human cancer
Initiative, A. P. C. G., Alexandrov, L. B., ICGC Breast Cancer Consortium, ICGC MMML-Seq Consortium, PedBrain, I., Nik-Zainal, S., Wedge, D. C., Aparicio, S. A. J. R., Behjati, S., Biankin, A. V., et al. (2013) · Nature · doi:10.1038/nature12477 · Cited by 9,660
Self-citationComprehensive molecular profiling of lung adenocarcinoma
The Cancer Genome Atlas Research Network (2014) · Nature · doi:10.1038/nature13385 · Cited by 5,732
First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer
Horn, L., Mansfield, A. S., Szczęsna, A., Havel, L., Krzakowski, M., Hochmair, M. J., Huemer, F., Losonczy, G., Johnson, M. L., Nishio, M., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1809064 · Cited by 3,586
Using Multiplexed Assays of Oncogenic Drivers in Lung Cancers to Select Targeted Drugs
Kris, M. G., Johnson, B. E., Berry, L. D., Kwiatkowski, D. J., Iafrate, A. J., Wistuba, I. I., Varella-Garcia, M., Franklin, W. A., Aronson, S. L., Su, P.-F., et al. (2014) · JAMA · doi:10.1001/jama.2014.3741 · Cited by 1,724
Self-citationDistinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas
Cancer Genome Atlas Research Network, Campbell, J. D., Alexandrov, A., Kim, J., Wala, J., Berger, A. H., Pedamallu, C. S., Shukla, S. A., Guo, G., Brooks, A. N., et al. (2016) · Nature Genetics · doi:10.1038/ng.3564 · Cited by 1,200
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Metadata
- Authors
- Peifer, M., Fernández-Cuesta, L., Sos, M. L., George, J., Seidel, D., Kasper, L. H., Plenker, D., Leenders, F., Sun, R., Zander, T., Menon, R., Koker, M., Dahmen, I., Müller, C., Di Cerbo, V., Schildhaus, H.-U., Altmüller, J., Baessmann, I., Becker, C., de Wilde, B., Vandesompele, J., Böhm, D., Ansén, S., Gabler, F., Wilkening, I., Heynck, S., Heuckmann, J. M., Lu, X., Carter, S. L., Cibulskis, K., Banerji, S., Getz, G., Park, K.-S., Rauh, D., Grütter, C., Fischer, M., Pasqualucci, L., Wright, G., Wainer, Z., Russell, P., Petersen, I., Chen, Y., Stoelben, E., Ludwig, C., Schnabel, P., Hoffmann, H., Muley, T., Brockmann, M., Engel-Riedel, W., Muscarella, L. A., Fazio, V. M., Groen, H., Timens, W., Sietsma, H., Thunnissen, E., Smit, E., Heideman, D. A. M., Snijders, P. J. F., Cappuzzo, F., Ligorio, C., Damiani, S., Field, J., Solberg, S., Brustugun, O. T., Lund-Iversen, M., Sänger, J., Clement, J. H., Soltermann, A., Moch, H., Weder, W., Solomon, B., Soria, J.-C., Validire, P., Besse, B., Brambilla, E., Brambilla, C., Lantuejoul, S., Lorimier, P., Schneider, P. M., Hallek, M., Pao, W., Meyerson, M., Sage, J., Shendure, J., Schneider, R., Büttner, R., Wolf, J., Nürnberg, P., Perner, S., Heukamp, L. C., Brindle, P. K., Haas, S., & Thomas, R. K.
- Venue
- Nature Genetics
- Published
- 2012-09-02
- Volume
- 44
- Issue
- 10
- Pages
- 1104-1110
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2108927999
- Cited by
- 1,397
- References
- 14
- FWCI
- 44.03
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Peifer, M., Fernández-Cuesta, L., Sos, M. L., George, J., Seidel, D., Kasper, L. H., Plenker, D., Leenders, F., Sun, R., Zander, T., Menon, R., Koker, M., Dahmen, I., Müller, C., Di Cerbo, V., Schildhaus, H.-U., Altmüller, J., Baessmann, I., Becker, C., . . . Thomas, R. K. (2012). Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nature Genetics. https://doi.org/10.1038/ng.2396
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