Comprehensive genomic profiles of small cell lung cancer

We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. We found bi-allelic inactivation of TP53 and RB1 in nearly all the tumors analyzed, sometimes by complex genomic rearrangements. Two tumors with wild-type RB1 had evidence of chromothripsis leading to overexpression of Cyclin D1, revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumor suppressors TP53 and RB1 is obligatory in SCLC. We further discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In few cases, SCLC tumors exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signaling in a pre-clinical SCLC mouse model dramatically reduced the number of tumors and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

3 Datasets 28 Publications

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001001244	RNA-sequencing (RNA-seq) was performed with RNA extracted from fresh-frozen human tumor tissue samples. cDNA libraries were prepared from poly-A selected RNA applying the Illumina TruSeq protocol for mRNA. The libraries were then sequenced with a 2 x 100bp paired-end protocol to a minimum mean coverage of 30x of the annotated transcriptome.	Illumina HiSeq 2000	59
EGAD00001001273	Whole genome sequencing was performed with DNA extracted from fresh-frozen tumor and normal material. Short insert DNA libraries were prepared with the TruSeq DNA PCRfree sample preparation kit (Illumina) for paired-end sequencing at a minimum read length of 2x100bp. Human DNA libraries were sequenced to an average coverage of minimum 30x for both tumor and matched normal. Murine DNA libraries of tumor and matched normal were both sequenced to a coverage of 25x.	Illumina HiSeq 2000	100
EGAD00010000558	SNP 6.0 arrays of small cell lung cancer	Affymetrix SNP 6.0	54

Publications	Citations
Comprehensive genomic profiles of small cell lung cancer. George J, Lim JS, Jang SJ, Cun Y, Ozretić L, Kong G, Leenders F, Lu X, Fernández-Cuesta L, Bosco G, Müller C, Dahmen I, Jahchan NS, Park KS, Yang D, Karnezis AN, Vaka D, Torres A, Wang MS, Korbel JO, Menon R, Chun SM, Kim D, Wilkerson M, Hayes N, Engelmann D, Pützer B, Bos M, Michels S, Vlasic I, Seidel D, Pinther B, Schaub P, Becker C, Altmüller J, Yokota J, Kohno T, Iwakawa R, Tsuta K, Noguchi M, Muley T, Hoffmann H, Schnabel PA, Petersen I, Chen Y, Soltermann A, Tischler V, Choi CM, Kim YH, Massion PP, Zou Y, Jovanovic D, Kontic M, Wright GM, Russell PA, Solomon B, Koch I, Lindner M, Muscarella LA, la Torre A, Field JK, Jakopovic M, Knezevic J, Castaños-Vélez E, Roz L, Pastorino U, Brustugun OT, Lund-Iversen M, Thunnissen E, Köhler J, Schuler M, Botling J, Sandelin M, Sanchez-Cespedes M, Salvesen HB, Achter V, Lang U, Bogus M, Schneider PM, Zander T, Ansén S, Hallek M, Wolf J, Vingron M, Yatabe Y, Travis WD, Nürnberg P, Reinhardt C, Perner S, Heukamp L, Büttner R, Haas SA, Brambilla E, Peifer M, Sage J, Thomas RK. Nature 524: 2015 47-53	1143
Intertumoral Heterogeneity in SCLC Is Influenced by the Cell Type of Origin. Yang D, Denny SK, Greenside PG, Chaikovsky AC, Brady JJ, Ouadah Y, Granja JM, Jahchan NS, Lim JS, Kwok S, Kong CS, Berghoff AS, Schmitt A, Reinhardt HC, Park KS, Preusser M, Kundaje A, Greenleaf WJ, Sage J, Winslow MM. Cancer Discov 8: 2018 1316-1331	86
A Human Adult Stem Cell Signature Marks Aggressive Variants across Epithelial Cancers. Smith BA, Balanis NG, Nanjundiah A, Sheu KM, Tsai BL, Zhang Q, Park JW, Thompson M, Huang J, Witte ON, Graeber TG. Cell Rep 24: 2018 3353-3366.e5	65
Pan-cancer Convergence to a Small-Cell Neuroendocrine Phenotype that Shares Susceptibilities with Hematological Malignancies. Balanis NG, Sheu KM, Esedebe FN, Patel SJ, Smith BA, Park JW, Alhani S, Gomperts BN, Huang J, Witte ON, Graeber TG. Cancer Cell 36: 2019 17-34.e7	78
Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids. Alcala N, Leblay N, Gabriel AAG, Gabriel AAG, Mangiante L, Hervas D, Giffon T, Sertier AS, Ferrari A, Derks J, Ghantous A, Delhomme TM, Chabrier A, Cuenin C, Abedi-Ardekani B, Boland A, Olaso R, Meyer V, Altmuller J, Le Calvez-Kelm F, Durand G, Voegele C, Boyault S, Moonen L, Lemaitre N, Lorimier P, Toffart AC, Soltermann A, Clement JH, Saenger J, Field JK, Brevet M, Blanc-Fournier C, Galateau-Salle F, Le Stang N, Russell PA, Wright G, Sozzi G, Pastorino U, Lacomme S, Vignaud JM, Hofman V, Hofman P, Brustugun OT, Lund-Iversen M, Thomas de Montpreville V, Muscarella LA, Graziano P, Popper H, Stojsic J, Deleuze JF, Herceg Z, Viari A, Nuernberg P, Pelosi G, Dingemans AMC, Milione M, Roz L, Brcic L, Volante M, Papotti MG, Caux C, Sandoval J, Hernandez-Vargas H, Brambilla E, Speel EJM, Girard N, Lantuejoul S, McKay JD, Foll M, Fernandez-Cuesta L. Nat Commun 10: 2019 3407	71
Epigenomic Profiling Discovers Trans-lineage SOX2 Partnerships Driving Tumor Heterogeneity in Lung Squamous Cell Carcinoma. Sato T, Yoo S, Kong R, Sinha A, Chandramani-Shivalingappa P, Patel A, Fridrikh M, Nagano O, Masuko T, Beasley MB, Powell CA, Zhu J, Watanabe H. Cancer Res 79: 2019 6084-6100	17
A molecular map of lung neuroendocrine neoplasms. Gabriel AAG, Mathian E, Mangiante L, Voegele C, Cahais V, Ghantous A, McKay JD, Alcala N, Fernandez-Cuesta L, Foll M. Gigascience 9: 2020 giaa112	9
Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Gay CM, Stewart CA, Park EM, Diao L, Groves SM, Heeke S, Nabet BY, Fujimoto J, Solis LM, Lu W, Xi Y, Cardnell RJ, Wang Q, Fabbri G, Cargill KR, Vokes NI, Ramkumar K, Zhang B, Della Corte CM, Robson P, Swisher SG, Roth JA, Glisson BS, Shames DS, Wistuba II, Wang J, Quaranta V, Minna J, Heymach JV, Byers LA. Cancer Cell 39: 2021 346-360.e7	340
Ferroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes. Bebber CM, Thomas ES, Stroh J, Chen Z, Androulidaki A, Schmitt A, Höhne MN, Stüker L, de Pádua Alves C, Khonsari A, Dammert MA, Parmaksiz F, Tumbrink HL, Beleggia F, Sos ML, Riemer J, George J, Brodesser S, Thomas RK, Reinhardt HC, von Karstedt S. Nat Commun 12: 2021 2048	61
Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress. Thomas A, Takahashi N, Rajapakse VN, Zhang X, Sun Y, Ceribelli M, Wilson KM, Zhang Y, Beck E, Sciuto L, Nichols S, Elenbaas B, Puc J, Dahmen H, Zimmermann A, Varonin J, Schultz CW, Kim S, Shimellis H, Desai P, Klumpp-Thomas C, Chen L, Travers J, McKnight C, Michael S, Itkin Z, Lee S, Yuno A, Lee MJ, Redon CE, Kindrick JD, Peer CJ, Wei JS, Aladjem MI, Figg WD, Steinberg SM, Trepel JB, Zenke FT, Pommier Y, Khan J, Thomas CJ. Cancer Cell 39: 2021 566-579.e7	84
Notch signaling and efficacy of PD-1/PD-L1 blockade in relapsed small cell lung cancer. Roper N, Velez MJ, Chiappori A, Kim YS, Wei JS, Sindiri S, Takahashi N, Mulford D, Kumar S, Ylaya K, Trindade C, Manukyan I, Brown AL, Trepel JB, Lee JM, Hewitt S, Khan J, Thomas A. Nat Commun 12: 2021 3880	57
ISOTOPE: ISOform-guided prediction of epiTOPEs in cancer. Trincado JL, Reixachs-Solé M, Pérez-Granado J, Fugmann T, Sanz F, Yokota J, Eyras E. PLoS Comput Biol 17: 2021 e1009411	2
Cold and heterogeneous T cell repertoire is associated with copy number aberrations and loss of immune genes in small-cell lung cancer. Chen M, Chen R, Jin Y, Li J, Hu X, Zhang J, Fujimoto J, Hubert SM, Gay CM, Zhu B, Tian Y, McGranahan N, Lee WC, George J, Hu X, Chen Y, Wu M, Behrens C, Chow CW, Pham HHN, Fukuoka J, Wu J, Parra ER, Little LD, Gumbs C, Song X, Wu CJ, Diao L, Wang Q, Cardnell R, Zhang J, Wang J, Le X, Gibbons DL, Heymach JV, Jack Lee J, William WN, Cheng C, Glisson B, Wistuba I, Andrew Futreal P, Thomas RK, Reuben A, Byers LA, Zhang J. Nat Commun 12: 2021 6655	19
Heterogeneity of neuroendocrine transcriptional states in metastatic small cell lung cancers and patient-derived models. Lissa D, Takahashi N, Desai P, Manukyan I, Schultz CW, Rajapakse V, Velez MJ, Mulford D, Roper N, Nichols S, Vilimas R, Sciuto L, Chen Y, Guha U, Rajan A, Atkinson D, El Meskini R, Weaver Ohler Z, Thomas A. Nat Commun 13: 2022 2023	28
ABBV-011, A Novel, Calicheamicin-Based Antibody-Drug Conjugate, Targets SEZ6 to Eradicate Small Cell Lung Cancer Tumors. Wiedemeyer WR, Gavrilyuk J, Schammel A, Zhao X, Sarvaiya H, Pysz M, Gu C, You M, Isse K, Sullivan T, French D, Lee C, Dang AT, Zhang Z, Aujay M, Bankovich AJ, Vitorino P. Mol Cancer Ther 21: 2022 986-998	10
Topoisomerase I poison-triggered immune gene activation is markedly reduced in human small-cell lung cancers by impairment of the cGAS/STING pathway. Marinello J, Arleo A, Russo M, Delcuratolo M, Ciccarelli F, Pommier Y, Capranico G. Br J Cancer 127: 2022 1214-1225	13
Immunogenicity of small-cell lung cancer associates with STING pathway activation and is enhanced by ATR and TOP1 inhibition. Li X, Li Y, Zhao Z, Miao N, Liu G, Deng L, Wei S, Hou J. Cancer Med 12: 2023 4864-4881	9
POU2AF2/C11orf53 functions as a coactivator of POU2F3 by maintaining chromatin accessibility and enhancer activity. Szczepanski AP, Tsuboyama N, Watanabe J, Hashizume R, Zhao Z, Wang L. Sci Adv 8: 2022 eabq2403	19
Transcriptional Profiling Reveals Mesenchymal Subtypes of Small Cell Lung Cancer with Activation of the Epithelial-to-Mesenchymal Transition and Worse Clinical Outcomes. Cho HJ, Hong SA, Ryu D, Hong SH, Kim TM. Cancers (Basel) 14: 2022 5600	1
Extrachromosomal DNA Amplification Contributes to Small Cell Lung Cancer Heterogeneity and Is Associated with Worse Outcomes. Pongor LS, Schultz CW, Rinaldi L, Wangsa D, Redon CE, Takahashi N, Fialkoff G, Desai P, Zhang Y, Burkett S, Hermoni N, Vilk N, Gutin J, Gergely R, Zhao Y, Nichols S, Vilimas R, Sciuto L, Graham C, Caravaca JM, Turan S, Tsai-Wei S, Rajapakse VN, Kumar R, Upadhyay D, Kumar S, Kim YS, Roper N, Tran B, Hewitt SM, Kleiner DE, Aladjem MI, Friedman N, Hager GL, Pommier Y, Ried T, Thomas A. Cancer Discov 13: 2023 928-949	21
Antigene <i>MYCN</i> Silencing by BGA002 Inhibits SCLC Progression Blocking mTOR Pathway and Overcomes Multidrug Resistance. Bortolotti S, Angelucci S, Montemurro L, Bartolucci D, Raieli S, Lampis S, Amadesi C, Scardovi A, Nieddu G, Cerisoli L, Paganelli F, Chiarini F, Teti G, Falconi M, Pession A, Hrelia P, Tonelli R. Cancers (Basel) 15: 2023 990	2
Immune surveillance of brain metastatic cancer cells is mediated by IFITM1. She X, Shen S, Chen G, Gao Y, Ma J, Gao Y, Liu Y, Gao G, Zhao Y, Wang C, Jiang C, Wang P, Qin H, Gao H. EMBO J 42: 2023 e111112	5
Expression of down-regulated ERV LTR elements associates with immune activation in human small-cell lung cancers. Russo M, Morelli S, Capranico G. Mob DNA 14: 2023 2	1
MYC activation impairs cell-intrinsic IFNγ signaling and confers resistance to anti-PD1/PD-L1 therapy in lung cancer. Alburquerque-Bejar JJ, Navajas-Chocarro P, Saigi M, Ferrero-Andres A, Morillas JM, Vilarrubi A, Gomez A, Mate JL, Munoz-Marmol AM, Romero OA, Blecua P, Davalos V, Esteller M, Pros E, Llabata P, Torres-Diz M, Esteve-Codina A, Sanchez-Cespedes M. Cell Rep Med 4: 2023 101006	4
Tumor-derived Vimentin as a novel biomarker for distinct subtypes predicting adjuvant chemotherapy resistance and T-cell-inflamed phenotype in small cell lung cancer. Deng C, Wang Y, Fu F, Li D, Zheng Q, Jin Y, Li Y, Chen H, Zhang Y. MedComm (2020) 4: 2023 e370	0
Leveraging Tissue-Specific Enhancer-Target Gene Regulatory Networks Identifies Enhancer Somatic Mutations That Functionally Impact Lung Cancer. Hariprakash JM, Salviato E, La Mastra F, Sebestyén E, Tagliaferri I, Silva RS, Lucini F, Farina L, Cinquanta M, Rancati I, Riboni M, Minardi SP, Roz L, Gorini F, Lanzuolo C, Casola S, Ferrari F. Cancer Res 84: 2024 133-153	1
A 15-Gene-Based Risk Signature for Predicting Overall Survival in SCLC Patients Who Have Undergone Surgical Resection. Atay S. Cancers (Basel) 15: 2023 5219	0
Tumor- and circulating-free DNA methylation identifies clinically relevant small cell lung cancer subtypes. Heeke S, Gay CM, Estecio MR, Tran H, Morris BB, Zhang B, Tang X, Raso MG, Rocha P, Lai S, Arriola E, Hofman P, Hofman V, Kopparapu P, Lovly CM, Concannon K, De Sousa LG, Lewis WE, Kondo K, Hu X, Tanimoto A, Vokes NI, Nilsson MB, Stewart A, Jansen M, Horváth I, Gaga M, Panagoulias V, Raviv Y, Frumkin D, Wasserstrom A, Shuali A, Schnabel CA, Xi Y, Diao L, Wang Q, Zhang J, Van Loo P, Wang J, Wistuba II, Byers LA, Heymach JV. Cancer Cell 42: 2024 225-237.e5	6