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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.

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 Illumina HiSeq 2000 59
EGAD00001001273 Illumina HiSeq 2000 100
EGAD00010000558 Affymetrix SNP 6.0 54
Publications Citations
Comprehensive genomic profiles of small cell lung cancer.
Nature 524: 2015 47-53
1119
Intertumoral Heterogeneity in SCLC Is Influenced by the Cell Type of Origin.
Cancer Discov 8: 2018 1316-1331
84
A Human Adult Stem Cell Signature Marks Aggressive Variants across Epithelial Cancers.
Cell Rep 24: 2018 3353-3366.e5
63
Pan-cancer Convergence to a Small-Cell Neuroendocrine Phenotype that Shares Susceptibilities with Hematological Malignancies.
Cancer Cell 36: 2019 17-34.e7
73
Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids.
Nat Commun 10: 2019 3407
65
Epigenomic Profiling Discovers Trans-lineage SOX2 Partnerships Driving Tumor Heterogeneity in Lung Squamous Cell Carcinoma.
Cancer Res 79: 2019 6084-6100
15
A molecular map of lung neuroendocrine neoplasms.
Gigascience 9: 2020 giaa112
8
Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities.
Cancer Cell 39: 2021 346-360.e7
294
Ferroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes.
Nat Commun 12: 2021 2048
52
Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress.
Cancer Cell 39: 2021 566-579.e7
73
Notch signaling and efficacy of PD-1/PD-L1 blockade in relapsed small cell lung cancer.
Nat Commun 12: 2021 3880
45
ISOTOPE: ISOform-guided prediction of epiTOPEs in cancer.
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.
Nat Commun 12: 2021 6655
17
Heterogeneity of neuroendocrine transcriptional states in metastatic small cell lung cancers and patient-derived models.
Nat Commun 13: 2022 2023
22
ABBV-011, A Novel, Calicheamicin-Based Antibody-Drug Conjugate, Targets SEZ6 to Eradicate Small Cell Lung Cancer Tumors.
Mol Cancer Ther 21: 2022 986-998
5
Topoisomerase I poison-triggered immune gene activation is markedly reduced in human small-cell lung cancers by impairment of the cGAS/STING pathway.
Br J Cancer 127: 2022 1214-1225
11
Immunogenicity of small-cell lung cancer associates with STING pathway activation and is enhanced by ATR and TOP1 inhibition.
Cancer Med 12: 2023 4864-4881
8
POU2AF2/C11orf53 functions as a coactivator of POU2F3 by maintaining chromatin accessibility and enhancer activity.
Sci Adv 8: 2022 eabq2403
17
Transcriptional Profiling Reveals Mesenchymal Subtypes of Small Cell Lung Cancer with Activation of the Epithelial-to-Mesenchymal Transition and Worse Clinical Outcomes.
Cancers (Basel) 14: 2022 5600
1
Extrachromosomal DNA Amplification Contributes to Small Cell Lung Cancer Heterogeneity and Is Associated with Worse Outcomes.
Cancer Discov 13: 2023 928-949
14
Antigene <i>MYCN</i> Silencing by BGA002 Inhibits SCLC Progression Blocking mTOR Pathway and Overcomes Multidrug Resistance.
Cancers (Basel) 15: 2023 990
2
Immune surveillance of brain metastatic cancer cells is mediated by IFITM1.
EMBO J 42: 2023 e111112
3
Expression of down-regulated ERV LTR elements associates with immune activation in human small-cell lung cancers.
Mob DNA 14: 2023 2
0
MYC activation impairs cell-intrinsic IFNγ signaling and confers resistance to anti-PD1/PD-L1 therapy in lung cancer.
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.
MedComm (2020) 4: 2023 e370
0
Leveraging Tissue-Specific Enhancer-Target Gene Regulatory Networks Identifies Enhancer Somatic Mutations That Functionally Impact Lung Cancer.
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.
Cancers (Basel) 15: 2023 5219
0
Tumor- and circulating-free DNA methylation identifies clinically relevant small cell lung cancer subtypes.
Cancer Cell 42: 2024 225-237.e5
3