Comprehensive genomic profiles of small cell lung cancer

By J. George, Jing S. Lim, S. Jang, Yupeng Cun, L. Ozretić, G. Kong, F. Leenders, Xin Lu, L. Fernandez-Cuesta, Graziella Bosco and 86 more. Nature, 2015

2,050 citations recorded by the source corpus.

We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours 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 signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours 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.

Subfields: Cancer Research, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/656a58f517b55ec36189fb01971cf3e6be534e31

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Citations in the corpus

• Targeting DNA damage response promotes anti-tumor immunity through STING-mediated T-cell activation in small cell lung cancer (2019, background): “Also, because the mouse tumors have previously been shown to have low mutation burden (41), future studies to monitor the effects of DDR inhibition in patients with SCLC will be valuable to provide further insights into the effect of DDRmediated STING activation and immune response.”
• Early Detection of Molecular Residual Disease in Localized Lung Cancer by Circulating Tumor DNA Profiling (2017, background): “Candidate driver genes were defined as genes that were found to be statistically significantly mutated in NSCLC or SCLC in prior studies (Supplemental Methods, Supplemental Table S6) (12-15).”
• Tumor Mutation Burden and Efficacy of Nivolumab Monotherapy and in Combination With Ipilimumab in Small Cell Lung Cancer (2018, neutral): “Inclusion of a control arm would further confirm the predictive (rather than prognostic) nature of tumor mutational burden, although no association of tumor mutational burden and survival was seen in previously published data of SCLC not treated with immunotherapy (George et al., 2015).”
• Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities (2021, methodology): “Tumor gene expression data is available via the European Genome-phenome Archive under the accession code EGAS00001000925 (George et al., 2015) and via NCBI Gene Expression Omnibus (GEO) Database under the accession code: GSE99312 (Sato et al.”
• Targeting p53 pathways: mechanisms, structures and advances in therapy (2023, background): “However, under conditions of Rb/p53 functional deficiency, neuroendocrine cells can acquire a sustained proliferative function and develop into small cell lung cancer.(148,149) Activation of p53 in breast,(150) prostate,(151) epidermis,(152) central nervous system(153) and hematopoietic stem cells h”