{"entity":{"id":"paper-george-small-cell-lung-cancer-genomes-nature-2015","kind":"paper","name":"Comprehensive genomic profiles of small cell lung cancer","aka":[],"tldr":"Sequencing the whole genomes of 110 small-cell lung cancers showed that losing both the p53 and the retinoblastoma genes is not merely common in this cancer, it is obligatory, and that a quarter of tumours have broken a signalling system that would otherwise force them to stop behaving like nerve cells.","summary":"The genomes of 110 small-cell lung cancers were sequenced. In nearly all tumours there was biallelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangement. Two tumours with wild-type RB1 showed chromothripsis leading to overexpression of cyclin D1, an alternative route to deregulating the same pathway, so loss of both tumour suppressors is obligatory. Somatic genomic rearrangements of TP73 were discovered that create an oncogenic isoform lacking exons 2 and 3. Kinase gene mutations appeared in rare cases, offering a possible therapeutic opportunity for individual patients. Inactivating mutations in NOTCH family genes were found in 25% of tumours; activating Notch signalling in a mouse model strikingly reduced tumour number and extended survival, and Notch activity abolished neuroendocrine gene expression in small-cell cells.","asOf":"2026-09-25","links":[{"label":"George et al., Nature 2015: comprehensive genomic profiles of 110 small-cell lung cancers","url":"https://doi.org/10.1038/nature14664"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/26168399/"},{"label":"cBioPortal study sclc_ucologne_2015 (University of Cologne, Nature 2015; 120 small-cell lung cancers, no copy-number profile deposited)","url":"https://www.cbioportal.org/study/summary?id=sclc_ucologne_2015"}],"tags":[],"related":[],"cancers":["sclc"],"sections":[],"technologies":["wes-wgs"],"targets":["tp53","rb1","notch1","kmt2d","crebbp","ep300","pten","mycl","myc-gene"],"drugs":[],"companies":[],"institutions":[],"pathways":["sclc-signalling","p53-cell-cycle","notch","lineage-plasticity-neuroendocrine","chromosomal-instability"],"terms":["driver-mutation","somatic-mutations-wxs-wgs","copy-number-variation-term"],"trials":[],"people":["roman-thomas"],"bottlenecks":[],"keyPapers":[],"journals":["nature"],"dependsOn":[],"notes":[],"journal":"Nature","year":2015,"doi":"10.1038/nature14664","pmid":"26168399","authors":"George J, Lim JS, Jang SJ, et al.","paperType":"basic","findings":["Biallelic TP53 and RB1 inactivation in nearly all tumours, sometimes by complex rearrangement.","Oncogenic TP73 rearrangements, a new class of event in this disease.","NOTCH family inactivating mutations in 25%, with NOTCH acting as a tumour suppressor that switches off the neuroendocrine programme.","Kinase mutations only in rare individual cases."],"whatItMeans":"It settled that small-cell lung cancer has no targetable recurrent driver beyond the two tumour suppressors that are already gone, which is why the field moved to surface antigens and transcriptional states instead of kinase inhibitors.","caveats":["Small-cell tumours are rarely resected, so the cohort is skewed towards the minority that come to surgery.","Biallelic inactivation by rearrangement is invisible to a mutation call, so panel-based frequencies read much lower.","No copy-number profile is deposited with the public dataset, so amplification rates cannot be recomputed from it."],"changedPractice":false,"participants":110},"route":"/key-papers/paper-george-small-cell-lung-cancer-genomes-nature-2015/","neighbours":{"cancer":[{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"sclc","kind":"cancer","name":"Small-cell lung cancer","route":"/cancers/sclc/"}],"technology":[{"id":"wes-wgs","kind":"technology","name":"Whole-exome & whole-genome sequencing","route":"/technologies/wes-wgs/"}],"target":[{"id":"crebbp","kind":"target","name":"CREBBP","route":"/targets/crebbp/"},{"id":"ep300","kind":"target","name":"EP300","route":"/targets/ep300/"},{"id":"kmt2d","kind":"target","name":"KMT2D","route":"/targets/kmt2d/"},{"id":"myc-gene","kind":"target","name":"MYC","route":"/targets/myc-gene/"},{"id":"mycl","kind":"target","name":"MYCL","route":"/targets/mycl/"},{"id":"notch1","kind":"target","name":"NOTCH1","route":"/targets/notch1/"},{"id":"pten","kind":"target","name":"PTEN","route":"/targets/pten/"},{"id":"rb1","kind":"target","name":"RB1","route":"/targets/rb1/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"pathway":[{"id":"chromosomal-instability","kind":"pathway","name":"Chromosomal instability & aneuploidy","route":"/pathways/chromosomal-instability/"},{"id":"lineage-plasticity-neuroendocrine","kind":"pathway","name":"Lineage plasticity & neuroendocrine transformation","route":"/pathways/lineage-plasticity-neuroendocrine/"},{"id":"notch","kind":"pathway","name":"Notch signalling","route":"/pathways/notch/"},{"id":"p53-cell-cycle","kind":"pathway","name":"p53 / RB / cell-cycle checkpoint","route":"/pathways/p53-cell-cycle/"},{"id":"sclc-signalling","kind":"pathway","name":"Small cell lung cancer (KEGG map)","route":"/pathways/sclc-signalling/"}],"term":[{"id":"copy-number-variation-term","kind":"term","name":"Copy number alteration (CNA)","route":"/terms/copy-number-variation-term/"},{"id":"driver-mutation","kind":"term","name":"Driver mutation","route":"/terms/driver-mutation/"},{"id":"somatic-mutations-wxs-wgs","kind":"term","name":"Somatic mutations from exome and genome sequencing (WXS, WGS)","route":"/terms/somatic-mutations-wxs-wgs/"}],"person":[{"id":"roman-thomas","kind":"person","name":"Roman Thomas","route":"/people/roman-thomas/"}],"journal":[{"id":"nature","kind":"journal","name":"Nature","route":"/journals/nature/"}]}}