{"entity":{"id":"paper-lee-clonal-history-small-cell-transformation-jco-2017","kind":"paper","name":"Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas","aka":[],"tldr":"Some lung cancers escape a targeted pill by changing into a different kind of cancer. Reading whole genomes from the same patients over time showed the change was set up from the beginning, in tumours that had already lost two particular genes.","summary":"Twenty-one patients with advanced EGFR-mutant lung adenocarcinoma that transformed into resistant small-cell lung cancer were investigated, with whole-genome sequencing of nine tumours from four patients at various time points to reconstruct clonal evolutionary history. The resistant adenocarcinomas and small-cell cancers shared a common clonal origin and followed branched evolutionary trajectories, with the small-cell ancestors diverging before the first treatment. Complete inactivation of both RB1 and TP53 was present from the early adenocarcinoma stage. Immunohistochemistry in early-stage tissue from 75 patients treated with EGFR inhibitors found inactivation of both Rb and p53 in 82% of the transformed group against 3% of the non-transformed group, odds ratio 131. Among 65 patients in a predefined cohort, an adenocarcinoma with both proteins inactivated carried a 43-fold higher risk of transformation. APOBEC-induced hypermutation was frequent in the branches leading to transformation.","asOf":"2026-09-25","links":[{"label":"Lee et al., J Clin Oncol 2017: clonal history and genetic predictors of small-cell transformation from lung adenocarcinoma","url":"https://doi.org/10.1200/JCO.2016.71.9096"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/28498782/"}],"tags":[],"related":[],"cancers":["nsclc","sclc"],"sections":[],"technologies":["wes-wgs","histopathology-ihc"],"targets":["egfr","rb1","tp53"],"drugs":[],"companies":[],"institutions":[],"pathways":["lineage-plasticity-neuroendocrine","clonal-evolution","resistance-routes-map","mutagenesis-signatures"],"terms":["histologic-transformation","resistance","mutational-signature","ihc"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2017,"doi":"10.1200/JCO.2016.71.9096","pmid":"28498782","authors":"Lee JK, Lee J, Kim S, et al.","paperType":"translational","findings":["Transformed small-cell cancers branch from the adenocarcinoma clone before treatment begins.","Both RB1 and TP53 are completely inactivated from the early adenocarcinoma stage.","Inactivation of both proteins was present in 82% of transformed against 3% of non-transformed cases.","APOBEC hypermutation marks the branches that transform."],"whatItMeans":"It made transformation predictable from the first biopsy, using two stains that most pathology laboratories can already run, which is the practical way to know which patients need close watching and early rebiopsy.","caveats":["Twenty-one transformed patients and four with serial whole genomes.","The immunohistochemistry validation is retrospective.","Predicting risk does not yet change treatment, since no intervention has been shown to prevent transformation."],"changedPractice":false,"participants":21},"route":"/key-papers/paper-lee-clonal-history-small-cell-transformation-jco-2017/","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":"histopathology-ihc","kind":"technology","name":"Histopathology & immunohistochemistry","route":"/technologies/histopathology-ihc/"},{"id":"wes-wgs","kind":"technology","name":"Whole-exome & whole-genome sequencing","route":"/technologies/wes-wgs/"}],"target":[{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"rb1","kind":"target","name":"RB1","route":"/targets/rb1/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"pathway":[{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/"},{"id":"lineage-plasticity-neuroendocrine","kind":"pathway","name":"Lineage plasticity & neuroendocrine transformation","route":"/pathways/lineage-plasticity-neuroendocrine/"},{"id":"mutagenesis-signatures","kind":"pathway","name":"Mutagenesis & mutational signatures","route":"/pathways/mutagenesis-signatures/"},{"id":"resistance-routes-map","kind":"pathway","name":"Resistance routes: how a blocked pathway comes back","route":"/pathways/resistance-routes-map/"}],"term":[{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"},{"id":"histologic-transformation","kind":"term","name":"Histologic transformation","route":"/terms/histologic-transformation/"},{"id":"ihc","kind":"term","name":"Immunohistochemistry (IHC)","route":"/terms/ihc/"},{"id":"mutational-signature","kind":"term","name":"Mutational signature","route":"/terms/mutational-signature/"}],"journal":[{"id":"jco","kind":"journal","name":"Journal of Clinical Oncology","route":"/journals/jco/"}]}}