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Clonal History and Genetic Predictors of Transformation Into Small-Cell Carcinomas From Lung Adenocarcinomas

Cited 121 time in Web of Science Cited 148 time in Scopus
Authors
Lee, June-Koo; Lee, Junehawk; Kim, Sehui; Kim, Soyeon; Youk, Jeonghwan; Park, Seongyeol; An, Yohan; Keam, Bhumsuk; Kim, Dong-Wan; Heo, Dae Seog; Kim, Young Tae; Kim, Jin-Soo; Kim, Se Hyun; Lee, Jong Seok; Lee, Se-Hoon; Park, Keunchil; Ku, Ja-Lok; Jeon, Yoon Kyung; Chung, Doo Hyun; Park, Peter J.; Kim, Joon; Kim, Tae Min; Ju, Young Seok
Issue Date
2017-09
Citation
Journal of Clinical Oncology, Vol.35 No.26, pp.3065-3074
Abstract
Purpose Histologic transformation of EGFR mutant lung adenocarcinoma (LADC) into small-cell lung cancer (SCLC) has been described as one of the major resistant mechanisms for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, the molecular pathogenesis is still unclear. Methods We investigated 21 patients with advanced EGFR-mutant LADCs that were transformed into EGFR TKI-resistant SCLCs. Among them, whole genome sequencing was applied for nine tumors acquired at various time points from four patients to reconstruct their clonal evolutionary history and to detect genetic predictors for small-cell transformation. The findings were validated by immunohistochemistry in 210 lung cancer tissues. Results We identified that EGFR TKI-resistant LADCs and SCLCs share a common clonal origin and undergo branched evolutionary trajectories. The clonal divergence of SCLC ancestors from the LADC cells occurred before the first EGFR TKI treatments, and the complete inactivation of both RB1 and TP53 were observed from the early LADC stages in sequenced tumors. We extended the findings by immunohistochemistry in the early-stage LADC tissues of 75 patients treated with EGFR TKIs; inactivation of both Rb and p53 was strikingly more frequent in the small-cell-transformed group than in the nontransformed group (82% v 3%; odds ratio, 131; 95% CI, 19.9 to 859). Among patients registered in a predefined cohort (n = 65), an EGFR mutant LADC that harbored completely inactivated Rb and p53 had a 433greater risk of small-cell transformation (relative risk, 42.8; 95% CI, 5.88 to 311). Branch-specific mutational signature analysis revealed that apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)-induced hypermutation was frequent in the branches toward small-cell transformation. Conclusion EGFR TKI-resistant SCLCs are branched out early from the LADC clones that harbor completely inactivated RB1 and TP53. The evaluation of RB1 and TP53 status in EGFR TKI-treated LADCs is informative in predicting small-cell transformation. (C) 2017 by American Society of Clinical Oncology
ISSN
0732-183X
URI
http://hdl.handle.net/10371/165253
DOI
https://doi.org/10.1200/JCO.2016.71.9096
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College of Medicine/School of Medicine (의과대학/대학원)Cancer Research Institute (암연구소)Journal Papers (저널논문_암연구소)
College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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