한빛사논문, 상위피인용논문
- 조회3,897
June-Koo Lee, Junehawk Lee, Sehui Kim, Soyeon Kim, Jeonghwan Youk, Seongyeol Park, Yohan An, Bhumsuk Keam, Dong-Wan Kim, Dae Seog Heo, Young Tae Kim, Jin-Soo Kim, Se Hyun Kim, Jong Seok Lee, Se-Hoon Lee, Keunchil Park, Ja-Lok Ku, Yoon Kyung Jeon, Doo Hyun Chung, Peter J. Park, Joon Kim, Tae Min Kim, and Young Seok Ju
June-Koo Lee, Jeonghwan Youk, Seongyeol Park, Yohan An, Joon Kim, Young Seok Ju, Korea Advanced Institute of Science and Technology; Junehawk Lee, Korea Institute of Science and Technology Information, Daejeon; Sehui Kim, Bhumsuk Keam, Dong-Wan Kim, Dae Seog Heo, Young Tae Kim, Yoon Kyung Jeon, Doo Hyun Chung, Tae Min Kim, Seoul National University Hospital; Soyeon Kim, Bhumsuk Keam, Dong-Wan Kim, Dae Seog Heo, Young Tae Kim, Ja-Lok Ku, Yoon Kyung Jeon, Tae Min Kim, Seoul National University Cancer Research Institute; Jin-Soo Kim, Seoul Metropolitan Government?Seoul National University Boramae Medical Center; Se-Hoon Lee, Keunchil Park, Sungkyunkwan University School of Medicine; Doo Hyun Chung, Seoul National University College of Medicine, Seoul; Se Hyun Kim, Jong Seok Lee, Seoul National University Bundang Hospital, Seongnam, Republic of Korea; and Peter J. Park, Harvard Medical School, Boston, MA.
T.M.K. and Y.S.J. are principal investigators who contributed equally to this study.
Corresponding author: Tae Min Kim, MD, PhD, Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea
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 43× greater 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.
논문정보
- Research article
- 2017년 05월 (BRIC 등록일 2017-05-17)
- 국내(교신)+국외 연구진
- 생명과학 > 노화/암생물학
- 60회 이상 인용된 논문 (상위피인용논문 등록일 2020-03-17)
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