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

作者：Jake 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, Young Seok Ju · 发表于：Journal of Clinical Oncology · 年份：2017 · DOI：10.1200/jco.2016.71.9096 · 被引用次数：519 · 研究领域：Lung Cancer Research Studies、Lung Cancer Treatments and Mutations、Cancer Genomics and Diagnostics

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 inac...