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Clonal History and Genetic Predictors of Transformation Into Small-Cell Carcinomas From Lung Adenocarcinomas
June-Koo Lee1, Junehawk Lee1, Sehui Kim1
1June-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.
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.
Insights
Small-cell transformation in EGFR-mutant lung adenocarcinoma is driven by early RB1 and TP53 inactivation. This genetic profile predicts resistance to EGFR tyrosine kinase inhibitors (TKIs) and informs treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Histologic transformation of EGFR-mutant lung adenocarcinoma (LADC) to small-cell lung cancer (SCLC) is a key mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs).
- The molecular underpinnings of this transformation remain incompletely understood, hindering the development of effective therapeutic strategies.
Purpose of the Study:
- To elucidate the molecular pathogenesis of EGFR TKI-resistant SCLC transformation from LADC.
- To identify genetic predictors for small-cell transformation in EGFR-mutant lung adenocarcinoma.
Main Methods:
- Whole genome sequencing of tumors from 21 patients with advanced EGFR-mutant LADCs transformed into SCLCs.
- Reconstruction of clonal evolutionary history and identification of genetic drivers of small-cell transformation.
- Validation of findings using immunohistochemistry in 210 lung cancer tissues and analysis of early-stage LADC tissues.
Main Results:
- EGFR TKI-resistant LADCs and SCLCs share a common clonal origin with branched evolutionary trajectories.
- Complete inactivation of RB1 and TP53 was observed in early LADC stages, preceding SCLC transformation.
- Inactivation of Rb and p53 was significantly more frequent in transformed SCLC cases (82%) versus non-transformed (3%), with a 43-fold increased risk of transformation in LADCs harboring both inactivated genes.
Conclusions:
- EGFR TKI-resistant SCLCs arise from early-branching LADC clones characterized by complete RB1 and TP53 inactivation.
- Assessing RB1 and TP53 status in EGFR TKI-treated LADCs is crucial for predicting the risk of small-cell transformation.
- APOBEC-induced hypermutation is associated with the evolutionary branches leading to small-cell transformation.
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