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Comparative analysis of co-occurring mutations of specific tumor suppressor genes in lung adenocarcinoma between Asian and Caucasian populations

  • Yiliang Zhang
  • Yuan Ma
  • Yuan Li
  • Xuxia Shen
  • Yongfu Yu
  • Yunjian Pan
  • Yang Zhang
  • Difan Zheng
  • Yue Zhao
  • Ting Ye
  • Bin Li
  • Hong Hu
  • Yihua Sun
  • Yawei Zhang
  • Jiaqing Xiang
  • Haiquan ChenEmail author
Original Article – Clinical Oncology
  • 65 Downloads

Abstract

Introduction

Mutated tumor suppressor genes (TSG) such as TP53, STK11, and MGA are widely-reported. We hypothesized the presence of single mutation or co-occurring mutations in these specific genes may represent a significant therapeutic target for lung adenocarcinoma.

Methods

We sequenced lung adenocarcinoma samples from 677 East-Asian patients, combined them with those from cBioPortal public database (including TCGA) and performed a comparative analysis between Asian and Caucasian populations.

Results

East-Asian lung adenocarcinomas presented distinct driver-mutational distribution compared to that of Caucasians (79% vs 56%, p < 0.001). Similar results were observed in TSG mutations of TP53 (35% vs 46%, p = 0.150), STK11 (4% vs 17%, p = 0.006) and MGA (10% vs 4%, p = 0.166). Compared with none-mutational cases, the patients harboring TSG mutations are more likely to be male (p = 0.009), smokers (p < 0.001), and more advanced disease (p = 0.004). In addition, the TSG-mutated tumors had poorer differentiation (p < 0.001), and more likely to be solid or micropapillary-predominant adenocarcinomas (p < 0.001). Survival analysis showed that both overall survival (OS, p < 0.001) and post-recurrence survival (PRS, p < 0.001) became worse with the accumulation of TSG mutations. However, the prognostic variety was not found in Caucasian patients. Moreover, multivariate analysis proved the accumulation of TSG mutations independently predicts both unfavorable OS (HR = 0.435, 95% CI 0.245–0.774, p = 0.005) and PRS (HR = 0.491, 95% CI 0.269–0.894, p = 0.020) in East-Asian patients, adjusting all other survival-associated factors.

Conclusions

Co-occurring mutations of specific TSGs define unfavorable subgroups of lung adenocarcinoma, implying that the tumor promotion mechanisms contribute to the heterogeneity in tumor evolution. However, the Caucasian population did not show the same results, providing insights into the molecular basis underlying the striking racial disparities of this disease and evidence for different gene-panel designs for different population in the purpose of targeted therapy.

Keywords

Lung adenocarcinoma Tumor suppressor gene (TSG) Survival 

Notes

Funding

This work was supported by Grants 81330056; 81172218; 81572253 from the National Natural Science Foundation of China.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

432_2018_2828_MOESM1_ESM.docx (21 kb)
Supplementary material 1 (DOCX 21 KB)
432_2018_2828_MOESM2_ESM.tif (20.7 mb)
Supplementary material 2 (TIFF 21172 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Yiliang Zhang
    • 1
    • 3
  • Yuan Ma
    • 1
    • 3
  • Yuan Li
    • 2
    • 3
  • Xuxia Shen
    • 2
    • 3
  • Yongfu Yu
    • 4
  • Yunjian Pan
    • 1
    • 3
  • Yang Zhang
    • 1
    • 3
  • Difan Zheng
    • 1
    • 3
  • Yue Zhao
    • 1
    • 3
  • Ting Ye
    • 1
    • 3
  • Bin Li
    • 1
    • 3
  • Hong Hu
    • 1
    • 3
  • Yihua Sun
    • 1
    • 3
  • Yawei Zhang
    • 1
    • 3
  • Jiaqing Xiang
    • 1
    • 3
  • Haiquan Chen
    • 1
    • 3
    Email author
  1. 1.Department of Thoracic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
  2. 2.Department of PathologyFudan University Shanghai Cancer CenterShanghaiChina
  3. 3.Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
  4. 4.Department of Clinical EpidemiologyAarhus University HospitalAarhusDenmark

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