Clinical Research Papers:

MLH1 V384D polymorphism associates with poor response to EGFR tyrosine kinase inhibitors in patients with EGFR L858R-positive lung adenocarcinoma

Chao-Hua Chiu, Hsiang-Ling Ho, Howard Doong, Yi-Chen Yeh, Mei-Yu Chen, Teh-Ying Chou and Chun-Ming Tsai _

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Oncotarget. 2015; 6:8407-8417. https://doi.org/10.18632/oncotarget.3511

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Chao-Hua Chiu1,2,4,*, Hsiang-Ling Ho5,*, Howard Doong6, Yi-Chen Yeh1,5, Mei-Yu Chen3, Teh-Ying Chou1,5 and Chun-Ming Tsai2,4

1 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan

2 Department of Medicine, National Yang-Ming University, Taipei, Taiwan

3 Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan

4 Division of Thoracic Oncology, Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

5 Division of Molecular Pathology, Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

6 Taipei VGH-Lihpao Laboratory of Cancer Genomic Medicine, Lihpao Life Science Corporation, Taipei, Taiwan

* These authors contributed equally to this work

Correspondence to:

Teh-Ying Chou, email:

Chun-Ming Tsai, email:

Keywords: MLH1, EGFR, Lung adenocarcinoma, Tyrosine kinase inhibitor, Resistance

Received: January 05, 2015 Accepted: February 02, 2015 Published: March 08, 2015


A significant fraction of patients with lung adenocarcinomas harboring activating epidermal growth factor receptor (EGFR) mutations do not experience clinical benefits from EGFR tyrosine kinase inhibitor (TKI) therapy. Using next-generation sequencing, we screened 739 mutation hotspots in 46 cancer-related genes in EGFR L858R-mutant lung adenocarcinomas from 29 patients who received EGFR-TKI therapy; 13 had short (< 3 months) and 16 had long (> 1 year) progression-free survival (PFS). We discovered MLH1 V384D as a genetic variant enriched in the group of patients with short PFS. Next, we investigated this genetic variation in 158 lung adenocarcinomas with the EGFR L858R mutation and found 14 (8.9%) patients had MLH1 V384D; available blood or non-tumor tissues from patients were also tested positive for MLH1 V384D. Patients with MLH1 V384D had a significantly shorter median PFS than those without (5.1 vs. 10.6 months; P= 0.001). Multivariate analysis showed that MLH1 V384D polymorphism was an independent predictor for a reduced PFS time (hazard ratio, 3.5; 95% confidence interval, 1.7 to 7.2; P= 0.001). In conclusion, MLH1 V384D polymorphism is associated with primary resistance to EGFR-TKIs in patients with EGFR L858R-positive lung adenocarcinoma and may potentially be a novel biomarker to guide treatment decisions.

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