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Genetic Variant of Notch Regulator DTX1 Predicts Survival After Lung Cancer Surgery

Jang Hyuck Lee MS, Kyung Min Shin MD, Shin Yup Lee MD, PhD, Mi Jeong Hong PhD, Jin Eun Choi PhD, Hyo-Gyoung Kang PhD, Sook Kyung Do MS, Won Kee Lee PhD, Eung Bae Lee MD, PhD, Yangki Seok MD, PhD, Ji Yun Jeong MD, Seung Soo Yoo MD, PhD, Jaehee Lee MD, PhD, Seung Ick Cha MD, PhD, Chang Ho Kim MD, PhD, Sukki Cho MD, PhD, Sanghoon Jheon MD, PhD, Young Chul Kim MD, PhD, In Jae Oh MD, PhD, Kook Joo Na M
Translational Research and Biomarkers
Volume 26, Issue 11 / October , 2019

Abstract

Background

We evaluated the association between genetic variants in the Notch pathway and survival outcomes of patients with surgically resected NSCLC.

Methods

Sixty-four single nucleotide polymorphisms (SNPs) in the Notch pathway genes were evaluated in the discovery study (n = 354) and two sequential validation studies (n = 772 and n = 746, respectively). The association of genotype with overall survival (OS) and disease-free survival (DFS) was evaluated.

Results

Of the 64 SNPs analyzed in the discovery study, 9 were significantly associated with OS or DFS. Among them, the association remained significant only for Deltex-1 (DTX1) rs1732786A>G in the first validation study. The second validation study confirmed again the association between DTX1 rs1732786A>G and survival outcomes. In the combined analysis, rs1732786A>G was significantly associated with better OS and DFS (adjusted HR ·aHR· for OS, 0.75; 95% CI 0.64–0.87; P = 0.0002; aHR for DFS, 0.79; 95% CI 0.71–0.89; P = 0.0001). In vitro luciferase assay showed that the rs1732786G allele was associated with higher promoter activity compared to rs1732786A allele. Consistently, relative mRNA expression level of DTX1 showed significant positive correlation with rs1732786 A-to-G change (Ptrend = 0.02) in tumor tissues.

Conclusions

These results suggest that DTX1 rs1732786 is a potential prognostic factor that may have clinical utility in the management of early stage NSCLC.

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