Novel genetic variants of SYK and ITGA1 related lymphangiogenesis signaling pathway predict non-small cell lung cancer survival.

Liu, Lihua

Liu, Hongliang

Luo, Sheng

Patz, Edward F

Glass, Carolyn

Su, Li

Lin, Lijuan

Christiani, David C

Wei, Qingyi

2020-10-01T14:32:26Z

2020-10-01T14:32:26Z

2020-01

2020-10-01T14:32:24Z

Although lymphangiogenesis is a vital step in lung cancer metastasis, the association between lymphangiogenesis and non-small cell lung cancer (NSCLC) survival remains unclear. Since single-nucleotide polymorphisms (SNPs) have been reported to predict NSCLC survival, we investigated associations between SNPs in lymphangiogenesis-related pathway genes and NSCLC survival in a discovery genotyping dataset of 1,185 patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the findings in another genotyping dataset of 984 patients from the Harvard Lung Cancer Susceptibility Study. We evaluated associations between 34,509 genetic variants (3252 genotyped and 31,257 imputed) in 247 genes involved in lymphangiogenesis-related pathway and NSCLC survival. After validation, we finally identified two independent SNPs (SYK rs11787670 A>G and ITGA1 rs67715745 T>C) to be significantly associated with NSCLC overall survival (OS), with adjusted hazards ratios of 0.77 and 0.83 (95% confidence interval =0.66-0.90, P=7.20×10-4) and 0.84 (95% confidence interval =0.75-0.92, P=3.50×10-4), respectively. Moreover, an increasing number of combined protective alleles of these two SNPs was significantly associated with an improved NSCLC OS and disease-specific survival (DSS) in the PLCO dataset (P trend=0.011 and 0.006, respectively). Furthermore, the addition of these protective alleles to the prediction model for the 5-year survival increased the time-dependent area under the curve both from 87% to 87.67% for OS (P=0.029) and from 88.54% to 89.06% for DSS (P=0.022). Subsequent expression quantitative trait loci (eQTL) functional analysis revealed that the rs11787670 G allele was significantly associated with an elevated SYK mRNA expression in normal tissues. Additional analyses suggested a suppressor role for both SYK and ITGA1 in NSCLC survival. Collectively, these findings indicated that SYK rs11787670 A>G and ITGA1 rs67715745 T>C may be independent prognostic factors for NSCLC survival once further validated.

2156-6976

2156-6976

https://hdl.handle.net/10161/21560

eng

American journal of cancer research

Non-small cell lung cancer

lymphangiogenesis

single-nucleotide polymorphism

survival

Novel genetic variants of SYK and ITGA1 related lymphangiogenesis signaling pathway predict non-small cell lung cancer survival.

Journal article

Luo, Sheng|0000-0003-4214-5809

Patz, Edward F|0000-0003-3374-1596

Glass, Carolyn|0000-0002-8850-9906

Wei, Qingyi|0000-0002-3845-9445|0000-0003-4115-4439

2603

2616

8

School of Medicine

Duke Cancer Institute

Pharmacology & Cancer Biology

Pathology

Radiology, Cardiothoracic Imaging

Duke

Institutes and Centers

Basic Science Departments

Clinical Science Departments

Radiology

Population Health Sciences

Medicine, Medical Oncology

Medicine

Duke Clinical Research Institute

Biostatistics & Bioinformatics

Published

10