Novel genetic variants of SYK and ITGA1 related lymphangiogenesis signaling pathway predict non-small cell lung cancer survival.
Abstract
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.
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Carolyn Glass
Associate Professor of Pathology
Cardiac and Thoracic PathologistDivision Chief, Cardiovascular Pathology Co-Director,
Division of Artificial Intelligence and Computational PathologyDirector, Duke University
Hospital Autopsy Service Associate Residency Program Director
Dr. Glass completed medical residency in Anatomic Pathology at the Brigham and Women’s
Hospital/Harvard Medical School followed by fellowships in Cardiothoracic Pathology
also at Brigham and Women&rsq
Sheng Luo
Professor of Biostatistics & Bioinformatics
Edward F. Patz Jr.
James and Alice Chen Distinguished Professor of Radiology
There are numerous ongoing clinical studies primarily focused on the early detection
of cancer.
The basic science investigations in our laboratory concentration on three fundamental
translational areas, 1) Development of molecular imaging probes - We have used several
different approaches to develop novel imaging probes that characterize and phenotype
tumors. 2) Discovery of novel lung cancer biomarkers - We ex
Qingyi Wei
Professor in Population Health Sciences
Qingyi Wei, MD, PhD, Professor in the Department of Medicine, is Associate Director
for Cancer Control and Population Sciences, Co-leader of CCPS and Co-leader of Epidemiology
and Population Genomics (Focus Area 1). He is a professor of Medicine and an internationally
recognized epidemiologist focused on the molecular and genetic epidemiology of head
and neck cancers, lung cancer, and melanoma. His research focuses on biomarkers and
genetic determinants for the DNA repair deficient phenotype and
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