AUTHOR=Zhang Haorui , Chen Bocen , Zou Zixiu , Feng Jian , Li Yutao , Wang Yi , He Xing , Xu Chang , Wang Haijian , Guo Shicheng , Jin Li , Li Qiang , Wang Jiucun , Xiao Man , Li Feng , Wu Junjie 

TITLE=Associations Between CAMKK1 Polymorphism rs7214723 and the Prognosis of Patients With Lung Cancer

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.757484

DOI=10.3389/fonc.2021.757484

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>The 5-year survival rate of patients with lung cancer in China is less than 20% and predicting their prognosis is challenging. We investigated the association between a common non-synonymous single nucleotide polymorphism (SNP), rs7214723, in the Ca<sup>2+</sup>/calmodulin-dependent protein kinase kinase 1 (<italic>CAMKK1</italic>) gene and the prognosis of patients with lung cancer.</p></sec><sec><title>Methods</title><p>Genomic DNA was extracted from the blood samples of 839 patients with lung cancer, recruited from Changhai Hospital (n = 536) and Taizhou Institute of Health Sciences (n = 352), and genotyped using the SNPscan technique. The association between patient prognosis and the genotypic data for <italic>CAMKK1</italic> was analyzed using a multivariate Cox proportional hazards model adjusted for multiple potential confounders. The CRISPR/Cas9 gene-editing system was used to introduce point mutations in the <italic>CAMKK1</italic> rs7214723 of A549 and NCI-H358 cells. Subsequently, Cell proliferation and migration ability were assessed with the Cell Counting Kit-8 and scratch assay. The Annexin V-FITC apoptosis detection kit was used to detect cell apoptosis.</p></sec><sec><title>Results</title><p>The <italic>CAMKK1</italic> rs7214723 recessive CC genotype conferred significantly better overall survival (CC <italic>vs</italic>. TT + TC: adjusted hazard ratio = 0.78, 95% confidence interval [CI], 0.61-1.00, <italic>P</italic> = 0.049) than the TT + TC genotypes. Stratified analysis showed that the <italic>CAMKK1</italic> rs7214723 CC genotype and recessive CC genotype conferred a significantly decreased risk of death in patients who were male, had a smoking history, or had stage III + IV cancer, compared with the TT and TT + TC genotypes. Relative to the TT + TC genotypes, the rs7214723 recessive CC genotype was also associated with a decreased risk of death in patients aged &lt; 60 years (CC <italic>vs</italic>. TT + TC: adjusted hazard ratio = 0.59, 95% CI, 0.37-0.93, <italic>P</italic> = 0.024) and patients with squamous cell carcinoma (CC <italic>vs</italic>. TT + TC: adjusted hazard ratio = 0.65, 95% CI, 0.44-0.98, <italic>P</italic> = 0.038). Remarkably, CRISPR/Cas9-guided single nucleotide editing demonstrated that <italic>CAMKK1</italic> rs7214723 T &gt; C mutation significantly inhibits cell proliferation and migration and promotes cell apoptosis.</p></sec><sec><title>Conclusions</title><p><italic>CAMKK1</italic> SNP rs7214723 may be a significant prognostic factor for the risk of death among patients with lung cancer.</p></sec>