Abstract
Accumulated evidence indicates that rare variants exert a vital role on predisposition and progression of human diseases, which provides neoteric insights into disease etiology. In the current study, based on three independently retrospective studies of 5,016 lung cancer patients and 5,181 controls, we analyzed the associations between five rare polymorphisms (i.e., p.Glu116Lys, p.Asn118Ser, p.Arg138Cys, p.Ala195Thr and p.Leu259Phe) in MKK7 and lung cancer risk and prognosis. To decipher the precise mechanisms of MKK7 rare variants on lung cancer, a series of biological experiments was further performed. We found that the MKK7 p.Glu116Lys rare polymorphism was significantly associated with lung cancer risk, progression and prognosis. Compared with Glu/Glu common genotype, the 116Lys rare variants (Lys/Glu/+ Lys/Lys) presented an adverse effect on lung cancer susceptibility (odds ratio [OR] = 3.29, 95% confidence interval [CI] = 2.70–4.01). These rare variants strengthened patients’ clinical progression that patients with 116Lys variants had a significantly higher metastasis rate and advanced N, M stages at diagnosis. In addition, the patients with 116Lys variants also contributed to worse cancer prognosis than those carriers with Glu/Glu genotype (hazard ratio [HR] = 1.53, 95% CI = 1.32–1.78). Functional experiments further verified that the MKK7 p.116Lys variants altered the expression of several cancer-related genes and thus affected lung cancer cells proliferation, tumor growth and metastasis in vivo and in vitro. Taken together, our findings proposed that the MKK7 p.Glu116Lys rare polymorphism incurred a pernicious impact on lung cancer risk and prognosis through modulating expressions of a serial of cancer-related genes.
Highlights
Ever-increasing epidemiological studies, especially the genome-wide association studies (GWAS), have extensively identified numerous genetic variants, including single-nucleotide polymorphisms (SNPs), to be associated with risk and progression of various human malignancies[1,2,3]
Rare variants have been identified to be associated with a variety of human malignancies, which account for a considerable fraction of heredity for complex diseases
We tested the associations between rare variants in MKK7 and lung cancer risk and prognosis in two-stage retrospective studies with a total of 5,016 lung cancer patients and 5,181 controls in Chinese
Summary
Ever-increasing epidemiological studies, especially the genome-wide association studies (GWAS), have extensively identified numerous genetic variants, including single-nucleotide polymorphisms (SNPs), to be associated with risk and progression of various human malignancies[1,2,3]. An example is that the rare variants located in proto-oncogenes or tumor suppressor genes may contribute to phenotypic variations through modifying their biological functions or genes expression, and play an important role in cancer initiations and progressions[9, 10]. These findings provide novel approaches for the exploration of cancer mechanism. Several studies indicated that MKK7 acts as a suppressor in tumors migration, invasion and metastasis [17,18,19]
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