Dataset Information

Associations of TIMP-3 Genetic Polymorphisms with EGFR Statuses and Cancer Clinicopathologic Development in Lung Adenocarcinoma Patients.

ABSTRACT: Lung adenocarcinoma (LADC) is a major subtype of lung cancer, particularly among populations of East Asia. The epidermal growth factor receptor (EGFR) is the most frequently mutated oncogene promoting LADC progression and can serve as a therapeutic target in LADC. The tissue inhibitor of metalloproteinases (TIMP)-3 is a major regulator of extracellular matrix turnover via targeting of matrix metalloproteinases (MMPs), and thus, plays a critical role in tumor development and progression. The purpose of this study was to investigate potential associations among TIMP-3 genetic polymorphisms, EGFR statuses, and cancer clinicopathologic development in patients with LADC. In this study, 277 LADC patients with different EGFR statuses were recruited to dissect the allelic discrimination of TIMP-3 -1296 T>C (rs9619311), TIMP3 249T>C (rs9862), and TIMP3 261C>T (rs11547635) polymorphisms using a TaqMan allelic discrimination assay. Our data showed that compared to those LADC patients with wild-type CC homozygotes of TIMP-3 rs9862, patients harboring TT homozygotes of rs9862 were at a higher risk of developing mutant EGFR (adjusted odds ratio (AOR) = 2.530; 95% confidence interval (CI): 1.230-5.205; p = 0.012), particularly the EGFR L858R point mutation (AOR = 2.975; 95% CI: 1.182-7.488; p = 0.021). Moreover, we observed that TIMP-3 TT homozygotes of rs9862 were correlated with the incidence of EGFR mutations in patients with a smoking habit (p = 0.045). Within male patients harboring a mutant EGFR, TIMP-3 rs9862 T (CT+TT) allele carriers were at higher risk of developing an advanced stage (p = 0.025) and lymph node metastasis (p = 0.043). Further analyses of clinical datasets revealed correlations of TIMP-3 expression with a favorable prognosis in patients with LADC. In conclusion, the data suggest that TIMP-3 rs9862 polymorphisms may contribute to identify subgroups of lung cancer patients at high risk for tumor progression, among carriers of LADC-bearing mutant EGFR.

SUBMITTER: Chang JH

PROVIDER: S-EPMC7662501 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Associations of <i>TIMP-3</i> Genetic Polymorphisms with <i>EGFR</i> Statuses and Cancer Clinicopathologic Development in Lung Adenocarcinoma Patients.

Chang Jer-Hwa JH Lai Tsung-Ching TC Yang Po-Jen PJ Shih Pei-Chun PC Yang Yi-Chieh YC Lee Kai-Ling KL Liu Tu-Chen TC Tsao Thomas Chang-Yao TC Yang Shun-Fa SF Chien Ming-Hsien MH

International journal of molecular sciences 20201028 21

Lung adenocarcinoma (LADC) is a major subtype of lung cancer, particularly among populations of East Asia. The epidermal growth factor receptor (EGFR) is the most frequently mutated oncogene promoting LADC progression and can serve as a therapeutic target in LADC. The tissue inhibitor of metalloproteinases (TIMP)-3 is a major regulator of extracellular matrix turnover via targeting of matrix metalloproteinases (MMPs), and thus, plays a critical role in tumor development and progression. The purp ...[more]

PMID: 33126605

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Project description:Accumulation of genetic and epigenetic changes alters regulation of a web of interconnected genes including miRNAs, which confer hallmark capabilities and characteristic cancer features. In this study, the miRNA and mRNA expression profiles of 126 non-small cell lung cancer specimens were analyzed, with special attention given to the diversity of lung adenocarcinomas. Of those, 76 adenocarcinomas were classified into two major subtypes, developing lung-like and adult lung-like, based on their distinctive miRNA expression profiles resembling those of either developing or adult lungs, respectively. A systems biology-based approach using a Bayesian network and nonparametric regression was employed to estimate the gene regulatory circuitry functioning in patient tumors in order to identify subnetworks enriched for genes with differential expression between the two major subtypes. miR-30d and miR-195, identified as hub genes in such subnetworks, had lower levels of expression in the developing lung-like subtype, while introduction of miR-30d or miR-195 into the lung cancer cell lines evoked shifts of mRNA expression profiles towards the adult lung-like subtype. Conversely, the influence of miR-30d and miR-195 was significantly different between the developing lung- and adult lung-like subtypes in our analysis of the patient dataset. In addition, RRM2, a child gene of the miR-30d-centered subnetwork, was found to be a direct target of miR-30d. Together, our findings reveal the existence of two miRNA expression profile-defined lung adenocarcinoma subtypes with distinctive clinicopathologic features and also suggest the usefulness of a systems biology-based approach to gain insight into the altered regulatory circuitry involved in cancer development. Microarray analysis using a Whole Human Genome 4 x 44K Microarray G4112F (Agilent) was conducted to examine changes in expression of 400 genes in SiGN network by transfection of Pre-miR-30d, Pre-miR-195 or Pre-miR-NC#2 (Ambion) in SK-LC-7 cells, which were then harvested at 72 hours after transfection.

Project description:BackgroundEpidermal growth factor receptor exon 20 insertions (EGFR ex20ins) occur in about 4-14% of lung adenocarcinoma (LUAD) patients with EGFR mutations. Recently some targeted drugs have been approved for the treatment of LUAD patients with EGFR ex20ins. However, the heterogeneity of EGFR ex20ins mutations and resultant challenges in identifying them have led to the underestimation of their frequency.MethodsWe investigated the molecular and clinicopathologic features of EGFR ex20ins in 3,892 Chinese LUAD patients using next-generation sequencing (NGS). The frequency and distribution of EGFR ex20ins mutations between Chinese and Western LUAD patients were also compared by integrating the data of this study and the data of previous studies.ResultsA total of 23 unique EGFR ex20ins were identified in 77 LUAD patients, accounting for 1.98% of all LUAD patients and 3.49% of EGFR mutant LUDA patients. The 2 most common EGFR ex20ins subtypes were S768_D770dup and A767_V769dup, which together accounted for 55.84% of the EGFR ex20ins cases. About 61% (14/23) of the EGFR ex20ins subtypes occurred only once. Additionally, 8 of the EGFR ex20ins subtypes were not recorded in the COSMIC database. These results showed that the EGFR ex20ins mutations were highly heterogeneous. There was no significant difference in the frequency and distribution of EGFR ex20ins mutations between Chinese and Western LUAD patients, but the frequency of EGFR ex20ins mutations was significantly lower in EGFR-mutant Chinese LUAD patients than Western LUAD patients. The co-mutation analysis showed that EGFR ex20ins occurred significantly and exclusively with certain driver genes in LUAD, including ALK fusion (χ2=7.133, P=0.008), KRAS (χ2=8.468, P=0.004), and PIK3CA (χ2=5.792, P=0.016). No gene was observed to be significantly co-mutated with EGFR ex20ins. In general, patients with EGFR ex20ins shared a similar age and gender to patients with other EGFR mutations or without EGFR ex20ins.ConclusionsOverall, our results revealed the molecular and clinicopathologic features of EGFR ex20ins in Chinese LUAD patients, which will be helpful for drug development and in clinical trials targeting EGFR ex20ins.

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Dataset Information

Associations of TIMP-3 Genetic Polymorphisms with EGFR Statuses and Cancer Clinicopathologic Development in Lung Adenocarcinoma Patients.

Publications

Associations of <i>TIMP-3</i> Genetic Polymorphisms with <i>EGFR</i> Statuses and Cancer Clinicopathologic Development in Lung Adenocarcinoma Patients.

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