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KMT2D promotes proliferation of gastric cancer cells: evidence from ctDNA sequencing

Qiaolian Li^1,2, Riping Wu¹, Fan Wu^1,3

¹Fujian Medical University Union Hospital, Fuzhou, China.

Journal of Clinical Laboratory Analysis

|April 1, 2021

Abstract

Background:

ctDNA sequencing could be used for early cancer screening, prognosis prediction, and medication guidance. However, data of its application in gastric cancer are still lacking. In this study, using ctDNA sequencing, we aimed to screen the mutant genes closely associated with gastric cancer and to explore the impact of these genes on gastric cancer development.

Methods:

ctDNA for high-throughput sequencing was obtained from gastric cancer patients, and the high-frequency mutant gene KMT2D was identified. Immunohistochemical examination was conducted to assess the expression of KMT2D in gastric cancer tissues. KMT2D knockdown was performed to establish the stably transfected gastric cancer cells. Then, CCK8, plate clone formation assay, and Transwell assay were conducted, and a subcutaneous tumor-bearing model was induced in nude mice to investigate the changes in cell proliferation and invasion capability. Transcriptome sequencing was also performed to investigate the differences in cellular gene expression.

Results:

Detection of ctDNA found 113 gastric cancer-related mutations, 11 of which are the top 20 high-frequency mutations of gastric cancer recorded by COSMIC (Catalogue of Somatic Mutations in Cancer, COSMIC). They are TP53, ARID1A, CDH1, PIK3CA, KMT2C, KMT2D, APC, SPEN, CTNNB1, SETBP1, and KMT2A. The gene closely related to the clinical characteristics of the patient is KMT2D. The high-frequency mutant gene KMT2D was identified in gastric cancer tissues. The positive rate of KMT2D expression in cancer tissues was 74.3%, which was higher than that in para-carcinoma tissues (56.8%). The knockdown of KMT2D inhibited the proliferation, invasion, and tumor formation capacity of the gastric cancer cells, causing differences in the gene expression profiles, and the expression of different functional gene clusters was up- or downregulated.

Conclusion:

The findings of this study revealed that KMT2D could be an oncogene capable of promoting gastric cancer proliferation.

Insights

This study identifies KMT2D as a key gene in gastric cancer development. Knocking down KMT2D inhibits cancer cell proliferation and invasion, suggesting its role as an oncogene.

Area of Science:

Oncology
Molecular Biology
Genetics

Background:

Circulating tumor DNA (ctDNA) sequencing shows potential in cancer detection and management.
Limited data exists on ctDNA applications in gastric cancer.
This study investigates ctDNA for identifying gastric cancer-associated mutations and their impact.

Purpose of the Study:

To screen for mutant genes linked to gastric cancer using ctDNA sequencing.
To explore the role of identified genes in gastric cancer development.
To investigate the oncogenic potential of the KMT2D gene.

Main Methods:

High-throughput sequencing of ctDNA from gastric cancer patients.
Identification of high-frequency mutant gene KMT2D.
Immunohistochemistry to assess KMT2D expression in tissues.
KMT2D knockdown in gastric cancer cell lines.
In vitro assays (CCK8, colony formation, Transwell) and in vivo tumor models.
Transcriptome sequencing to analyze gene expression changes.

Main Results:

Identified 113 gastric cancer-related mutations, including 11 top COSMIC mutations.
KMT2D was frequently mutated and highly expressed in gastric cancer tissues (74.3% vs 56.8%).
KMT2D knockdown significantly inhibited gastric cancer cell proliferation, invasion, and tumor formation.

Conclusions:

KMT2D is a frequently mutated gene in gastric cancer.
Elevated KMT2D expression is associated with gastric cancer.
KMT2D acts as an oncogene promoting gastric cancer proliferation and invasion.

Read full analysis

Keywords:

KMT2D ctDNA gastric cancer

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