N6-methyladenosine methylation-related genes YTHDF2, METTL3, and ZC3H13 predict the prognosis of hepatocellular carcinoma patients

Yun Wang; Tianjun Li; Haiping Liu; Yu Liang; Guanqun Wang; Guangming Fu; Mitsuhisa Takatsuki; Haijun Qu; Fanbo Jing; Jing Li; Man Jiang

doi:10.21037/atm-22-5964

N6-methyladenosine methylation-related genes YTHDF2, METTL3, and ZC3H13 predict the prognosis of hepatocellular carcinoma patients

Ann Transl Med. 2022 Dec;10(24):1398. doi: 10.21037/atm-22-5964.

Authors

Yun Wang^#^{1

2

3}, Tianjun Li^#³, Haiping Liu⁴, Yu Liang⁴, Guanqun Wang⁵, Guangming Fu⁵, Mitsuhisa Takatsuki⁶, Haijun Qu¹, Fanbo Jing¹, Jing Li¹, Man Jiang^{1

3}

Affiliations

¹ Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China.
² Department of Radiotherapy, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China.
³ Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China.
⁴ Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, China.
⁵ Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China.
⁶ Department of Digestive and General Surgery, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.

^# Contributed equally.

Abstract

Background: Hepatocellular carcinoma (HCC) is a common primary malignant tumor and cause of cancer-related death in humans. Increasing evidence indicates that an imbalance in N6-methyladenosine (m6A) methylation is strongly linked to the occurrence and development of cancer. We used comprehensive bioinformatics to establish a potential prognostic model of HCC based on m6A methylation-related genes. And case analyses were used to verify the results.

Methods: The clinical data and gene expressions were obtained from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. The prognostic value of m6A methylation-related genes in HCC patients and their relationship with the immune microenvironment were explored by comprehensive bioinformatics analyses. We also collected pathological specimens from 70 patients with HCC from the Department of Pathology, Affiliated Hospital of Qingdao University, and performed immunohistochemical staining on the specimens. We compared tumor specimens from 27 patients positive for METTL3, YTHDF2, and ZC3H13 staining with their adjacent normal tissues and against 27 patient specimens negative for METTL3, YTHDF2, and ZC3H13. The influence of METTL3, YTHDF2, and ZC3H13 on survival was analyzed, and the prognostic model for METTL3, YTHDF2, and ZC3H13 in HCC was verified by clinical data.

Results: Most m6A methylation-related genes showed significantly different expressions between cancer and normal tissues. Three candidate m6A methylation-related genes (YTHDF2, METTL3, and ZC3H13) were significantly correlated with the overall survival (OS) of HCC patients. A Kaplan-Meier survival analysis indicated a worse prognosis of high-risk patients than that of low-risk patients. Immunological analysis showed that the high-risk group was more likely to have higher follicular helper T cell counts and lower resting memory CD4 T cell counts. The expression of YTHDF2, METTL3, and ZC3H13 was validated by other databases, including the Oncomine database, the Human Protein Atlas (HPA), and the Kaplan-Meier plotter.

Conclusions: Our prognostic model based on m6A methylation-related genes effectively predicted the prognosis of HCC patients.

Keywords: Hepatocellular carcinoma (HCC); International Cancer Genome Consortium database (ICGC database); N6-methyladenosine methylation-related genes (m6A methylation-related genes); The Cancer Genome Atlas database (TCGA database); prognostic model.