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Promoter hypermethylation of GALR1 acts as an early epigenetic susceptibility event in colorectal carcinogenesis

Journal of Human Genetics volume 67, pages 519–525 (2022)Cite this article

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Abstract

Epigenetics play an essential role in colorectal neoplasia process. There is a need to determine the appropriateness of epigenetic biomarkers for early detection as well as expand our understanding of the carcinogenic process. Therefore, the aim of the study was to assess how DNA methylation pattern of GALR1 gene evolves in a sample set representing colorectal neoplastic progression. The study was designed into three phases. Firstly, Methylation status of GALR1 was assessed with genome-wide DNA methylation beadchip and pyrosequencing assays in colorectal lesions and paired normal tissues. Then, linear mixed-effects modeling analyses were applied to describe the trend of DNA methylation during the progression of colorectal neoplasia. In the third phase, quantitative RT-PCR was used to examine GALR1 expression in patients with precursor lesion and colorectal cancer. We found that significant hypermethylation of GALR1 promoter was a widely existent modification in CRCs (P < 0.001). When further examined methylation pattern of GALR1 during neoplastic progression of CRC, we found that DNA methylation level of GALR1 showed a significant stepwise increase from normal to hyperplastic polyps, to adenomas and to carcinoma samples (P < 0.001). Besides, loss of mRNA expression is a common accompaniment to adenomas and carcinomas. Public omics data analyses showed an inverse correlation between gene expression and DNA methylation (P < 0.001). Our findings indicate that epigenetic alteration of GALR1 promoter is gradually accumulated during the colorectal neoplastic progression. It can potentially be a promising biomarker used for screening and surveillance of colorectal cancer.

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Acknowledgements

We sincerely thank all participants in the study.

Funding

This study is supported by National Basic Research Program of China (973 Program No.2015CB554003), National Science Foundation of China (NSFC No.81673262) and Zhejiang Provincial Natural Science Foundation of China (Q22H260581).

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Author notes

  1. These authors contributed equally: Simeng Gu, Sangni Qian.

Authors and Affiliations

  1. Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China

    Simeng Gu, Sangni Qian, Shujuan Lin, Kun Chen & Mingjuan Jin

  2. Department of Environmental Health, Zhejiang Provincial Center for Disease Control and Prevention, 3399 Binsheng Road, Hangzhou, 310051, China

    Simeng Gu

  3. Department of Epidemiology and Biostatistics, Zhejiang Chinese Medical University School of Public Health, 548 Binwen Road, Hangzhou, 310053, China

    Ding Ye

  4. Jiashan Institute of Cancer Prevention and Treatment, 345 Jiefangdong Road, Jiashan, 314100, China

    Qilong Li & Jinhua Yang

  5. Department of Anorectal Surgery, Shaoxing People’s Hospital, 568 Zhongxingbei Road, Shaoxing, 312000, China

    Xiaojiang Ying & Zhenjun Li

  6. Department of Public Health, Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China

    Mengling Tang

  7. Department of Public Health, National Clinical Research Center for Child Health of Children’s Hospital, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China

    Jianbing Wang

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Contributions

SG and MJ designed and supervised the whole study. SG, SQ and SL performed the experiments. SG and DY made contributions to statistical analyses. QL, JY, XY, ZL, MT and JW recruited the participants and collected samples and clinical information. SG completed the manuscript with intellectual input from MJ and KC. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Kun Chen or Mingjuan Jin.

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The authors declare no competing interests.

Ethics approval and consent to participate

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by Ethics Committee of Zhejiang University School of Medicine. The patients/participants provided their written informed consent to participate in this study.

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Gu, S., Qian, S., Lin, S. et al. Promoter hypermethylation of GALR1 acts as an early epigenetic susceptibility event in colorectal carcinogenesis. J Hum Genet 67, 519–525 (2022). https://doi.org/10.1038/s10038-022-01038-9

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