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IGF2 DMR0 Methylation, Loss of Imprinting, and Patient Prognosis in Esophageal Squamous Cell Carcinoma

  • Gastrointestinal Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Insulin like growth factor 2 gene (IGF2) is normally imprinted. Loss of imprinting (LOI) of IGF2 in humans is associated with an increased risk of cancer and is controlled by CpG-rich regions known as differentially methylated regions (DMRs). Specifically, the methylation level at IGF2 DMR0 is correlated with IGF2 LOI and is a suggested surrogate marker for IGF2 LOI. A relationship between IGF2 DMR0 hypomethylation and poor prognosis has been shown in colorectal cancer. However, to our knowledge, no study has examined the relationships among the IGF2 DMR0 methylation level, LOI, and clinical outcome in esophageal squamous cell carcinoma (ESCC).

Methods

The IGF2 imprinting status was screened using ApaI polymorphism, and IGF2 protein expression was evaluated by immunohistochemistry with 30 ESCC tissue specimens. For survival analysis, IGF2 DMR0 methylation was measured using a bisulfite pyrosequencing assay with 216 ESCC tissue specimens.

Results

Twelve (40 %) of 30 cases were informative (i.e., heterozygous for ApaI), and 5 (42 %) of 12 informative cases displayed IGF2 LOI. IGF2 LOI cases exhibited lower DMR0 methylation levels (mean 23 %) than IGF2 non-LOI cases (37 %). The IGF2 DMR0 methylation level was significantly associated with IGF2 protein expression. Among 202 patients eligible for survival analysis, IGF2 DMR0 hypomethylation was significantly associated with higher cancer-specific mortality.

Conclusions

The IGF2 DMR0 methylation level in ESCC was associated with IGF2 LOI and IGF2 protein expression. In addition, IGF2 DMR0 hypomethylation was associated with a shorter survival time, suggesting its potential role as a prognostic biomarker.

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Acknowledgment

Supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS) (Grant 24659617).

Disclosures

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto City, Kumamoto, Japan

    Asuka Murata MD, Yoshifumi Baba MD, PhD, Masayuki Watanabe MD, PhD, FACS, Hironobu Shigaki MD, PhD, Keisuke Miyake MSc, Takatsugu Ishimoto MD, PhD, Masaaki Iwatsuki MD, PhD, Shiro Iwagami MD, PhD, Naoya Yoshida MD, PhD, FACS & Hideo Baba MD, PhD, FACS

  2. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka City, Fukuoka, Japan

    Eiji Oki MD, PhD & Masaru Morita MD, PhD

  3. Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto City, Kumamoto, Japan

    Mitsuyoshi Nakao MD, PhD

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  1. Asuka Murata MD
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  2. Yoshifumi Baba MD, PhD
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  13. Hideo Baba MD, PhD, FACS
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Correspondence to Hideo Baba MD, PhD, FACS.

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Murata, A., Baba, Y., Watanabe, M. et al. IGF2 DMR0 Methylation, Loss of Imprinting, and Patient Prognosis in Esophageal Squamous Cell Carcinoma. Ann Surg Oncol 21, 1166–1174 (2014). https://doi.org/10.1245/s10434-013-3414-7

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  • DOI: https://doi.org/10.1245/s10434-013-3414-7

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