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Clinical Outcomes of Patients with Microsatellite-Unstable Colorectal Carcinomas Depend on L1 Methylation Level

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

Abstract

Background

The prognostic significance of microsatellite instability (MSI) in colorectal cancers (CRCs) has been addressed in many studies since the initial description of better survival rates in MSI-positive (MSI+) tumors than in MSI-negative (MSI−) tumors. Recent studies have demonstrated that a higher degree of hypomethylation of long interspersed nuclear element-1 (L1) is related to poor prognosis of CRCs and that a wide variation of L1 methylation levels exist within MSI+ CRCs. Our aim was to identify whether L1 and Alu methylation status could predict clinical outcomes within MSI+ CRCs.

Methods

We analyzed 207 MSI+ CRCs for their methylation levels in L1 and Alu repetitive DNA elements using pyrosequencing and correlated them with clinicopathological information including survival data.

Results

Univariate survival analysis showed that low Alu methylation status (<18.60 %) and low L1 methylation status (<53.00 %) were significantly associated with shorter overall survival time (log-rank test, P = 0.009 and P < 0.001, respectively). Multivariate analysis using nine parameters (Alu methylation status, L1 methylation status, patient’s age, disease stage [tumor, node, metastasis staging system], differentiation, Crohn-like lymphoid reaction, KRAS/BRAF mutation status, CpG island methylator phenotype [CIMP] status, and peritumoral lymphocytic infiltration), which were significantly prognostic in MSI+ CRCs, revealed that low L1 methylation status was an independent prognostic factor of MSI+ CRCs (P = 0.009), whereas low Alu methylation status was not.

Conclusions

Clinical outcomes of MSI+ CRCs depend on L1 methylation status, suggesting that lower L1 methylation status serves as a significant prognostic parameter of adverse prognosis in MSI+ CRCs.

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Acknowledgment

This study was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (0720540), by a grant from the Seoul National University Hospital Research Fund (0320110220), by A3 Foresight Program from National Research Foundation of Korea (NRF), and by a Mid-career Researcher Program through NRF grant funded by the Ministry of Education, Science and Technology (MEST) (2011-0015646).

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Authors and Affiliations

  1. Department of Pathology, Second Stage Brain Korea Project and Seoul National University College of Medicine, Seoul, Korea

    Ye-Young Rhee MD, Jeong Mo Bae MD, Jae Moon Koh MD & Gyeong Hoon Kang MD

  2. Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

    Ye-Young Rhee MD, Jeong Mo Bae MD, Nam-Yun Cho MSc & Gyeong Hoon Kang MD

  3. Department of Diagnostic Pathology, Asan Medical Center, Seoul, Korea

    Mi Jung Kim MD

  4. Department of Biochemistry, Seoul National University College of Medicine, Seoul, Korea

    Yong-Sung Juhnn MD

  5. Department of Statistics, Sungkyunkwan University, Seoul, Korea

    Donguk Kim PhD

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  1. Ye-Young Rhee MD
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Correspondence to Gyeong Hoon Kang MD.

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Rhee, YY., Kim, M.J., Bae, J.M. et al. Clinical Outcomes of Patients with Microsatellite-Unstable Colorectal Carcinomas Depend on L1 Methylation Level. Ann Surg Oncol 19, 3441–3448 (2012). https://doi.org/10.1245/s10434-012-2410-7

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  • DOI: https://doi.org/10.1245/s10434-012-2410-7

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