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Expression and methylation status of MMR and MGMT in well-differentiated pancreatic neuroendocrine tumors and potential clinical applications

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Abstract

Purpose

Recent studies claim that immune checkpoint inhibitors are effective in defective mismatch repair (dMMR) cancers. This raises the question of whether similar therapies are effective in PanNETs (pancreatic neuroendocrine tumors); however, in general, assessment of MMR status in PanNETs has been inconsistent in previous studies. MGMT (O6-methylguanine-DNA methyltransferase) is potentially important for guiding temozolomide (TMZ) therapy in glioblastoma. The number of reports on MGMT expression and promoter methylation in PanNETs are limited.

Methods

In this study we assessed the expression of MGMT and MMR proteins MSH2, MSH6, MLH1 and PMS2 in a series of PanNETs by IHC. The methylation status of MGMT and MMR genes in a subset of PanNETs was further assessed by MS-MLPA analysis. Survival curves were constructed using the Kaplan-Meier method, and differences were assessed using the log-rank test. Multivariate Cox proportional hazards regression models were used to determine the prognostic value of the variables.

Results

According to evaluation criteria for mismatch repair defects, none of PanNETs shown nuclear staining loss for MSH2, MSH6, MLH1, and PMS2. MGMT low-intensity PanNETs were more commonly found in higher grade, higher Ki67 index and non-functional tumors (P < 0.05). In multivariate analysis, stage III–IV and low-intensity MGMT were shown to be independent risk factors for progression of PanNETs in the entire cohort, non-functioning subgroup and G2 subgroup (P < 0.05 for all). MGMT promoter methylation tended to be higher in the group with low expression of MGMT, However, methylation of MGMT did not statistically correlate with low expression of MGMT (P = 0.153).

Conclusions

In conclusion, our study suggests that decreased expression of MGMT but not MMR is associated with a higher risk of progression of pancreatic neuroendocrine tumors.

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Acknowledgements

We thank Yiwei Yang of Xiamen Zeesan Biotechnology Co., Ltd. for his technical assistance with the MS-MLPA analysis.

Funding

This work was supported by the CAMS Science and Technology Innovation Program Fund for Medical Sciences and Health (Grant number [2016-I2M-1-001]), the National Scientific Data Sharing Platform for Population and Health (Grant number [NCMI–YF01N–201906]), the National Natural Science Foundation of China (C.N.) (Grant numbers [81672648], [81472326], [81341070], and [81400664]), and special funds from the Molecular Pathology Center and the Central Public Welfare Institutions of CAMS (Grant numbers [2016ZX310176-4] and [2017PT31008]). The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

    Xinchao Ban, Shengwei Mo, Zhaohui Lu, Congwei Jia, Huilin Shao, Xiaoyan Chang, Xinxin Mao, Yue Zhang, Junyi Pang, Yuhan Zhang, Shuangni Yu & Jie Chen

  2. Department of Pathology, Tianjin Medical University, Tianjin, China

    Xinchao Ban

  3. Department of Pathology, Tianjin Medical University General Hospital, Tianjin, China

    Xinchao Ban

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  1. Xinchao Ban
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Contributions

S.Y., J.C. and Z.L. contributed to the study conception and design. Material preparation, data collection and analysis were performed by S.mo., C.J., and H.S. Experimental procedure (IHC and MS-MLPA) was performed by X.B., Y.Z., J.P., and Y.Z. X.C. and X.M. reviewed the H&E slide and evaluated the IHC results. The first draft of the manuscript was written by X.B. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Shuangni Yu or Jie Chen.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Peking Union Medical College Hospital (No. [S-K523]).

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Ban, X., Mo, S., Lu, Z. et al. Expression and methylation status of MMR and MGMT in well-differentiated pancreatic neuroendocrine tumors and potential clinical applications. Endocrine 77, 538–545 (2022). https://doi.org/10.1007/s12020-022-03102-y

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