The clinicopathological significance of <em>hMLH1</em> hypermethylation in non-small-cell lung cancer: a meta-analysis and literature review

Abstract

The hMLH1 gene plays an essential role in DNA repair. Methylation of the hMLH1 gene is common in many types of cancer and can lead to the loss of hMLH1 expression. However, the association and clinicopathological significance between hMLH1 promoter hypermethylation and non-small-cell lung cancer (NSCLC) is elusive. Here, we investigated the correlation of hMLH1 promoter hypermethylation and NSCLC using 13 studies by comprising 1,056 lung cancer patients via a meta-analysis. We observed that 1) loss of hMLH1 protein expression was significantly associated with its promoter hypermethylation, 2) hMLH1 gene inactivation through hypermethylation contributed to the tumorigenesis of NSCLC, which could be a decisive factor for the pathogenesis of NSCLC due to its high occurrence in NSCLC tissues compared to normal lung tissues, 3) a correlation exists between histologic subtypes/disease stages (TNM I+II vs III+IV) and hypermethylation status of hMLH1 gene, and 4) NSCLC patients with hMLH1 hypermethylation and subsequent low expression levels of hMLH1 have a short overall survival period than those patients with normal expression of hMLH1 gene. hMLH1 mRNA predicts patient survival in lung cancer, and this was confirmed by using a public database. We then discussed the tumor suppressor function of hMLH1 and the clinicopathological significance of hMLH1 in NSCLC. We concluded that hMLH1 hypermethylation should be an early diagnostic marker for NSCLC and also a prognostic index for NSCLC. hMLH1 is an interesting therapeutic target in human lung cancers.

Association Between hMLH1 Promoter Methylation and Risk of Gastric Cancer: A Meta-Analysis

“…We confirmed that the frequency of hMLH1 promoter methylation in gastric cancer was 7.94-fold higher than that in control groups, meanwhile, the expression of hMLH1 protein substantially decreased in stomach cancer patients with hMLH1 hypermethylation. Our conclusion was similar to some results reported in other types of carcinomas (Mitchell et al, 2002 ; Han et al, 2016 ). hMLH1 promoter methylation often leads to transcriptional silencing accompanied by down-regulation of mRNA expression, resulting in decrease of hMLH1 protein expression and mismatch repair dysfunction which contribute to tumorigenesis.…”

UNC5A, an epigenetically silenced gene, functions as a tumor suppressor in non-small cell lung cancer

“…Increasing studies have been reported that promoter hypermethylation of tumor suppressor gene may be used as a sensitive marker for NSCLC early diagnosis, prognosis prediction, and potential therapeutic target ( Hulbert et al, 2017 , Feng et al, 2016 , Han et al, 2016 ). In our study, UNC5A is firstly demonstrated as tumor suppressor in the development of NSCLC.…”

HDAC6 regulates DNA damage response via deacetylating MLH1

“…Much attention has been focused on how germline or somatic mutations, as well as promoter methylation, modulate the MLH1 gene, leading to the accumulation of DNA replication errors (7,23). These errors eventually manifest in a high frequency of microsatellite instability (MSI-H).…”