DLEC1 and MLH1 promoter methylation are associated with poor prognosis in non-small cell lung carcinoma

Abstract

The significance of chromosome 3p gene alterations in lung cancer is poorly understood. This study set out to investigate promoter methylation in the deleted in lung and oesophageal cancer 1 (DLEC1), MLH1 and other 3p genes in 239 non-small cell lung carcinomas (NSCLC). DLEC1 was methylated in 38.7%, MLH1 in 35.7%, RARb in 51.7%, RASSF1A in 32.4% and BLU in 35.3% of tumours. Any two of the gene alterations were associated with each other except RARb. DLEC1 methylation was an independent marker of poor survival in the whole cohort (P ¼ 0.025) and in squamous cell carcinoma (P ¼ 0.041). MLH1 methylation was also prognostic, particularly in large cell cancer (P ¼ 0.006). Concordant methylation of DLEC1/MLH1 was the strongest independent indicator of poor prognosis in the whole cohort (P ¼ 0.009). However, microsatellite instability and loss of MLH1 expression was rare, suggesting that MLH1 promoter methylation does not usually lead to gene silencing in lung cancer. This is the first study describing the prognostic value of DLEC1 and MLH1 methylation in NSCLC. The concordant methylation is possibly a consequence of a long-range epigenetic effect in this region of chromosome 3p, which has recently been described in other cancers.

Methylation of Twelve CpGs in Human Papillomavirus Type 16 (HPV16) as an Informative Biomarker for the Triage of Women Positive for HPV16 Infection

“…The prognostic potential of our HPV16 methylation biomarker is consistent with what has been reported for certain host gene DNA methylation differences between pre/cancer cells and normal cells at other body sites (e.g., refs. [46][47][48][49].…”

Genetic and epigenetic changes in lung carcinoma and their clinical implications

“…Hypermethylation of RASSF1A, PTEN, DAPK, p16, Wif-1, CXCL12, DLEC1, MLH1, H-cadherin, APC, RUNX3, H-cadherin, SPARC, and DAL-1 was significantly associated with poor prognosis in patients with surgically resected lung adenocarcinomas/ squamous cell carcinomas. 101,106,[108][109][110][111][112][113] In addition, methylation of 14-3-3 sigma in pretreatment serum DNA was found to be an independent prognostic factor for survival in patients with lung adenocarcinoma, squamous cell carcinoma, and large cell carcinoma who were treated with platinum-based chemotherapy. 114 Previous researchers have reported that methylation, in addition to occurring in tumor tissues, can also be detected in blood samples or in exfoliated material of the aero-digestive tract epithelium from lung cancer patients, such as the methylation of RASSF1A, 115,116 p16, H-cadherin, 117 MAGE A1, and MAGE B2.…”

Methylation of the 3p22 region encompassing MLH1 is representative of the CpG island methylator phenotype in colorectal cancer

“…in various types of human cancers, 14,[19][20][21][22][23] suggesting that their loss of activity has a contributory role in cancer development or progression. Long-range epigenetic silencing across the 3p22 region was strongly associated with the presence of the activating BRAF V600E mutation, consistent with previous findings for MLH1 alone.…”