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. 2008 Jul 22;99(2):375-82.
doi: 10.1038/sj.bjc.6604452. Epub 2008 Jul 1.

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

T J Seng  1 , N Currey, W A Cooper, C-S Lee, C Chan, L Horvath, R L Sutherland, C Kennedy, B McCaughan, M R J Kohonen-Corish
Affiliations

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

T J Seng et al. Br J Cancer. .

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%, RARbeta 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 RARbeta. DLEC1 methylation was an independent marker of poor survival in the whole cohort (P=0.025) and in squamous cell carcinoma (P=0.041). MLH1 methylation was also prognostic, particularly in large cell cancer (P=0.006). Concordant methylation of DLEC1/MLH1 was the strongest independent indicator of poor prognosis in the whole cohort (P=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.

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Figures

Figure 1
Figure 1
(A) Schematic drawing of the short arm of chromosome 3 and the relative location of the RARβ, MLH1, DLEC1, RASSF1A and BLU genes. (B) DLEC1 (NM_005106) and GAPDH expression using RT–PCR (two upper panels) and methylation status using MSP (two bottom panels) in lung cancer cell lines and in normal human lung tissue. (C) Restoration of DLEC1 expression and concomitant demethylation of the CpG island in H1299 cells using the 5-aza treatment.
Figure 2
Figure 2
Kaplan–Meier log-rank analysis of overall survival of NSCLC patients stratified by promoter methylation of (A) DLEC1; (B) MLH1, (C) RASSF1A, (D) RARβ, (E) BLU, (F) DLEC1/MLH1, (G) MLH1/RASSF1A and (H) DLEC1/RASSF1A (*P<0.05; **P<0.005; ***P<0.0001).
See this image and copyright information in PMC

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