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

Seng TJ, Currey N, Cooper WA, Lee CS, Chan C, Horvath L, Sutherland RL, Kennedy C, McCaughan B, Kohonen-Corish MR - Br. J. Cancer (2008)

Bottom Line: Any two of the gene alterations were associated with each other except RARbeta.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.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.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research Program, Garvan Institute of Medical Research, Sydney 2010, Australia.

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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Related in: MedlinePlus

(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.
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fig1: (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.

Mentions: The deleted in lung and oesophageal cancer 1 (DLEC1) gene is located about 1 Mb centromeric from MLH1 (Figure 1A). The 3p21.3 region was identified as one of the common deleted regions in lung cancer. Four candidate genes in this region were analysed but no evidence of their involvement in cancer development was found (Ishikawa et al, 1997). Further analysis led to the identification of the DLC1 gene (Daigo et al, 1999), which was later renamed DLEC1. Loss of DLEC1 expression has been observed in lung, oesophageal, renal, ovarian and nasopharyngeal carcinoma cell lines and primary tumours and functional analyses strongly suggest that DLEC1 is a tumour suppressor gene (Daigo et al, 1999; Kwong et al, 2006, 2007). Promoter hypermethylation has been shown to be responsible for silencing of DLEC1 in ovarian cancer and in nasopharyngeal carcinoma (Kwong et al, 2006, 2007) but there has been no comprehensive methylation analysis reported for lung cancer.


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

Seng TJ, Currey N, Cooper WA, Lee CS, Chan C, Horvath L, Sutherland RL, Kennedy C, McCaughan B, Kohonen-Corish MR - Br. J. Cancer (2008)

(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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2480971&req=5

fig1: (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.
Mentions: The deleted in lung and oesophageal cancer 1 (DLEC1) gene is located about 1 Mb centromeric from MLH1 (Figure 1A). The 3p21.3 region was identified as one of the common deleted regions in lung cancer. Four candidate genes in this region were analysed but no evidence of their involvement in cancer development was found (Ishikawa et al, 1997). Further analysis led to the identification of the DLC1 gene (Daigo et al, 1999), which was later renamed DLEC1. Loss of DLEC1 expression has been observed in lung, oesophageal, renal, ovarian and nasopharyngeal carcinoma cell lines and primary tumours and functional analyses strongly suggest that DLEC1 is a tumour suppressor gene (Daigo et al, 1999; Kwong et al, 2006, 2007). Promoter hypermethylation has been shown to be responsible for silencing of DLEC1 in ovarian cancer and in nasopharyngeal carcinoma (Kwong et al, 2006, 2007) but there has been no comprehensive methylation analysis reported for lung cancer.

Bottom Line: Any two of the gene alterations were associated with each other except RARbeta.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.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.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research Program, Garvan Institute of Medical Research, Sydney 2010, Australia.

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.

Show MeSH
Related in: MedlinePlus