title: 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%, 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.
authors.affiliation: Cancer Research Program, Garvan Institute of Medical Research, Sydney 2010, Australia.
authors.forename: T J
authors.initials: TJ
authors.lastname: Seng
authors.forename: N
authors.initials: N
authors.lastname: Currey
authors.forename: W A
authors.initials: WA
authors.lastname: Cooper
authors.forename: C-S
authors.initials: CS
authors.lastname: Lee
authors.forename: C
authors.initials: C
authors.lastname: Chan
authors.forename: L
authors.initials: L
authors.lastname: Horvath
authors.forename: R L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: C
authors.initials: C
authors.lastname: Kennedy
authors.forename: B
authors.initials: B
authors.lastname: McCaughan
authors.forename: M R J
authors.initials: MR
authors.lastname: Kohonen-Corish
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D002893:Chromosomes, Human, Pair 3; D003598:Cytoskeletal Proteins; D019175:DNA Methylation; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C119064:DLEC1 protein, human; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C411762:RASSF1 protein, human; D018168:Receptors, Retinoic Acid; D025521:Tumor Suppressor Proteins; C472720:ZMYND10 protein, human; C082925:retinoic acid receptor beta; D000070957:MutL Protein Homolog 1