Integrated analysis of genetic and epigenetic alterations reveals CpG island methylator phenotype associated with distinct clinical characters of lung adenocarcinoma
Menée initialement sur 41 échantillons tumoraux prélevés sur des patients atteints d'un adénocarcinome pulmonaire, puis sur 128 échantillons complémentaires, cette étude identifie la présence du phénotype méthylateur des îlots Cpg en association avec un pronostic défavorable
DNA methylation affects the aggressiveness of human malignancies. Cancers with CpG island methylator phenotype (CIMP), a distinct group with extensive DNA methylation, show characteristic features in several types of tumors. In this study, we initially defined the existence of CIMP in 41 lung adenocarcinomas (AdCas) through genome-wide DNA methylation microarray analysis. DNA methylation status of six CIMP markers newly identified by microarray analysis was further estimated in a total of 128 AdCas by bisulfite pyrosequencing analysis, which revealed that 10 (7.8%), 40 (31.3%), and 78 (60.9%) cases were classified as CIMP-high (CIMP-H), CIMP-low, and CIMP-negative, respectively. Notably, CIMP-H AdCas were strongly associated with wild type epidermal growth factor receptor (EGFR), males, and heavy smokers (P=0.0089, 0.0047, 0.0036, respectively). In addition, CIMP-H was significantly associated with worse prognosis; especially among male smokers, CIMP-H was an independent prognostic factor (HR 1.7617, 95%CI 1.0030-2.9550, P=0.0489). Compellingly, the existence of CIMP in AdCas was supported by the available public datasets, such as data from the Cancer Genome Atlas. Intriguingly, analysis of AdCa cell lines revealed that CIMP-positive AdCa cell lines were more sensitive to a DNA methylation inhibitor than CIMP-negative ones regardless of EGFR mutation status. Our data demonstrate that CIMP in AdCas appears to be a unique subgroup that has distinct clinical traits from other AdCas. CIMP classification using our six-marker panel has implications for personalized medical strategies for lung cancer patients; in particular, DNA methylation inhibitor might be of therapeutic benefit to patients with CIMP-positive tumors.
Carcinogenesis , résumé, 2012