A Prognostic DNA Methylation Signature for Stage I Non–Small-Cell Lung Cancer

Abstract

A B S T R A C T PurposeNon-small-cell lung cancer (NSCLC) is a tumor in which only small improvements in clinical outcome have been achieved. The issue is critical for stage I patients for whom there are no available biomarkers that indicate which high-risk patients should receive adjuvant chemotherapy. We aimed to find DNA methylation markers that could be helpful in this regard. Patients and MethodsA DNA methylation microarray that analyzes 450,000 CpG sites was used to study tumoral DNA obtained from 444 patients with NSCLC that included 237 stage I tumors. The prognostic DNA methylation markers were validated by a single-methylation pyrosequencing assay in an independent cohort of 143 patients with stage I NSCLC. ResultsUnsupervised clustering of the 10,000 most variable DNA methylation sites in the discovery cohort identified patients with high-risk stage I NSCLC who had shorter relapse-free survival (RFS; hazard ratio [HR], 2.35; 95% CI, 1.29 to 4.28; P ϭ .004). The study in the validation cohort of the significant methylated sites from the discovery cohort found that hypermethylation of five genes was significantly associated with shorter RFS in stage I NSCLC: HIST1H4F, PCDHGB6, NPBWR1, ALX1, and HOXA9. A signature based on the number of hypermethylated events distinguished patients with high-and low-risk stage I NSCLC (HR, 3.24; 95% CI, 1.61 to 6.54; P ϭ .001). ConclusionThe DNA methylation signature of NSCLC affects the outcome of stage I patients, and it can be practically determined by user-friendly polymerase chain reaction assays. The analysis of the best DNA methylation biomarkers improved prognostic accuracy beyond standard staging.

LLPi: Liverpool Lung Project Risk Prediction Model for Lung Cancer Incidence

“…Advancement in high-throughput methodologies and their application in molecular and genetic epidemiological studies have expanded the potential for "omic"-based risk prediction (41). Genome-wide association studies have identified inherited susceptibility patterns for lung cancer at different loci (42)(43)(44), and several methylation (45)(46)(47) and microRNA biomarkers (48-51) associated with lung cancer have been identified. It is anticipated that many more DNA polymorphism and biomarkers will be developed.…”

Global methylation and promoter-specific methylation of the P16, SOCS-1, E-cadherin, P73 and SHP-1 genes and their expression in patients with multiple myeloma during active disease and remission

“…Hypermethylation, which involves the enzymatic addition of a methyl group to the fifth position of the deoxycytidine residue in each affected CpG dinucleotide (6,7,9), leads to chromatin remodeling. This results in gene silencing and has been associated with cancer development through the inactivation of tumor suppressor genes (10)(11)(12)(13)(14)(15)(16). Unlike DNA sequence alterations, epigenetic modifications, such as DNA methylation, are dynamic and reversible with proven therapeutic implications (17)(18)(19).…”

936 Quantitative genome-wide methylation analysis of high-grade non-muscle invasive bladder cancer

“…In this case, methylation may hold promise as an 'at diagnosis' biomarker of long-term tumor outcome, similar to that described in colorectal, breast and lung cancers. [52][53][54] Although many of the novel genes we identified have not been previously reported in bladder cancer, their inappropriate methylation, accompanied with gene-silencing, has been reported in the context of other tumor types and suggests potential roles as tumor suppressor genes. 55,56,57 To determine associations between methylation and gene expression, we confined our studies to genes showing frequent and/or high mean levels of methylation.…”