DNA methylation signature marks recurrence in early stage lung cancer

Oct 31 2013

By Sara Freeman, medwireNews Reporter

An international research team has identified a DNA methylation signature that identifies patients with stage I non-small-cell lung cancer (NSCLC) who are at high risk for relapse.

Their findings could potentially help clinicians to determine which patients with early stage lung cancer are most at risk of relapse and would therefore benefit from adjuvant chemotherapy following surgical treatment.

“[P]atients with stage I NSCLC who undergo potentially curative surgical resection are [still] at high risk of dying from recurrent disease,” they write in the Journal of Clinical Oncology.

Manel Esteller (Hospital Duran I Reynals, Barcelona, Spain) and colleagues performed a prospective study involving tumor samples from a discovery cohort of 444 patients with NSCLC, of whom 237 had stage I disease. The median age of these patients was 65 years.

They used DNA methylation to identify 10,000 promoter CpGs that showed the most variation in methylation between with the 444 primary NSCLCs and 25 histologically normal tissues. Clustering of these, divided the patients in two groups, the smallest of which was significantly more likely to have adenocarcinoma type NSCLC than squamous cell carcinoma and a shorter relapse-free survival.

Plotting these 10,000 promoter CpGs in the 237 patients with stage I disease, the researchers again distinguished a group of patients with high-risk stage I NSCLC who had a shorter relapse-free survival.

The researchers narrowed down the methylation sites to the 338 most significant, 150 of which were located in regulatory regions. They then tested the methylation value of these 150 CpG promoters in a sub-sample of 147patients with stage I NSCLC and found 42 genes common to both groups and associated with a shorter relapse-free survival in these patients.

The top 10 of these 42 single DNA methylation markers were validated in an additional cohort of 143 patients with stage I NSCLC and whittled down to five that were linked to recurrence in both groups.

The team then developed a methylation signature that divided patients into high or low risk for recurrence based on the number of methylation sites (0–1 vs ≥2). In the validation cohort, patients with two or more methylated sites were a significant three times more likely to experience recurrence than those with none or one methylated site.

“The DNA methylation markers identified herein, once they have been externally validated, could be useful for generating treatment guidelines for early-stage lung tumors,” comment Esteller et al in the Journal of Clinical Oncology.

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