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Study Uncovers Sites With Low Methylation in Future Lung Cancer Patients

NEW YORK (GenomeWeb) – A study appearing online today in Nature Communications suggests that lower-than-usual methylation at a handful of smoking-related genes may be linked to future lung cancer diagnoses.

An international team did array-based methylation profiling on blood samples taken prior to lung cancer diagnoses in 132 individuals from the Norwegian Women and Cancer (NOWAC) cohort, along with 132 matched control individuals. The results suggested future lung cancer development was associated with diminished methylation at several cytosine sites, including sites in AHRR and F2RL3 — genes that have been found to be hypomethylated in blood samples from smokers in the past.

The researchers subsequently replicated the association between AHRR and F2RL3 hypomethylation in more than 1,300 case or control samples from three prospective cohorts in Australia, Sweden, or Germany.

"[O]ur study shows that smoking-induced hypomethylation in the AHRR and F2RL3 genes is associated with important risk increases of subsequent lung cancer, and indicates that these specific methylation alterations may mediate the carcinogenic effect of tobacco exposure in lung cancer etiology," corresponding and co-senior author Paolo Vineis, an epidemiology researcher affiliated with the Human Genetics Foundation in Italy and Imperial College London.

Along with DNA mutations induced by cigarette smoke, the team suspected some of the epigenetic changes associated with tobacco use in the prior studies — including a dip in methylation in and around the AHRR and F2RL3 genes — might contribute to lung cancer risk.

For the discovery stage of the study, the researchers used the Illumina Infinium HM450 array to profile cytosine methylation patterns in pre-diagnosis blood samples for 132 lung cancer case-control pairs from the NOWAC cohort.

Cases in the cohort were diagnosed with lung cancer anywhere from a few months to almost eight years after being enrolled in a Norwegian registry.

The cases and controls appeared to differ in their methylation status at 11 cytosine sites. The team focused on two sites where decreased methylation showed particularly pronounced lung cancer ties: cg03636183 in an enzyme-activated receptor-coding gene called F2RL3 and cg05575921 in AHRR, a gene coding for an aryl hydrocarbon receptor repressor.

The researchers saw similar associations when they looked at cg03636183 and cg05575921 methylation status in data for three other prospective cohorts: 367 lung cancer cases from the Melbourne Collaborative Cohort Study and as many matched controls; a group of 234 case-control pairs from the Northern Sweden Health and Disease study; and 63 cases and 63 controls from the EPIC Heidelberg study.

In each of the cohorts, the association between hypomethylation and future lung cancer risk appeared to remain regardless of smoking duration, they reported, though hypomethylation in the AHRR and F2RL3 gene sites did not seem to occur in never smokers.

The team saw slightly stronger ties between lung cancer risk and decreased cg03636183 and cg05575921 methylation in former smokers than in current smokers — a result that requires further investigation to rule out confounding risk factors.

To try to tease apart the contribution that these methylation shifts might make to cancer risk beyond those associated with smoking in general, meanwhile, the researchers assessed data from the discovery set using a so-called mediation analysis.

Results from the analysis supported the notion that hypomethylation at cg03636183 and cg05575921 enhances lung cancer risk, though the study's authors cautioned that "residual confounding from tobacco smoking might still explain the association with risk."