Three-gene test may aid earlier lung cancer detection

Methylation of three genes may help with the early diagnosis of non-small-cell lung cancer (NSCLC), research suggests.

Malcolm Brock (The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA) and co-workers found that DNA methylation of one or more of CD01, HOXA9 and TAC1 was almost universal in lung cancer samples from the USA.

While methylation of these three genes was also seen in lung cancer samples from Japan, the percentage was slightly lower, suggesting there might be a need to develop population-specific three-gene tests.

Brock and team notes, in Clinical Cancer Research, that methylation of these three genes is highly sensitive and specific and thus could play a significant role in improving the early detection of NSCLC, especially as analytic advances now allow sensitive detection of DNA methylation in plasma and sputum samples.

Using a validated experimental method of eliciting frequently methylated genes in cancer, the team initially identified 305 candidate genes that were upregulated by the hypomethylating agent decitabine in eight NSCLC cell lines.

The researchers then examined lung cancer samples taken from more than 600 patients in The Cancer Genome Atlas (TCGA) and two independent cohorts of resected NSCLC patients treated at Johns Hopkins Hospital (n=59) and Shinshu University in Matsumoto, Japan (n=30).

The list of candidate genes was narrowed down to 63, with 172 probes able to differentiate cancerous from noncancerous tissue. Further analysis identified CD01, HOXA9 and TAC1 as potential candidates for use in combination in a diagnostic test.

“The three-gene panel is 100% specific,” Brock et al report, with no methylation found for 82 healthy tissue samples. By contrast, 94.9% and 83.3% of the tumour samples from US and Japanese patients, respectively, were methylated for at least one of the three genes.

The researchers also explored whether methylation had prognostic value using TCGA samples and corresponding survival data and found a “marginal association”. However, they were unable to assess lymph node tissue for methylation which previous research has indicated to be prognostic for recurrent lung cancer.

“As might be expected, these genes without an established role in the pathogenesis of lung cancer and/or an extremely high prevalence of methylation prove to be of no prognostic value when examined individually,” the team concludes.

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