Could Leukocyte DNA Methylation Patterns Inform Treatment of Thyroid Cancer?

Extensive epigenetic non-exonic alterations, known as “global methylation,” seem to be associated with thyroid tumor histology, according to a cross-sectional analysis of samples from 42 patients published by a team of Brazilian investigators in Experimental and Molecular Pathology.

Global methylation was more common in the immune blood cells of patients with medullary thyroid carcinoma (MTC) than papillary thyroid cancer (PTC), lead author Lucieli Ceolin, PhD, and coauthors reported. All authors are from the Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, in Porto Alegre, Brazil.

“These results suggest the overall DNA methylation profile may be influenced by the histological subtype of thyroid cancer,” they concluded.

Patients with sporadic MTC also had higher levels of methylation than those with inherited medullary thyroid cancer, which is caused by inheritance of a RET gene mutation.

“There is growing evidence that leukocyte DNA methylation status is associated with cancer,” Ceolin and colleagues noted. “DNA methylation can directly interfere with the binding of transcription factors to inhibit replication.”

Previous studies have shown that hypermethylation of thyroid cancer–associated genes’ promoter regions (for example, in PTEN, P16, CDH1, RASSF1, and other loci) increases the risk of thyroid tumorigenesis.

To clarify the association between thyroid cancer histology and methylation patterns, the researchers analyzed DNA from 24 MTC, 12 PTC, and 6 control patients’ peripheral leukocytes for methylation analysis with the Imprint Methylated DNA Quantification kit (Sigma-Aldrich).

Variation in aggressivity among thyroid carcinomas with similar gene-mutation profiles has complicated molecular prognostication, leading some researchers to turn to searching for epigenetic biomarkers.

However, the authors found that global methylation levels did not predict clinical or tumor characteristics. While methylation is only one form of epigenetic alteration that can modulate gene expression, and the field is young, that is likely to be unwelcome news for those searching the epigenome for predictive and prognostic biomarkers that might clarify which thyroid tumors will remain indolent and which are likely to progress and metastasize.

Genome-wide analysis of DNA methylation is now possible, but the field is younger than genetic research. Methylome reference datasets have not been established. Such tools are needed to elucidate the roles of methylation patterns in tumorigenesis, tumor progression, and metastasis-and to better understand the epigenetic regulation of endogenous retroviral sequences in the human genome, which are sometimes activated in cancer cells.

Efforts are under way to develop therapeutic regimens combining immunotherapy and epigenetic agents that reverse DNA methylation. Combining epigenetic drugs with tyrosine kinase inhibitors might be a promising experimental strategy for treating advanced thyroid carcinomas, Ceolin et al suggested.