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Differential Methylation of a Short CpG-Rich Sequence within Exon 1 of TCF21 Gene: A Promising Cancer Biomarker Assay

¹ Hamon Center for Therapeutic Oncology Research and Departments of ² Pathology, ³ Clinical Sciences, ⁴ Internal Medicine, and ⁵ Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas; ⁶ Pathology, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands; and ⁷ University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Narayan Shivapurkar, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390. Phone: 214-648-1456; Fax: 214-648-4940. E-mail: Narayan.Shivapurkar{at}UTSouthwestern.edu

Detection of cancer cells at early stages could potentially increase survival rates in cancer patients. Aberrant promoter hypermethylation is a major mechanism for silencing tumor suppressor genes in many kinds of human cancers. A recent report from our laboratory described the use of quantitative methylation-specific PCR assays for discriminating patients with lung cancer from those without lung cancer using lung biopsies as well as sputum samples. TCF21 is known to be essential for differentiation of epithelial cells adjacent to mesenchyme. Using restriction landmark genomic scanning, a recent study identified TCF21 as candidate tumor suppressor at 6q23-q24 that is epigenetically inactivated in lung and head and neck cancers. Using DNA sequencing technique, we narrowed down a short CpG-rich segment (eight specific CpG sites in the CpG island within exon 1) of the TCF21 gene, which was unmethylated in normal lung epithelial cells but predominantly methylated in lung cancer cell lines. We specifically targeted this short CpG-rich sequence and developed a quantitative methylation-specific PCR assay suitable for high-throughput analysis. We showed the usefulness of this assay in discriminating patients with lung cancer from those without lung cancer using biopsies and sputum samples. We further showed similar applications with multiple other malignancies. Our assay might have important implications in early detection and surveillance of multiple malignancies. (Cancer Epidemiol Biomarkers Prev 2008;17(4):995–1000)