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Infrequent Detection of Germline Allele-Specific Expression of TGFBR1 in Lymphoblasts and Tissues of Colon Cancer Patients

¹ Department of Medicine, Ireland Cancer Center, ² Howard Hughes Medical Institute, ³ Department of Genetics and Center for Human Genetics, ⁴ Department of Epidemiology and Biostatistics, and ⁵ Department of Pathology, Case Western Reserve University and Case Medical Center, Cleveland, Ohio; and ⁶ Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio

Requests for reprints: Sanford D. Markowitz, Howard Hughes Medical Institute Laboratory, 2103 Cornell Road, Wolstein Research Building, 3rd Floor, Mailstop 7285, Case Western Reserve University, Cleveland, OH 44106. Phone: 216-368-1976; Fax: 216-368-8928; E-mail: sxm10{at}cwru.edu.

Key Words: TGFβ • pyrosequence • colon cancer • allele

Recently, germline allele-specific expression (ASE) of the gene encoding for transforming growth factor-β type I receptor (TGFBR1) has been proposed to be a major risk factor for cancer predisposition in the colon. Germline ASE results in a lowered expression of one of the TGFBR1 alleles (>1.5-fold), and was shown to occur in 20% of informative familial and sporadic colorectal cancer (CRC) cases. In the present study, using the highly quantitative pyrosequencing technique, we estimated the frequency of ASE in TGFBR1 in a cohort of affected individuals from familial clusters of advanced colon neoplasias (cancers and adenomas with high-grade dysplasia), and also from a cohort of individuals with sporadic CRCs. Cases were considered positive for the presence of ASE if demonstrating an allelic expression ratio <0.67 or >1.5. Using RNA derived from lymphoblastoid cell lines, we find that of 46 informative Caucasian advanced colon neoplasia cases with a family history, only 2 individuals display a modest ASE, with allelic ratios of 1.65 and 1.73, respectively. Given that ASE of TGFBR1, if present, would likely be more pronounced in the colon compared with other tissues, we additionally determined the allele ratios of TGFBR1 in the RNA derived from normal-appearing colonic mucosa of sporadic CRC cases. We, however, found no evidence of ASE in any of 44 informative sporadic cases analyzed. Taken together, we find that germline ASE of TGFBR1, as assayed in lymphoblastoid and colon epithelial cells of colon cancer patients, is a relatively rare event. [Cancer Res 2009;69(12):4959–61]