Constitutively decreased TGFBR1 allelic expression is a common finding in colorectal cancer and is associated with three TGFBR1 SNPs

Journal of Experimental & Clinical Cancer Research, May 2010

Purpose Constitutively decreased TGFBR1 allelic expression is emerging as a potent modifier of colorectal cancer risk in mice and humans. This phenotype was first observed in mice, then in lymphoblastoid cell lines from patients with microsatellite stable colorectal tumors. Patients and Methods We assessed the frequency of constitutively decreased TGFBR1 allelic expression and association with SNPs covering the TGFBR1 locus using RNA and DNA extracted from the peripheral blood lymphocytes of 118 consecutive patients with biopsy-proven adenocarcinoma of the colon or the rectum. Results We found that 11(9.3%) of 118 patients exhibited decreased TGFBR1 allelic expression (TGFBR1 ASE). TGFBR1 ASE was strongly associated with three SNPs in linkage disequilibrium with each other: rs7034462 (p = 7.2 × 10-4), TGFBR1*6A (p = 1.6 × 10-4) and rs11568785 (p = 1.4 × 10-4). Conclusion These results confirm the high prevalence of constitutively decreased TGFBR1 allelic expression among patients with colorectal cancer. The association of this phenotype with TGFBR1*6A, rs7034462 and rs1156875 suggests an association between TGFBR1 SNPs and colorectal cancer, which warrants additional studies.

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Constitutively decreased TGFBR1 allelic expression is a common finding in colorectal cancer and is associated with three TGFBR1 SNPs

Journal of Experimental & Clinical Cancer Research RCesoeanrcshtitutively decreased TGFBR1 allelic expression is a common finding in colorectal cancer and is associated with three TGFBR1 SNPs Boris Pasche 0 Kari B Wisinski 2 Maureen Sadim 1 Virginia Kaklamani 1 Michael J Pennison 0 Qinghua Zeng 0 Naresh Bellam 0 Jacquelyn Zimmerman 0 Nengjun Yi 6 Kui Zhang 6 John Baron 5 Daniel O Stram 4 M Geoffrey Hayes 3 7 8 0 Division of Hematology/Oncology, The University of Alabama at Birmingham and UAB Comprehensive Cancer Center , Birmingham, AL 35203 , USA 1 Cancer Genetics Program, Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University , Chicago, IL 60611 , USA 2 Section of Hematology/Oncology, University of Wisconsin School of Medicine and Public Health , Madison, WI 53792 , USA 3 Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University , Chicago, IL , USA 4 Department of Preventive Medicine, Keck School of Medicine, University of Southern California , Los Angeles, CA 90033 , USA 5 Departments of Medicine and Community and of Community and Family Medicine , Dartmouth, Hanover, NH 03755 , USA 6 Section of Statistical Genetics, Department of Biostatistics, School of Public Health, The University of Alabama at Birmingham , Birmingham, AL 35203 , USA 7 Department of Anthropology, Northwestern University , Evanston, IL , USA 8 Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University , Chicago, IL , USA Purpose: Constitutively decreased TGFBR1 allelic expression is emerging as a potent modifier of colorectal cancer risk in mice and humans. This phenotype was first observed in mice, then in lymphoblastoid cell lines from patients with microsatellite stable colorectal tumors. Patients and Methods: We assessed the frequency of constitutively decreased TGFBR1 allelic expression and association with SNPs covering the TGFBR1 locus using RNA and DNA extracted from the peripheral blood lymphocytes of 118 consecutive patients with biopsy-proven adenocarcinoma of the colon or the rectum. Results: We found that 11(9.3%) of 118 patients exhibited decreased TGFBR1 allelic expression (TGFBR1 ASE). TGFBR1 ASE was strongly associated with three SNPs in linkage disequilibrium with each other: rs7034462 (p = 7.2 10-4), TGFBR1*6A (p = 1.6 10-4) and rs11568785 (p = 1.4 10-4). Conclusion: These results confirm the high prevalence of constitutively decreased TGFBR1 allelic expression among patients with colorectal cancer. The association of this phenotype with TGFBR1*6A, rs7034462 and rs1156875 suggests an association between TGFBR1 SNPs and colorectal cancer, which warrants additional studies. - Introduction Clues regarding important genetic targets in colorectal cancer have come from the study of two hereditary neoplastic syndromes: Familial Adenomatous Polyposis (FAP) and Lynch syndrome, formerly named hereditary non-polyposis colorectal cancer (HNPCC). Although the genetic mechanisms underlying FAP and Lynch syndrome are well-understood, they only account for approximately 0.2% and 2% of all colorectal cancers, respectively. Inherited variants of the MYH gene have been shown to cause MYH-associated polyposis and are thought to account for an additional 1% of all colorectal cancers. Germline mutations of the STK11 gene underlie the Peutz-Jeghers syndrome, and mutations of SMAD4 and BMPR1A cause juvenile polyposis. Collectively, these syndromes account for 3 to 6% of all colorectal cancers[1]. Much of the remaining familial colorectal cancers and a large proportion of sporadic cases are likely due to lowpenetrance mutations, i.e. mutations that have low frequency of association with a specific phenotype[2]. Several recent genome-wide association studies have identified ten additional low penetrance susceptibility alleles including BMP2[3], BMP4[3] and SMAD7[3,4], which all belong to the Transforming Growth Factor Beta (TGF-) superfamily of growth factors. These findings provide strong support for the notion that the TGF- signaling pathway is implicated in colorectal cancer susceptibility[5]. We have previously mapped TGFBR1 to 9q22[6], and our search for TGFBR1 tumor-specific mutations led us to the discovery of a polymorphic allele of the type I receptor, TGFBR1*6A (6A)[6]. This allele has a deletion of three alanines within a 9-alanine stretch of TGFBR1 signal sequence, which results in decreased TGFBR1mediated signaling[7,8]. The fact that a significantly higher 6A allelic frequency was found among patients with a diagnosis of cancer than among healthy controls prompted us to postulate that 6A may act functionally as a tumor susceptibility allele[6]. Over the past few years, some studies have confirmed an association between 6A and cancer, but others have failed to establish any correlation. A combined analysis of 17 case control studies that included more than 13,00 (...truncated)


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Boris Pasche, Kari B Wisinski, Maureen Sadim, Virginia Kaklamani, Michael J Pennison, Qinghua Zeng, Naresh Bellam, Jacquelyn Zimmerman, Nengjun Yi, Kui Zhang, John Baron, Daniel O Stram, M Geoffrey Hayes. Constitutively decreased TGFBR1 allelic expression is a common finding in colorectal cancer and is associated with three TGFBR1 SNPs, Journal of Experimental & Clinical Cancer Research, 2010, pp. 57, 29, DOI: 10.1186/1756-9966-29-57