We have previously identified TGFBR1*6A, a common variant of the TGFBR1 gene, and shown that it transmits TGF-a growth inhibitory signals less effectively than TGFBR1. Our recent meta-analyses show that TGFBR1*6A carriers have a significantly increased risk of colon, breast and ovarian cancer as compared with non-carriers. Overall, cancer risk is increased by 19% among heterozygotes and 70% among homozygotes, a pattern indicative of an allelic dosing effect. We have also shown that TGFBR1*6A may contribute to hereditary colorectal cancer. More than one in eight healthy individuals and one in six patients with cancer is a TGFBR1*6A carrier, which establishes TGFBR1*6A as the first high-frequency low-penetrance candidate tumor susceptibility allele. In contrast, increased TGF-a circulating levels have been associated with a decreased cancer risk in animal models. A common Leucine to Proline substitution at the 10th amino acid position variant within the human TGF- a1 (TGFB1) gene results in higher in vitro extracellular TGFB1 secretion. Carriers of the TGFB1*CC genotype have higher in vivo TGFB1 circulating levels than carriers of the TGFB1*TT genotype. TGFBR1 and TGFB1 variants my have opposite or synergistic effects on colorectal cancer risk. Our central hypothesis is that a combined assessment of the two functionally-relevant TGF- a pathway signaling variants will predict colorectal cancer risk more accurately than each variant alone. The NCI-sponsored familial colorectal cancer registry is an ideal resource in which to test this hypothesis. Using a sibling-matched case-control design we will genotype a total of 4,208 full sibling case-control pairs and First: assess the association between TGFBR1*6A and colorectal cancer. Second: assess the association between TGFB1 and colorectal cancer and perform haplotype analysis of the TGFB1 gene; Third: analyze gene-gene interactions between TGFBR1 and TGFB1. This will explore the relationships between the two functional TGF-a pathway polymorphisms and colorectal risk and determine whether TGF- a signaling, as predicted by these two variants, is associated with colorectal cancer risk; and, Fourth: investigate the relationship between TGF-a pathway polymorphisms and tumor microsatellite instability. ? ? ?
| Pasche, Boris; Pennison, Michael J; Jimenez, Hugo et al. (2014) TGFBR1 and cancer susceptibility. Trans Am Clin Climatol Assoc 125:300-12 |
| Liu, Nan-nan; Xi, Yue; Callaghan, Michael U et al. (2014) SMAD4 is a potential prognostic marker in human breast carcinomas. Tumour Biol 35:641-50 |
| Pasche, Boris; Wang, Minghui; Pennison, Michael et al. (2014) Prevention and treatment of cancer with aspirin: where do we stand? Semin Oncol 41:397-401 |
| Borate, Uma; Absher, Devin; Erba, Harry P et al. (2012) Potential of whole-genome sequencing for determining risk and personalizing therapy: focus on AML. Expert Rev Anticancer Ther 12:1289-97 |
| Kaklamani, Virginia; Yi, Nengjun; Zhang, Kui et al. (2011) Polymorphisms of ADIPOQ and ADIPOR1 and prostate cancer risk. Metabolism 60:1234-43 |
| Moore-Smith, Lakisha; Pasche, Boris (2011) TGFBR1 signaling and breast cancer. J Mammary Gland Biol Neoplasia 16:89-95 |
| Yi, Nengjun; Kaklamani, Virginia G; Pasche, Boris (2011) Bayesian analysis of genetic interactions in case-control studies, with application to adiponectin genes and colorectal cancer risk. Ann Hum Genet 75:90-104 |
| Pasche, Boris (2010) Cancer genetics. Introduction. Cancer Treat Res 155:xi-xii |
| Pasche, Boris; Wisinski, Kari B; Sadim, Maureen et al. (2010) Constitutively decreased TGFBR1 allelic expression is a common finding in colorectal cancer and is associated with three TGFBR1 SNPs. J Exp Clin Cancer Res 29:57 |
| Bellam, Naresh; Pasche, Boris (2010) Tgf-beta signaling alterations and colon cancer. Cancer Treat Res 155:85-103 |
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