Abstract
Transforming growth factor beta (TGF-β) regulates many processes associated with tumor initiation and progression including proliferation, differentiation, migration, cell survival, angiogenesis, and immunosurveillance. The TGF-β signal is transduced by a membrane-bound serine-threonine kinase receptor complex including TGF-β type I and type II receptors. Germline variations in the gene for transforming growth factor beta receptor 1(TGFβR1), a G-to-A single nucleotide polymorphism within intron 7 of the TGFβR1 gene called Int7G24A, and TGFβR1*6A, a nine base pair deletion that occurs in the coding region in exon 1 of the TGFβR1 gene, have been associated with progression and/or initiation of cancers of the kidney and bladder, lung, and breast; however, the association of TGFβR1*6A and Int7G24A with colon cancer is controversial. Approximately 141,000 new cases of colorectal cancer (CRC) will be diagnosed in the US during 2012 and there will be more than 69,000 CRC related deaths. Detection of CRC at early stages is the key to survival, hence we sought to determine a possible association of TGFβR1*6A and Int7G24A with CRC risk. These two germline variants in TGFβR1 were analyzed by capillary electrophoresis in DNA extracted from FFPE archived specimens of normal tissues from 253 patients with colorectal neoplasms and 219 patients who never developed any form of cancer. We found that 46.5% of patients with CIS (stage 0), 46.7% of patients with invasive CRC (Stages I & II) and 46.7% of patients with metastatic CRC (Stages III & IV) were carriers of Int7G24A, compared to 24.7% of patients without any cancer, and this difference was highly significant (p < 0.0001). In contrast the prevalence of Int7G24A in people with benign adenomas who never developed cancer (13.3%) did not differ significantly from non-cancer controls. TGFβR1*6A, was not associated with CRC at any stage compared to non-cancer controls (p = 0.2163). Importantly, the prevalence of TGFβR1*6A in benign adenoma patients that did not develop cancer was significantly higher (33.3%) than in patients with CIS (9.3%, p = 0.02) or metastatic CRC (12.0%, p = 0.03), a finding that is consistent with recent studies of human CRC reporting that tumors with TGFβR1*6A have a lower degree of genetic instability. Neither variant was associated significantly with reduced survival; however, nearly 75% of patients with TGFβR1*6A survived compared to 50% with Int7G24A. We conclude that Int7G24A is associated with increased risk for all stages of CRC whereas TGFβR1*6A is not. These results suggest that Int7G24A may be a biomarker to aid in identification of people at a higher risk for developing CRC thereby promoting CRC detection at early stages and increased CRC survival.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1153. doi:1538-7445.AM2012-1153
- ©2012 American Association for Cancer Research
Volume 72, Issue 8 Supplement
