TGF-beta pathway polymorphisms and colon cancer risk

我们之前已经发现了TGFBR1*6A，它是TGFBR1基因的一个常见变体，并表明它比TGFBR1更有效地传递转化生长因子-α生长抑制信号。我们最近的荟萃分析显示，与非携带者相比，TGFBR1*6A携带者患结肠癌、乳腺癌和卵巢癌的风险显著增加。总体而言，在杂合子中癌症风险增加了19%，在纯合子中增加了70%，这一模式表明了等位基因剂量效应。我们还发现TGFBR1*6A可能与遗传性结直肠癌有关。超过八分之一的健康人和六分之一的癌症患者是TGFBR1*6A携带者，这将TGFBR1*6A确立为第一个高频低外显率候选肿瘤易感等位基因。相反，在动物模型中，转化生长因子-α循环水平的增加与癌症风险的降低有关。人转化生长因子-A1(TGFB1)基因第10位氨基酸变异中常见的亮氨酸到脯氨酸的替代导致TGFB1在体外产生更高的细胞外分泌。TGFB1*CC基因携带者体内TGFB1循环水平高于TGFB1*TT基因携带者。TGFBR1和TGFB1变异在结直肠癌风险上可能具有相反或协同的作用。我们的中心假设是，联合评估两个功能相关的转化生长因子-α通路信号变异体将比单独评估每个变异体更准确地预测结直肠癌风险。NCI赞助的家族性结直肠癌登记是检验这一假说的理想资源。使用同胞配对的病例对照设计，我们将对总共4208对完全同胞病例对照配对进行基因分型，首先：评估TGFBR1*6A与结直肠癌之间的关联。第二：评估TGFB1与结直肠癌的相关性，并对TGFB1基因进行单倍型分析；第三：分析TGFBR1和TGFB1之间的基因-基因相互作用。这将探索两个功能性的转化生长因子-α通路基因多态性与结直肠癌风险之间的关系，并确定这两个变异体所预测的转化生长因子-α信号是否与结直肠癌风险相关；第四：研究转化生长因子-α途径多态与肿瘤微卫星不稳定性的关系。

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.