GENETIC ALTERATIONS IN ADENOMATOUS POLYPS--DIETARY FIBER, FAT, AND BILE ACIDS

结直肠癌的分子遗传学是最好的之一 了解所有常见的人类癌症。涉及到的基因 包括癌基因在内的腺瘤-癌序列的进展 如K-ras和抑癌基因，如在大肠中缺失 癌(DCC)和P53。流行性感冒的流行病学和生化危险因素 结直肠癌已被确诊。饮食因素，尤其是 高脂肪和低纤维摄入量起着关键作用，似乎是由 通过粪便胆汁酸对大肠上皮细胞的影响。这个 分子遗传事件与流行病学和 生化风险因素尚未确定。 需要检验的假设是：(1)两者之间存在正相关 在高膳食脂肪和低膳食纤维摄入量之间，高粪便和 血中二次胆汁酸水平及其改变的频率 K-ras、DCC和P53基因在腺瘤中的表达 人口。(2)针对增加纤维摄入量的干预措施 降低粪便和血液胆汁酸水平将减少 与安慰剂相比，复发性息肉中的这些基因变化- 治疗的对照组患者。 主要的具体目标是： (1)对结直肠腺瘤进行横断面研究 腺瘤相关基因改变的频率- 癌序列(K-ras突变、DCC缺失、P53基因产物 过度表达作为突变的标记)，并确定 这些基因改变在老年人中的流行程度 息肉和膳食脂肪和纤维的摄入量指数，以及粪便和 血浆胆汁酸浓度。 (2)确定饮食干预的效果(高麦麸皮 纤维)或化学预防药物(熊去氧胆酸盐)对遗传的影响 与安慰剂治疗的对照组相比，复发性息肉的改变。 第二个具体目标是： (3)估计单项或多项指标的出现与 多基因改变和这些饮食的摄取模式 与胆汁酸生产有关的成分。

The molecular genetics of colorectal carcinoma are among the best understood of all common human cancers. The genes involved in progression through the adenoma-carcinoma sequence include oncogenes such as K-ras and suppressor genes such as Deleted In Colorectal Carcinoma (DCC) and p53. Epidemiologic and biochemical risk factors for colorectal cancer have been identified. Dietary factors, particularly high fat and low fiber intake, play a key role and appear to be mediated through the effects of fecal bile acids on colorectal epithelium. The link between the molecular genetic events and the epidemiologic and biochemical risk factors has not been characterized. The hypotheses to be tested are: (1) There is a positive association between high dietary fat and low dietary fiber intake, high fecal and blood secondary bile acid levels, and the frequency of alterations in K-ras,DCC and p53 genes in adenomas obtained from a cancer-free population. (2) Interventions directed at increasing fiber intake and lowering fecal and blood bile acid levels will reduce the frequency of these genetic alterations in recurrent polyps as compared to placebo- treated control patients. The primary specific aims are: (1) To conduct a cross-sectional study of colorectal adenomas examining the frequency of alterations in the genes involved in the adenoma- carcinoma sequence (K-ras mutations, DCC deletion, p53 gene product overexpression as a marker for mutation) and to determine the association between the prevalence of these genetic alterations in the index polyp and dietary fat and fiber intake, as well as fecal and plasma bile acid concentrations. (2) To determine the effect of a dietary intervention (high wheat bran fiber) or chemopreventive agent (ursodeoxycholate) on genetic alterations in recurrent polyps as compared to placebo-treated controls. The secondary specific aim is: (3) To estimate the associations between the occurrence of single or multiple genetic alterations and the intake patterns of those dietary components which are related to bile acid production.