Burt R W
Department of Medicine, University of Utah Health Sciences Center, Salt Lake City 84132, USA.
J Cell Biochem Suppl. 1996;25:131-5.
Colon cancer provides an attractive setting for chemoprevention trials because of the frequency and variation of familial predisposition that is observed in this malignancy. Additionally, the adenomatous polyp, the precursor of colon cancer, is a valuable intermediate marker for judging the effectiveness of candidate chemopreventive agents. Inherited colon cancer susceptibility varies from mild to severe. Conditions with extreme susceptibility include the autosomal dominantly inherited syndromes of familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). These are highly penetrant syndromes with extreme cancer risk. FAP arises from mutations of the APC gene and HNPCC from mutations of the mismatch repair genes. Specific and individual genetic diagnosis is now possible in both syndromes, thus allowing identification of genetically affected individuals for chemoprevention trials. FAP accounts for less than 1% of colon cancers, while HNPCC may be present in up to 5% of cases. Familial clustering is common in the remainder of cases, which are often referred to as sporadic, but probably arise in part from inherited susceptibility. Epidemiologic studies have shown that first-degree relatives have a two- to four-fold increased risk of acquiring colon cancer compared to the general population. Ten percent of individuals in the U.S. have a first-degree with colon cancer. This clinically identifiable higher risk group thus constitutes a large potential cohort for chemoprevention trials. The common familial cases of colon cancer can be further stratified by severity. A relative diagnosed under the age of 50 or two first-degree relatives affected with colon cancer confers an even greater risk for this malignancy, estimated to be four to six times that of the general population. Adenomatous polyps also precede the development of colon cancer in these categories, thereby providing a readily identifiable clinical endpoint to judge the effectiveness of chemoprevention. It is expected that genetic markers will soon be available for more precise identification of common colon cancer susceptibility. Candidate markers include mild mutations of the APC and mismatch repair genes, glutathione transferase isoenzymes, acetylator status, and phospholipase A2 expression. Bile acid concentrations of the bowel may be genetically and/or environmentally determined and likely have a role in colon cancer susceptibility. We recently identified a large kindred with polyp and cancer susceptibility arising from a mild mutation of the APC gene. There are over 4,000 kindred members and mutational testing has demonstrated 140 gene carriers to date. We expect to institute chemoprevention trials in this kindred using adenomatous polyp number as an endpoint of effectiveness.
由于在这种恶性肿瘤中观察到家族易感性的频率和变异性，结肠癌为化学预防试验提供了一个有吸引力的环境。此外，腺瘤性息肉作为结肠癌的前体，是判断候选化学预防剂有效性的一个有价值的中间标志物。遗传性结肠癌易感性从轻度到重度不等。易感性极高的情况包括常染色体显性遗传的家族性腺瘤性息肉病（FAP）综合征和遗传性非息肉病性结直肠癌（HNPCC）。这些是具有极高癌症风险的高外显率综合征。FAP由APC基因突变引起，HNPCC由错配修复基因突变引起。现在在这两种综合征中都可以进行特异性的个体基因诊断，从而能够识别出基因受影响的个体用于化学预防试验。FAP占结肠癌病例的比例不到1%，而HNPCC可能存在于高达5%的病例中。家族聚集在其余病例中很常见，这些病例通常被称为散发性的，但可能部分源于遗传易感性。流行病学研究表明，一级亲属患结肠癌的风险比一般人群增加两到四倍。在美国，10%的人有患结肠癌的一级亲属。因此，这个临床上可识别的高风险群体构成了化学预防试验的一个巨大潜在队列。常见的家族性结肠癌病例可以根据严重程度进一步分层。一名在50岁以下被诊断出患结肠癌的亲属或两名患结肠癌的一级亲属会使患这种恶性肿瘤的风险更大，估计是一般人群的四到六倍。在这些类型的病例中，腺瘤性息肉也先于结肠癌出现，从而提供了一个易于识别的临床终点来判断化学预防的有效性。预计很快将有基因标志物可用于更精确地识别常见的结肠癌易感性。候选标志物包括APC和错配修复基因的轻度突变、谷胱甘肽转移酶同工酶、乙酰化状态以及磷脂酶A2表达。肠道中的胆汁酸浓度可能由基因和/或环境决定，并且可能在结肠癌易感性中起作用。我们最近发现了一个因APC基因轻度突变而具有息肉和癌症易感性的大家族。有超过4000名家族成员，到目前为止，突变检测已证实有140名基因携带者。我们预计在这个家族中开展化学预防试验，将腺瘤性息肉数量作为有效性的一个终点指标。
