Smith R G
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-8593.
Am J Med Sci. 1994 Nov;308(5):295-308. doi: 10.1097/00000441-199411000-00008.
Hereditary predisposition to colorectal cancer assumes two well-defined forms: familial adenomatous polyposis and hereditary nonpolyposis colon cancer. These tumors segregate as autosomal dominant conditions whose penetrance increases with age; cancer is expected to develop ultimately in as much as 50% of the offspring of affected individuals. These traits account for less than 1% and approximately 5% of all colorectal cancer, respectively. In addition, first-degree relatives of patients with common (sporadic) colorectal neoplasia are at increased risk of colorectal cancer. This relative risk averages approximately twofold but is significantly higher for relatives of younger patients (age at diagnosis, < 55 years). Familial adenomatous polyposis and a major subset of hereditary nonpolyposis colon cancer are due to loss-of-function germline mutations of genes located on chromosomes 5q and 2p, respectively. Both of these genes have been cloned recently. The gene affected in familial polyposis, APC, encodes a protein of unknown function that normally is found on the surface of maturing cells in the upper colonic crypts. The relevant gene in many hereditary nonpolyposis colon cancer kindreds is hMSH2. This gene encodes the human homologue of a bacterial protein MutS, which is part of a system known to repair base mismatches in newly replicated DNA. Loss of hMSH2 function may explain the strikingly erroneous replication of short DNA repeats (microsatellites) in colon tumors from patients with hereditary nonpolyposis colon cancer. Because this error-prone replication is found in approximately 13% of nonfamilial colon cancers, defective mismatch repair may contribute to the development of both hereditary and sporadic colon neoplasia. Molecular genetic assays to detect mutated alleles of these genes will facilitate presymptomatic identification of carriers in families with familial polyposis and hereditary nonpolyposis colon cancer. Current recommendations for surveillance of family members are presented in the light of the new genetic understanding of these diseases.
家族性腺瘤性息肉病和遗传性非息肉病性结肠癌。这些肿瘤作为常染色体显性疾病进行遗传，其外显率随年龄增长而增加；预计受影响个体的后代中最终有多达50%会患上癌症。这些特征分别占所有结直肠癌的比例不到1%和约5%。此外，患有常见（散发性）结直肠肿瘤患者的一级亲属患结直肠癌的风险增加。这种相对风险平均约为两倍，但对于年轻患者（诊断时年龄小于55岁）的亲属而言明显更高。家族性腺瘤性息肉病和遗传性非息肉病性结肠癌的一个主要亚组分别是由于位于5号染色体长臂和2号染色体短臂上的基因发生种系功能丧失性突变所致。这两个基因最近都已被克隆。在家族性息肉病中受影响的基因APC，编码一种功能未知的蛋白质，该蛋白质通常存在于结肠上段隐窝中成熟细胞的表面。许多遗传性非息肉病性结肠癌家族中的相关基因是hMSH2。该基因编码细菌蛋白MutS的人类同源物，MutS是已知用于修复新复制DNA中碱基错配系统的一部分。hMSH2功能丧失可能解释了遗传性非息肉病性结肠癌患者结肠肿瘤中短DNA重复序列（微卫星）的明显错误复制。由于这种易出错的复制在约13%的非家族性结肠癌中也有发现，错配修复缺陷可能在遗传性和散发性结肠肿瘤的发生中都起作用。检测这些基因的突变等位基因的分子遗传学检测将有助于在家族性腺瘤性息肉病和遗传性非息肉病性结肠癌家族中对携带者进行症状前鉴定。根据对这些疾病的新遗传学认识，给出了当前对家庭成员进行监测的建议。
