Baglioni Silvana, Genuardi Maurizio
Section of Medical Genetics, Dept. of Clinical Pathophysiology, University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy.
Am J Med Genet C Semin Med Genet. 2004 Aug 15;129C(1):35-43. doi: 10.1002/ajmg.c.30023.
There are several hereditary conditions associated with an increased risk of colorectal cancer (CRC). These include well-characterized autosomal dominant syndromes, such as familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). A novel autosomal recessive form of FAP, caused by mutations in the base excision repair gene MYH, has recently been recognized. This discovery has provided further evidence for the importance of DNA repair mechanisms in CRC development, already documented by the involvement of the mismatch repair in HNPCC. Additional CRC-predisposing conditions, such as hyperplastic polyposis and hereditary mixed polyposis syndrome, are being outlined. Heterogeneity of genetic mechanisms has important consequences for counseling and surveillance in hereditary CRC. Nevertheless, classical mendelian conditions represent only a minor share of the total CRC population burden. Alleles of the same genes that are involved in hereditary syndromes might also act as low penetrance variants, as shown for APC 1307K in the Ashkenazi. However, the level of complexity of multifactorial CRC is such that current tools appear inadequate to pinpoint all the involved components. A combination of different strategies, including careful clinical observation, analysis of homogeneous patient populations, and critical evaluation of data derived from experimental models, along with methodological improvements in nucleic acid analysis, will probably be necessary to unravel the basis of nonmendelian CRC. Once this is achieved, it will be possible to realize the ultimate goal of targeted CRC prevention, with the adoption of measures tailored according to individual risk levels. .
有几种遗传性疾病与结直肠癌（CRC）风险增加相关。这些包括特征明确的常染色体显性综合征，如家族性腺瘤性息肉病（FAP）和遗传性非息肉病性结直肠癌（HNPCC）。最近发现了一种由碱基切除修复基因MYH突变引起的新型常染色体隐性FAP形式。这一发现进一步证明了DNA修复机制在CRC发生中的重要性，HNPCC中错配修复的参与已证明了这一点。其他增加CRC易感性的情况，如增生性息肉病和遗传性混合息肉病综合征，也正在被概述。遗传机制的异质性对遗传性CRC的咨询和监测具有重要影响。然而，经典的孟德尔疾病仅占CRC总人群负担的一小部分。参与遗传性综合征的相同基因的等位基因也可能作为低外显率变异起作用，如在德系犹太人中所见的APC 1307K。然而，多因素CRC的复杂程度使得目前的工具似乎不足以确定所有涉及的成分。可能需要结合不同策略，包括仔细的临床观察、对同质患者群体的分析、对实验模型数据的批判性评估，以及核酸分析方法的改进，来阐明非孟德尔CRC的基础。一旦实现这一点，就有可能通过采取根据个体风险水平量身定制的措施，实现靶向CRC预防的最终目标。
