Beck N E, Tomlinson I P, Homfray T F, Frayling I M, Hodgson S V, Bodmer W F
Cancer Genetics Laboratory, Imperial Cancer Research Fund, London.
Gut. 1997 Aug;41(2):235-8. doi: 10.1136/gut.41.2.235.
The hereditary non-polyposis colorectal cancer (HNPCC) syndrome is caused by germline mutations in mismatch repair genes and predisposes individuals to cancers of the colon and other specific sites. On theoretical grounds, it is expected that patients with HNPCC also develop more colorectal adenomas than the general population. In essence, if the mutation rate is raised owing to mutations at a mismatch repair locus, more mutations are expected at loci such as APC (adenomatous polyposis coli) and more adenomas will start to grow. Not all data support this expectation, however.
To search for germline mutations at HNPCC loci in patients with multiple adenomas.
Twenty five patients (without known APC mutations) who have developed colorectal adenomas in unusually large numbers and, in some cases, at an early age.
Germline APC mutations were excluded using the protein truction test for exon 15 and mismatch chemical cleavage analysis for remaining exons. Germline HNPCC mutations were detected by using PCR and single strand conformation polymorphism analysis.
Just one germline HNPCC mutation was found (4% of cases) and this was of uncertain functional effect.
In general, germline HNPCC mutations are not responsible for the phenotype of patients with multiple colonic adenomas. It is possible that patients with HNPCC tend to develop adenomas more frequently and earlier than the general population, but that this effect is relatively subtle. These results suggest that individuals with colorectal adenomas only should not strictly be classified as "affected" in HNPCC families (although they should certainly not be classified as "unaffected" either and may warrant intensive screening). In the absence of a personal or strong family history of colorectal cancer, it is probably not worthwhile performing diagnostic or predictive genetic testing for HNPCC mutations in subjects with colorectal adenomas. Although undetected APC mutations may be responsible for some of the phenotypes in this sample, as yet uncharacterised adenoma predisposing genes probably exist.
遗传性非息肉病性结直肠癌（HNPCC）综合征由错配修复基因的种系突变引起，使个体易患结肠癌及其他特定部位的癌症。从理论上讲，预计HNPCC患者发生的结直肠腺瘤也比普通人群更多。本质上，如果由于错配修复位点的突变导致突变率升高，那么在诸如腺瘤性息肉病（APC）等位点预计会出现更多突变，并且会有更多腺瘤开始生长。然而，并非所有数据都支持这一预期。
在多发腺瘤患者中寻找HNPCC位点的种系突变。
25例（无已知APC突变）结直肠腺瘤数量异常多且在某些情况下发病年龄较早的患者。
采用第15外显子的蛋白质截短试验及对其余外显子进行错配化学切割分析来排除种系APC突变。通过聚合酶链反应（PCR）和单链构象多态性分析检测种系HNPCC突变。
仅发现1个种系HNPCC突变（占病例的4%），其功能效应尚不确定。
一般而言，种系HNPCC突变并非多发结肠腺瘤患者表型的病因。HNPCC患者可能比普通人群更频繁、更早地发生腺瘤，但这种效应相对不明显。这些结果表明，仅患有结直肠腺瘤的个体在HNPCC家族中不应被严格归类为“患病”（尽管他们当然也不应被归类为“未患病”，可能需要进行强化筛查）。在没有个人或强烈的结直肠癌家族史的情况下，对结直肠腺瘤患者进行HNPCC突变的诊断性或预测性基因检测可能不值得。尽管未检测到的APC突变可能是该样本中某些表型的病因，但可能存在尚未明确的腺瘤易感基因。
