Clendenning M, Senter L, Hampel H, Robinson K Lagerstedt, Sun S, Buchanan D, Walsh M D, Nilbert M, Green J, Potter J, Lindblom A, de la Chapelle A
Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
J Med Genet. 2008 Jun;45(6):340-5. doi: 10.1136/jmg.2007.056150. Epub 2008 Jan 4.
When compared to the other mismatch repair genes involved in Lynch syndrome, the identification of mutations within PMS2 has been limited (<2% of all identified mutations), yet the immunohistochemical analysis of tumour samples indicates that approximately 5% of Lynch syndrome cases are caused by PMS2. This disparity is primarily due to complications in the study of this gene caused by interference from pseudogene sequences.
Using a recently developed method for detecting PMS2 specific mutations, we have screened 99 patients who are likely candidates for PMS2 mutations based on immunohistochemical analysis.
We have identified a frequently occurring frame-shift mutation (c.736_741del6ins11) in 12 ostensibly unrelated Lynch syndrome patients (20% of patients we have identified with a deleterious mutation in PMS2, n = 61). These individuals all display the rare allele (population frequency <0.05) at a single nucleotide polymorphism (SNP) in exon 11, and have been shown to possess a short common haplotype, allowing us to calculate that the mutation arose around 1625 years ago (65 generations; 95% confidence interval 22 to 120).
Ancestral analysis indicates that this mutation is enriched in individuals with British and Swedish ancestry. We estimate that there are >10 000 carriers of this mutation in the USA alone. The identification of both the mutation and the common haplotype in one Swedish control sample (n = 225), along with evidence that Lynch syndrome associated cancers are rarer than expected in the probands' families, would suggest that this is a prevalent mutation with reduced penetrance.
与林奇综合征中涉及的其他错配修复基因相比，PMS2内突变的鉴定一直很有限（在所有已鉴定的突变中<2%），然而肿瘤样本的免疫组化分析表明，约5%的林奇综合征病例是由PMS2引起的。这种差异主要是由于假基因序列的干扰导致该基因研究存在复杂性。
使用一种最近开发的检测PMS2特异性突变的方法，我们对99名基于免疫组化分析可能携带PMS2突变的患者进行了筛查。
我们在12名表面上无亲缘关系的林奇综合征患者中鉴定出一种常见的移码突变（c.736_741del6ins11）（在我们鉴定出的61名PMS2有害突变患者中占20%）。这些个体在第11外显子的一个单核苷酸多态性（SNP）处均表现出罕见等位基因（群体频率<0.05），并且已被证明拥有一个短的常见单倍型，据此我们计算出该突变大约出现在1625年前（65代；95%置信区间为22至120）。
祖先分析表明，这种突变在具有英国和瑞典血统的个体中富集。我们估计仅在美国就有超过10000名该突变的携带者。在一个瑞典对照样本（n = 225）中鉴定出该突变和常见单倍型，以及有证据表明先证者家族中与林奇综合征相关的癌症比预期的少，这表明这是一种具有降低外显率的常见突变。
