Sepp T, Yates J R, Green A J
Department of Pathology, University of Cambridge, UK.
J Med Genet. 1996 Nov;33(11):962-4. doi: 10.1136/jmg.33.11.962.
We have previously described in tuberous sclerosis (TSC) hamartomas the phenomenon of loss of heterozygosity (LOH) for DNA markers in the region of both the TSC2 gene on chromosome 16p13.3 and the TSC1 gene on 9q34. We now describe the spectrum of LOH in 51 TSC hamartomas from 34 cases of TSC. DNA was extracted from leucocytes or normal paraffin embedded tissue, and from frozen paraffin embedded hamartoma tissue from the same patient. The samples were analysed for 11 markers spanning the TSC1 locus and nine markers spanning the TSC2 locus. Twenty-one of 51 hamartomas showed LOH (41%). There was significantly more LOH on 16p13.3, with 16 hamartomas showing LOH around TSC2, and five in the vicinity of TSC1. No hamartoma showed LOH for markers around both loci. All the areas of LOH on chromosome 9 were large, but the smallest region of overlap lay between the markers D9S149 and D9S114, providing independent evidence for the localisation of the TSC1 gene. These data show that LOH is a common finding in a wide range of hamartomas, affecting the same TSC locus in different lesions from the same patient but not affecting both loci. These data support the hypothesis that both the TSC genes act as tumour suppressors and that the manifestations of TSC in patients with germline TSC mutations rise from "second hit" somatic mutations inactivating the remaining normal copy of the TSC gene.
我们之前曾描述过结节性硬化症（TSC）错构瘤中，位于16号染色体13.3区的TSC2基因和9号染色体34区的TSC1基因区域内DNA标记的杂合性缺失（LOH）现象。现在我们描述了来自34例TSC患者的51个TSC错构瘤中的LOH谱。从白细胞或正常石蜡包埋组织以及同一患者的冷冻石蜡包埋错构瘤组织中提取DNA。对跨越TSC1基因座的11个标记和跨越TSC2基因座的9个标记进行样本分析。51个错构瘤中有21个显示出LOH（41%）。16号染色体13.3区的LOH明显更多，有16个错构瘤在TSC2周围显示出LOH，5个在TSC1附近。没有错构瘤在两个基因座周围的标记处都显示出LOH。9号染色体上所有的LOH区域都很大，但最小的重叠区域位于标记D9S149和D9S114之间，为TSC1基因的定位提供了独立证据。这些数据表明，LOH在广泛的错构瘤中是一个常见发现，在同一患者的不同病变中影响相同的TSC基因座，但不会影响两个基因座。这些数据支持了以下假设：TSC两个基因均作为肿瘤抑制基因起作用，并且患有种系TSC突变的患者中TSC的表现源于使TSC基因的其余正常拷贝失活的“二次打击”体细胞突变。
