Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas
Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas
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DOI：
10.1111/j.1365-2133.2005.06353.x
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发表时间：
2005-01-01
影响因子：
10.3
通讯作者：
Reifenberger, G
中科院分区：
文献类型：
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作者：
Reifenberger, J;Wolter, M;Reifenberger, G
皮肤基底细胞癌（BCC）是最常见的人类癌症。BCC发展背后的基因改变只被部分理解。为了进一步研究散发性bcc的分子遗传学，我们对42例肿瘤中的10个皮肤癌相关基因进行了突变分析。方法采用单链构象多态性分析和DNA测序，筛选超音刺猬通路基因PTCH、SMOH、SUFUH、GLII、肿瘤抑制基因TP53、原癌基因NRAS、KRAS、HRAS、BRAF、CTNNB1突变。研究了PTCH、SUFUH和TP53位点分别位于9q22、10q24和17p13的微卫星标记的杂合性缺失（LOH）。结果42例肿瘤中有28例（67%）出现PTCH突变。微卫星分析显示38个肿瘤中有20个（53%）在9q22上存在LOH，包括14个有PTCH突变的肿瘤和6个没有PTCH突变的肿瘤。42例bcc中有4例（10%）发现了SMOH突变，而2例肿瘤显示了SUFUH突变，包括1例错义突变和1例沉默突变。所有bcc在SUFUH位点两侧的标记上均未显示LOH。17个bcc（40%）携带TP53突变，只有3个肿瘤显示双等位基因TP53失活的证据。TP53突变存在于伴有或不伴有PTCH、SMOH或SUFUH突变的bcc中。有趣的是，72%的TP53改变可能是紫外线（UV）诱导的过渡突变。相比之下，只有40%的PTCH和SMOH改变对应于紫外线特征突变。GLII、NRAS、KRAS、HRAS、BRAF或CTNNB1未发现突变。结论我们的数据证实了PTCH、SMOH和TP53突变在散发性bcc发病机制中的重要性。SUFUH的改变仅限于个别病例，而其他被研究的基因似乎不是bcc突变的重要靶点。
Background Basal cell carcinoma (BCC) of the skin is the most common human cancer. The genetic alterations underlying BCC development are only partly understood.Objectives To investigate further the molecular genetics of sporadic BCCs, we performed mutation analyses of 10 skin cancer-associated genes in 42 tumours.Methods Single-strand conformational polymorphism analysis followed by DNA sequencing was used to screen for mutations in the sonic hedgehog pathway genes PTCH, SMOH, SUFUH and GLII, in the TP53 tumour suppressor gene, and in the proto-oncogenes NRAS, KRAS, HRAS, BRAF and CTNNB1. Microsatellite markers flanking the PTCH, SUFUH and TP53 loci at 9q22, 10q24 and 17p13, respectively, were studied for loss of heterozygosity (LOH).Results PTCH mutations were found in 28 of 42 tumours (67%). Microsatellite analysis revealed LOH on 9q22 in 20 of 38 tumours investigated (53%), including 14 tumours with and six tumours without PTCH mutations. SMOH mutations were identified in four of the 42 BCCs (10%) while two tumours demonstrated mutations in SUFUH, including one missense mutation and one silent mutation. None of the BCCs showed LOH at markers flanking the SUFUH locus. Seventeen BCCs (40%) carried TP53 mutations, with only three tumours showing evidence of biallelic TP53 inactivation. TP53 mutations were present in BCCs with and without mutations in PTCH, SMOH or SUFUH. Interestingly, 72% of the TP53 alterations were presumably ultraviolet (UV)-induced transition mutations. In contrast, only 40% of the PTCH and SMOH alterations corresponded to UV signature mutations. No mutations were identified in GLII, NRAS, KRAS, HRAS, BRAF or CTNNB1.Conclusions Our data confirm the importance of PTCH, SMOH and TP53 mutations in the pathogenesis of sporadic BCCs. SUFUH alterations are restricted to individual cases while the other investigated genes do not appear to be important targets for mutations in BCCs.