PATCHED and p53 gene alterations in sporadic and hereditary basal cell cancer
PATCHED and p53 gene alterations in sporadic and hereditary basal cell cancer
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DOI：
10.1038/sj.onc.1204946
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发表时间：
2001-11-22
期刊：
影响因子：
8
通讯作者：
Pontén, F
中科院分区：
文献类型：
--
作者：
Ling, G;Ahmadian, A;Pontén, F
人们普遍认为，Hedgehog-Patch通路的中断是基底细胞癌发生的关键事件。除了修补的基因改变，p53基因突变在基底细胞癌中也很常见。我们测定了散发性和遗传性肿瘤中补丁基因和P53基因的杂合性丢失以及P53基因的序列。对70例肿瘤及癌旁皮肤标本进行了聚合酶链式反应、片段分析和DNA测序。我们在6/8例散发性基底细胞癌和17/19例遗传性肿瘤中发现了修补基因的等位基因缺失。所有散发性肿瘤和7/20遗传性肿瘤均有p53基因突变。P53基因杂合性缺失在两组中都很少见。在遗传性肿瘤中检测到的p53突变包括罕见的单核苷酸缺失和罕见的双碱基替换，而不是在散发性肿瘤中发现的典型的紫外光诱导错义突变。对单个肿瘤的仔细显微解剖发现了具有不同p53和/或补丁基因的基因联系的亚克隆，提供了对遗传事件的时间序列的洞察。Patch基因和P53基因的高频率和共存的遗传改变表明，这两个基因在基底细胞癌的发展中都是重要的。
It is widely accepted that disruption of the hedgehog-patched pathway is a key event in development of basal cell cancer. In addition to patched gene alterations, p53 gene mutations are also frequent in basal cell cancer. We determined loss of heterozygosity in the patched and p53 loci as well as sequencing the p53 gene in tumors both from sporadic and hereditary cases. A total of 70 microdissected samples from tumor and adjacent skin were subjected to PCR followed by fragment analysis and DNA sequencing. We found allelic loss in the patched locus in 6/8 sporadic basal cell cancer and 17/19 hereditary tumors. All sporadic and 7/20 hereditary tumors showed p53 gene mutations. Loss of heterozygosity in the p53 locus was rare in both groups. The p53 mutations detected in hereditary tumors included rare single nucleotide deletions and unusual double-base substitutions compared to the typical ultraviolet light induced missense mutations found in sporadic tumors. Careful microdissection of individual tumors revealed genetically linked subclones with different p53 and/or patched genotype providing an insight on time sequence of genetic events. The high frequency and co-existence of genetic alterations in the patched and p53 genes suggest that both these genes are important in the development of basal cell cancer.