Loss of Blm enhances basal cell carcinoma and rhabdomyosarcoma tumorigenesis in Ptch1+/- mice
Loss of Blm enhances basal cell carcinoma and rhabdomyosarcoma tumorigenesis in Ptch1+/- mice
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DOI：
10.1093/carcin/bgp309
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发表时间：
2010-06-01
期刊：
影响因子：
4.7
通讯作者：
Epstein, Ervin H., Jr.
中科院分区：
文献类型：
--
作者：
Davari, Parastoo;Hebert, Jennifer L.;Epstein, Ervin H., Jr.
基底细胞癌(BCC)具有相对的基因组稳定性和相对良性的临床行为，但这两者是否存在因果关系尚不清楚。为了研究将基因组不稳定性引入小鼠BCC的效果，我们比较了电离辐射诱导ptch1(+/-)小鼠和携带突变BLM等位基因的ptch1(+/-)小鼠的肿瘤形成。我们发现ptch1(+/-)BLM(tm3Brd/tm3Brd)小鼠的BCC有更大的基因组不稳定性的趋势，并且这些小鼠比ptch1(+/-)BLM(+/tm3Brd)或ptch1(+/-)BLm(+/+)小鼠发展出更多的微观BCC。突变的BLM等位基因还显著促进横纹肌肉瘤(RMS)的形成，横纹肌肉瘤是ptch1(+/-)小鼠和ptch1(+/-)(基底细胞痣综合征)患者易患的另一种癌症。高度复发但拷贝数不同的改变与两种肿瘤类型有关，包括所有基底细胞癌的4号和10号染色体的丢失，以及80%的RMS的10号染色体的增加。11号和13号染色体的丢失，包括Trp53和ptch1基因座，在基底细胞癌中频繁发生，提示组织特异性地选择与PTCH缺陷在肿瘤发生中协同作用的基因或途径。尽管有数量上的差异，但与突变的BLM基因相关的BCC或RMS肿瘤没有显著的定性差异。
Basal cell carcinomas (BCCs) have relative genomic stability and relatively benign clinical behavior but whether these two are related causally is unknown. To investigate the effects of introducing genomic instability into murine BCCs, we have compared ionizing radiation-induced tumorigenesis in Ptch1(+/-) mice versus that in Ptch1(+/-) mice carrying mutant Blm alleles. We found that BCCs in Ptch1(+/-) Blm(tm3Brd/tm3Brd) mice had a trend toward greater genomic instability as measured by array comprehensive genomic hybridization and that these mice developed significantly more microscopic BCCs than did Ptch1(+/-) Blm(+/tm3Brd) or Ptch1(+/-) Blm(+/+) mice. The mutant Blm alleles also markedly enhanced the formation of rhabdomyosarcomas (RMSs), another cancer to which Ptch1(+/-) mice and PTCH1(+/-) (basal cell nevus syndrome) patients are susceptible. Highly recurrent but different copy number changes were associated with the two tumor types and included losses of chromosomes 4 and 10 in all BCCs and gain of chromosome 10 in 80% of RMSs. Loss of chromosome 11 and 13, including the Trp53 and Ptch1 loci, respectively, occurred frequently in BCCs, suggesting tissue-specific selection for genes or pathways that collaborate with Ptch deficiency in tumorigenesis. Despite the quantitative differences, there was no dramatic qualititative difference in the BCC or RMS tumors associated with the mutant Blm genotype.