Mutational inactivation of TGFBR2 in Microsatellite unstable colon cancer arises from the cooperation of genomic instability and the clonal outgrowth of transforming growth factor β resistant cells
Mutational inactivation of TGFBR2 in Microsatellite unstable colon cancer arises from the cooperation of genomic instability and the clonal outgrowth of transforming growth factor β resistant cells
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DOI：
10.1002/gcc.20511
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发表时间：
2008-02-01
影响因子：
3.7
通讯作者：
Grady, William M.
中科院分区：
文献类型：
--
作者：
Biswas, Swati;Trobridge, Patricia;Grady, William M.
转化生长因子β受体II型（TGFBR2）突变失活发生在约30%的结肠癌中，并通过抑制TGFB信号通路的抑瘤活性促进结肠癌的形成。TGFBR2突变发生在90%的微卫星不稳定（MSI）结肠癌中，并影响TGFBR2外显子3上的多腺嘌呤束，称为BAT-RII，在DNA错配修复（MMR）系统缺陷的情况下易发生突变。鉴于MMR失活情况下BAT-RII通道的易损性以及TGFBR2失活在结肠癌中的有利作用，TGFBR2失活分析为评估基因组不稳定性与克隆选择在获得TGFBR2 BAT-RII通道突变的细胞在MSI结肠癌形成中的作用提供了机会。基因组不稳定性和/或克隆进化对MSI结肠癌中TGBFR2突变失活的贡献尚未进行系统的研究，以确定这两种机制在MSI结肠癌形成中的相对贡献。目前还没有证明BAT-RII通道突变是否严格地是由于在MMR缺乏的情况下BAT-R11区域是超可变的，或者突变是针对TGFB受体的克隆选择压力的结果。通过使用确定的细胞系系统，我们发现基因组不稳定性和TGFB耐药细胞的克隆选择导致MSI结肠癌中TGFBR2突变的高频率。(c) 2007 Wiley-Liss, Inc。
The mutational inactivation of transforming growth factor beta receptor type II (TGFBR2) occurs in similar to 30% of colon cancers and promotes the formation of colon cancer by inhibiting the tumor suppressor activity of the TGFB signaling pathway. TGFBR2 mutations occur in >90% of microsatellite unstable (MSI) colon cancers and affect a polyadenine tract in exon 3 of TGFBR2, called BAT-RII, which is vulnerable to mutation in the setting of DNA mismatch repair (MMR) system deficiency. In light of the vulnerable nature of the BAT-RII tract in the setting of MMR inactivation and the favorable effects of TGFBR2 inactivation in colon cancer, analysis of TGFBR2 inactivation provides an opportunity to assess the roles of genomic instability vs. clonal selection in cells acquiring TGFBR2 BAT-RII tract mutations in MSI colon cancer formation. The contribution of genomic instability and/or clonal evolution to the mutational inactivation of TGBFR2 in MSI colon cancers has not been studied in a systematic way that would allow a determination of the relative contribution of these two mechanisms in the formation of MSI colon cancer. It has not been demonstrated whether the BAT-RII tract mutations are strictly a consequence of the BAT-R11 region being hypermutable in the setting of MMR deficiency or if the mutations are rather a consequence of clonal selection pressure against the TGFB receptor. Through the use of defined cell line systems, we show that both genomic instability and clonal selection of TGFB resistant cells contribute to the high frequency of TGFBR2 mutations in MSI colon cancer. (c) 2007 Wiley-Liss, Inc.