Biswas Swati, Trobridge Patricia, Romero-Gallo Judith, Billheimer Dean, Myeroff Lois L, Willson James K V, Markowitz Sanford D, Grady William M
Department of Medicine, Vanderbilt University Medical School, Nashville, TN, USA.
Genes Chromosomes Cancer. 2008 Feb;47(2):95-106. doi: 10.1002/gcc.20511.
The mutational inactivation of transforming growth factor beta receptor type II (TGFBR2) occurs in approximately 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-RII 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.
约30%的结肠癌中会发生转化生长因子βII型受体（TGFBR2）的突变失活，其通过抑制TGFβ信号通路的肿瘤抑制活性来促进结肠癌的形成。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中的一个多聚腺嘌呤序列，称为BAT-RII，在DNA错配修复（MMR）系统缺陷的情况下，该序列易发生突变。鉴于在MMR失活情况下BAT-RII序列的易突变性质以及TGFBR2失活对结肠癌的有利影响，对TGFBR2失活的分析为评估基因组不稳定性与克隆选择在MSI结肠癌形成过程中获得TGFBR2 BAT-RII序列突变的细胞中的作用提供了一个机会。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得到系统研究，从而无法确定这两种机制在MSI结肠癌形成中的相对贡献。尚未证实BAT-RII序列突变是否严格是MMR缺陷情况下BAT-RII区域高突变的结果，或者这些突变是否更是针对TGFB受体的克隆选择压力的结果。通过使用特定的细胞系系统，我们表明基因组不稳定性和TGFB抗性细胞的克隆选择都导致了MSI结肠癌中TGFBR2突变的高频率发生。
