RNF43 and ZNRF3 are commonly altered in serrated pathway colorectal tumorigenesis.
RNF43 and ZNRF3 are commonly altered in serrated pathway colorectal tumorigenesis.
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DOI：
10.18632/oncotarget.12130
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发表时间：
2016-10-25
期刊：
影响因子：
--
通讯作者：
Whitehall VL
中科院分区：
文献类型：
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作者：
Bond CE;McKeone DM;Kalimutho M;Bettington ML;Pearson SA;Dumenil TD;Wockner LF;Burge M;Leggett BA;Whitehall VL
锯齿状通路结直肠癌（CRC）的特征在于BRAF突变和半显示微卫星不稳定性（MSI）。Wnt通路通常通过APC突变在常规CRC中上调。相比之下，锯齿状癌不会使APC突变。我们研究了泛素连接酶RNF 43和ZNRF 3的突变作为改变锯齿状结直肠肿瘤中Wnt信号的替代机制。RNF 43在47/54（87%）BRAF突变体/MSI和8/33（24%）BRAF突变体/微卫星稳定的癌症中突变，相比之下仅3/79（4%）BRAF野生型癌症（p<0.0001）。ZNRF 3在16/54（30%）BRAF突变体/MSI和5/33（15%）BRAF突变体/微卫星稳定中突变，相比之下，0/27 BRAF野生型癌症（p=0.004）。在80%的BRAF突变/MSI癌症中发生RNF 43移码突变（X659 fs）。在第二系列的25/35（71%）BRAF突变/MSI癌症中证实了这种高比率。RNF 43和ZNRF 3在BRAF突变体中的转录表达低于BRAF野生型癌症，并且在BRAF突变体/MSI中的胞质蛋白表达低于其他亚型。用豪猪抑制剂处理使RNF 43/ZNRF 3突变体集落生长减少50%，并且与MEK抑制剂协同作用以显著减少生长。这项研究表明RNF 43和ZNRF 3的失活在锯齿状肿瘤发生中很重要，并确定了这种癌症亚型的潜在治疗策略。
Serrated pathway colorectal cancers (CRCs) are characterised by a BRAF mutation and half display microsatellite instability (MSI). The Wnt pathway is commonly upregulated in conventional CRC through APC mutation. By contrast, serrated cancers do not mutate APC. We investigated mutation of the ubiquitin ligases RNF43 and ZNRF3 as alternate mechanism of altering the Wnt signal in serrated colorectal neoplasia. RNF43 was mutated in 47/54(87%) BRAF mutant/MSI and 8/33(24%) BRAF mutant/microsatellite stable cancers compared to only 3/79(4%) BRAF wildtype cancers (p<0.0001). ZNRF3 was mutated in 16/54(30%) BRAF mutant/MSI and 5/33(15%) BRAF mutant/microsatellite stable compared to 0/27 BRAF wild type cancers (p=0.004). An RNF43 frameshift mutation (X659fs) occurred in 80% BRAF mutant/MSI cancers. This high rate was verified in a second series of 25/35(71%) BRAF mutant/MSI cancers. RNF43 and ZNRF3 had lower transcript expression in BRAF mutant compared to BRAF wildtype cancers and less cytoplasmic protein expression in BRAF mutant/MSI compared to other subtypes. Treatment with a porcupine inhibitor reduced RNF43/ZNRF3 mutant colony growth by 50% and synergised with a MEK inhibitor to dramatically reduce growth. This study suggests inactivation of RNF43 and ZNRF3 is important in serrated tumorigenesis and has identified a potential therapeutic strategy for this cancer subtype.