The role of APC in WNT pathway activation in serrated neoplasia
The role of APC in WNT pathway activation in serrated neoplasia
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DOI：
10.1038/modpathol.2017.150
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发表时间：
2018-03-01
期刊：
影响因子：
7.5
通讯作者：
Whitehall, Vicki
中科院分区：
文献类型：
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作者：
Borowsky, Jennifer;Dumenil, Troy;Whitehall, Vicki
传统腺瘤是由激活WNT信号的APC基因突变引发的。锯齿状肿瘤通常由BRAF或KRAS突变引起。WNT通路激活也可能发生，然而，这在多大程度上是由于APC突变尚不清楚。我们检测了异常核β -连环蛋白免疫定位作为WNT通路激活的替代物，并分析了锯齿状和常规途径息肉和癌症中APC基因的整个编码序列。在90%和89%的常规腺瘤和82%和70%的BRAF野生型癌症中，WNT通路激活是常规通路病变中β -连环蛋白异常核免疫定位和APC突变截断的常见事件。在锯齿状通路病变中，WNT通路的激活程度较小。它发生在锯齿状息肉向发育不良过渡时，从无柄锯齿状腺瘤（10%）到无柄锯齿状腺瘤伴发育不良（55%），从传统锯齿状腺瘤（9%）到传统锯齿状腺瘤伴发育不良（39%），细胞核β -catenin标记显著增加（P = 0.0001）。然而，与传统途径不同的是，截断APC突变在锯齿状通路病变中很少见，尤其是无柄锯齿状腺瘤，即使发育不良（15%），以及在BRAF突变癌症中引起的微卫星不稳定性（8%）。相比之下，APC错义突变在传统途径腺瘤和癌症中罕见（BRAF野生型癌症中为3%），在具有微卫星不稳定性的BRAF突变型癌症中更为常见（32%）。我们得出结论，WNT信号的增加在锯齿状通路向恶性肿瘤的转变中是重要的，但APC突变不太常见，突变谱与传统的结直肠癌发生不同。与传统腺瘤中常见的截断型APC突变相比，中等影响型APC突变和WNT信号增加的非APC相关原因可能在锯齿状瘤中发挥更重要的作用。
Conventional adenomas are initiated by APC gene mutation that activates the WNT signal. Serrated neoplasia is commonly initiated by BRAF or KRAS mutation. WNT pathway activation may also occur, however, to what extent this is owing to APC mutation is unknown. We examined aberrant nuclear beta-catenin immunolocalization as a surrogate for WNT pathway activation and analyzed the entire APC gene coding sequence in serrated and conventional pathway polyps and cancers. WNT pathway activation was a common event in conventional pathway lesions with aberrant nuclear immunolocalization of beta-catenin and truncating APC mutations in 90% and 89% of conventional adenomas and 82% and 70% of BRAF wild-type cancers, respectively. WNT pathway activation was seen to a lesser extent in serrated pathway lesions. It occurred at the transition to dysplasia in serrated polyps with a significant increase in nuclear beta-catenin labeling from sessile serrated adenomas (10%) to sessile serrated adenomas with dysplasia (55%) and traditional serrated adenomas (9%) to traditional serrated adenomas with dysplasia (39%) (P = 0.0001). However, unlike the conventional pathway, truncating APC mutations were rare in the serrated pathway lesions especially sessile serrated adenomas even when dysplastic (15%) and in the BRAF mutant cancers with microsatellite instability that arise from them (8%). In contrast, APC missense mutations that were rare in conventional pathway adenomas and cancers (3% in BRAF wild-type cancers) were more frequent in BRAF mutant cancers with microsatellite instability (32%). We conclude that increased WNT signaling is important in the transition to malignancy in the serrated pathway but that APC mutation is less common and the spectrum of mutations is different than in conventional colorectal carcinogenesis. Moderate impact APC mutations and non-APC-related causes of increased WNT signaling may have a more important role in serrated neoplasia than the truncating APC mutations common in conventional adenomas.