Cancer Cell Biology Group, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS)-Universitat de les Illes Balears, Mallorca, Illes Balears, Spain.
J Pathol. 2010 May;221(1):57-67. doi: 10.1002/path.2685.
Recent studies have suggested that APC loss alone may be insufficient to promote aberrant Wnt/beta-catenin signalling. Our aim was to comprehensively characterize Wnt signalling components in a set of APC-associated familial adenomatous polyposis (FAP) tumours. Sixty adenomas from six FAP patients with known pathogenic APC mutations were included. Somatic APC and KRAS mutations, beta-catenin immunostaining, and qRT-PCR of APC, MYC, AXIN2 and SFRP1 were analysed. Array-comparative genomic hybridization (aCGH) was also assessed in 26 FAP adenomas and 24 paired adenoma-carcinoma samples. A somatic APC alteration was present in 15 adenomas (LOH in 11 and four point mutations). KRAS mutations were detected in 10% of the cases. APC mRNA was overexpressed in adenomas. MYC and AXIN2 were also overexpressed, with significant intra-case heterogeneity. Increased cytoplasmic and/or nuclear beta-catenin staining was seen in 94% and 80% of the adenomas. beta-Catenin nuclear staining was strongly associated with MYC levels (p value 0.03) but not with KRAS mutations. Copy number aberrations were rare. However, the recurrent chromosome changes observed more frequently contained Wnt pathway genes (p value 0.012). Based on beta-catenin staining and Wnt pathway target genes alterations the Wnt pathway appears to be constitutively activated in all APC-FAP tumours, with alterations occurring both upstream and downstream of APC. Wnt aberrations are present at both the DNA and the RNA level. Somatic profiling of APC-FAP tumours provides new insights into the role of APC in tumourigenesis.
最近的研究表明，单独 APC 缺失可能不足以促进异常的 Wnt/β-catenin 信号传导。我们的目的是全面描述一组 APC 相关家族性腺瘤性息肉病（FAP）肿瘤中的 Wnt 信号成分。纳入了 6 名已知致病性 APC 突变的 FAP 患者的 60 个腺瘤。分析了体细胞 APC 和 KRAS 突变、β-连环蛋白免疫组化、APC、MYC、AXIN2 和 SFRP1 的 qRT-PCR。还对 26 个 FAP 腺瘤和 24 对腺瘤-癌样本进行了阵列比较基因组杂交（aCGH）评估。15 个腺瘤中存在体细胞 APC 改变（11 个 LOI 和 4 个点突变）。检测到 10%的病例存在 KRAS 突变。腺瘤中 APC mRNA 过表达。MYC 和 AXIN2 也过表达，存在显著的病例内异质性。94%和 80%的腺瘤中可见细胞质和/或核β-连环蛋白染色增加。β-连环蛋白核染色与 MYC 水平密切相关（p 值 0.03），但与 KRAS 突变无关。拷贝数异常很少见。然而，观察到的染色体改变更频繁地包含 Wnt 通路基因（p 值 0.012）。基于β-连环蛋白染色和 Wnt 通路靶基因改变，Wnt 通路在所有 APC-FAP 肿瘤中似乎持续激活，APC 上游和下游均存在改变。Wnt 异常存在于 DNA 和 RNA 水平。APC-FAP 肿瘤的体细胞分析为 APC 在肿瘤发生中的作用提供了新的见解。
