Abnormalities of the APC/β-catenin pathway in endometrial cancer

Abstract

The activation of the APC/b-catenin signalling pathway due to b-catenin mutations has been implicated in the development of a subset of endometrial carcinomas (ECs). However, up to 25% of ECs have b-catenin nuclear accumulation without evidence of b-catenin mutations, suggesting alterations of other molecules that can modulate the Wnt pathway, such as APC, g-catenin, AXIN1 and AXIN2. We investigated the expression pattern of b-and g-catenin in a group of 128 endometrial carcinomas, including 95 endometrioid endometrial carcinomas (EECs) and 33 non-endometrioid endometrial carcinomas (NEECs). In addition, we evaluated the presence of loss of heterozygosity and promoter hypermethylation of the APC gene and mutations in the APC, b-and g-catenin, AXIN1, AXIN2, and RAS genes, and phospho-Akt expression. No APC mutations were detected but LOH at the APC locus was found in 24.3% of informative cases. APC promoter 1A hypermethylation was observed in 46.6% of ECs, and was associated with the endometrioid phenotype (P=0.034) and microsatellite instability (P=0.008). Neither LOH nor promoter hypermethylation of APC was associated with nuclear catenin expression. Nuclear b-catenin expression was found in 31.2% of EECs and 3% of NEECs (P=0.002), and was significantly associated with b-catenin gene exon 3 mutations (P50.0001). b-catenin gene exon 3 mutations were associated with the endometrioid phenotype, and were detected in 14 (14.9%) EECs, but in none of the NEECs (P=0.02). g-catenin nuclear expression was found in 10 ECs; it was not associated with the histological type but was associated with more advanced stages (P=0.042). No mutations in g-catenin, AXIN1 and 2 genes were detected in this series. Neither RAS mutations nor phospho-Akt expression, which were found in 16 and 27.6% of the cases, respectively, were associated with bcatenin nuclear expression. Our results demonstrated a high prevalence of alterations in molecules of the APC/ b-catenin pathway, but only mutations in b-catenin gene are associated with aberrant nuclear localization of bcatenin.

Nuclear β-Catenin Expression is Frequent in Sinonasal Hemangiopericytoma and Its Mimics

“…CTNNB1 alterations in sinonasal HPC have been consistently reported in exon 3, with missense mutations [4,5]; mutations affecting positions 32-45 of the amino-terminal region disrupt phosphorylation-dependent degradation of b-catenin [6]. Numerous other tumor types harbor CTNNB1 mutations, most frequently desmoid-type fibromatosis [7,8] as well as salivary basal cell adenoma [9], pilomatricoma and pilomatrix carcinoma [10], hepatocellular carcinoma [11], colorectal carcinoma [12], medulloblastoma [13], endometrial adenocarcinoma [14], Wilms tumor [15], and adrenocortical carcinoma [16]. Sinonasal HPC shares the features of a uniform spindle and ovoid cell population and HPC-like vessels with SFT, Fig.…”

APC promoter hypermethylation contributes to the loss of APC expression in colorectal cancers with allelic loss on 5q1

“…21 However, published studies to date have not addressed the relationship between APC hypermethylation and protein expression. APC hypermethylation might cause transcriptional repression in tumors and cell lines of various origins, including CRC, lung, breast, and esophageal cancer, 11,22,23 they had suffered allelic losses at the APC locus. We demonstrated that de novo methylation alone does not influence APC expression in CRC, as the same percentage of tumors with and without allelic loss of the APC gene expressing APC were aberrantly methylated at the APC promoter.…”

FGFR2 alterations in endometrial carcinoma

“…6 In contrast, endometrioid endometrial carcinomas show microsatellite instability, 7 and mutations in the PTEN, 8 KRAS, 9 and CTNNB-1 genes. [10][11][12] Oncogenic activation of tyrosine kinases is a common mechanism of carcinogenesis. Tyrosine kinases play a role in transduction of proliferating signals and can be good therapeutic target in several tumors.…”