Oncogenic mutations in extramammary Paget's disease and their clinical relevance
INTERNATIONAL JOURNAL OF CANCER
Authors: Kang, Zhihua; Xu, Feng; Zhang, Qiao-an; Wu, Zhiyuan; Zhang, Xinju; Xu, Jinhua; Luo, Yan; Guan, Ming
Abstract
Extramammary Paget's disease (EMPD) is a rare cutaneous malignant neoplasm. The genetic alterations underlying its pathogenesis have less been described. Therefore, we analyzed the possible mutations in the KRAS, HRAS, NRAS, BRAF, ARAF, RAF1, PIK3CA, AKT1, CTNNB1 and APC genes as well as methylation and expression of CDH1 in 144 EMPD cases and 42 matched normal skin tissues. A distinct mutation profile was identified in EMPDs with 27 (19%) cases mutant for RAS and RAF genes and 50 (35%) cases harboring oncogenic mutations in PIK3CA and AKT1. Moreover, a mutually exclusive pattern was observed in the genetic variants in these two signaling pathways. No mutation was detected in CTNNB1 and APC genes. High prevalence of low expression and hypermethylation of CDH1 gene was detected in 33 and 48% of the EMPD cases, respectively. Furthermore, PIK3CA and AKT1 mutations were significantly correlated with CDH1 hypermethylation which could explain why the majority of EMPD cases with mutant PIK3CA and AKT1 were invasive. Our study demonstrates that genetic variants associated with constitutive activation of RAS/RAF and PI3K/AKT pathways are involved in the pathogenesis of EMPD. This may represent novel therapeutic targets for this skin cancer.
Structural characteristics of oxalate-soluble polysaccharides of Sosnowsky's hogweed (Heracleum sosnowskyi Manden)
CARBOHYDRATE POLYMERS
Authors: Makarova, Elena N.; Shakhmatov, Evgeny G.; Belyy, Vladimir A.
Abstract
Arabinogalactan proteins (AGP) and pectic polysaccharides were isolated from above-ground parts of Heracleum sosnowskyi. The structural study has shown that a linear region of the pectic macromolecules consists of 1,4-alpha-D-galactopyranosyluronan blocks partially methyl esterified and acetylated. The branched region consists of 3-0- and partially 2-0-acetylated rhamnogalacturonan I. Side chains of the RG-I backbone include the regions of arabinogalactan I and branched 1,5-alpha-arabinan. The carbohydrate part of AGP consists of arabinogalactan II with a 1,3-beta-D-Galp main chain. The side chains of the branched area of AG-II are composed of 1,6-beta-D-Galp, 1,5-, 1,3,5-alpha-L-Araf, 4-0-Me-beta-D-GlcA and 1,4-beta-D-GlcpA, and non-reducing ends residues of beta-D-Galp, alpha-L-Araf, alpha-L-Rhap and alpha-L-Fucp. The branch points of the main and side chains are formed by 3,6-di-O-substituted beta-D-Galp. It was found that at least a portion of pectin is probably covalently linked to AGP, wherein AGP is linked to RG-I, but not with galacturonan. (C) 2016 Elsevier Ltd. All rights reserved.