title: Oncogenic mutations in extramammary Paget's disease and their clinical relevance.
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.
authors: Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai 200040, People's Republic of China.
authors: Zhihua
authors: Z
authors: Kang
authors: Feng
authors: F
authors: Xu
authors: Qiao-an
authors: QA
authors: Zhang
authors: Zhiyuan
authors: Z
authors: Wu
authors: Xinju
authors: X
authors: Zhang
authors: Jinhua
authors: J
authors: Xu
authors: Yan
authors: Y
authors: Luo
authors: Ming
authors: M
authors: Guan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics; D010145:Paget Disease, Extramammary / Q000235:genetics* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D048490:raf Kinases / Q000235:genetics
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases; D016283:Proto-Oncogene Proteins p21(ras)