title: Correlation of DLC1 gene methylation with oncogenic PIK3CA mutations in extramammary Paget's disease.
abstract: Extramammary Paget's disease is a rare cutaneous malignant neoplasm. The genetic and epigenetic mechanisms underlying its pathology remain unknown. In this study, we investigated the expression levels, and mutation and methylation status of a common tumor suppressor gene, deleted in liver cancer 1 (DLC1), and an oncogene, PIK3CA, in tumor (n=132) and normal tissues (n=20) from unrelated patients. The presence of epigenetic and genetic lesions was then correlated to the patient pathology data to determine the potential role of these genes in extramammary Paget's disease etiology and progression. The DLC1 gene was found to be downregulated in 43 (33%) tumors, as compared with immunohistochemistry results from normal tissues. Methylation-sensitive, high-resolution melting analysis indicated that the DLC1 promoter was hypermethylated in 51 (39%) extramammary Paget's disease tumors. This hypermethylation was associated with significantly decreased DLC1 levels (P=0.011), and had a strong positive correlation with advanced age (P=0.002). PIK3CA mutations were detected by direct sequencing in 32 (24%) tumors, the majority of which were invasive. Furthermore, PIK3CA mutations significantly correlated with DLC1 hypermethylation. Thus, aberrant DLC1 methylation and PIK3CA mutations may have important roles in extramammary Paget's disease pathogenesis, and may represent potential molecular targets for therapy.
authors.affiliation: Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai, The People's Republic of China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Kang
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.forename: Qiao-An
authors.initials: QA
authors.lastname: Zhang
authors.forename: Jinran
authors.initials: J
authors.lastname: Lin
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Wu
authors.forename: Xinju
authors.initials: X
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.forename: Jinhua
authors.initials: J
authors.lastname: Xu
authors.forename: Ming
authors.initials: M
authors.lastname: Guan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D058534:Class I Phosphatidylinositol 3-Kinases; D019175:DNA Methylation; D015536:Down-Regulation; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010145:Paget Disease, Extramammary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D012867:Skin / Q000033:anatomy & histology / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C112352:DLC1 protein, human; D020690:GTPase-Activating Proteins; D025521:Tumor Suppressor Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human