title: Genetic Analysis of Mismatch Repair Genes Alterations in Extramammary Paget Disease.
abstract: Extramammary Paget disease (EMPD) is a rare cutaneous malignant neoplasm. The familial occurrence of EMPD and the high risk of concomitant secondary tumors in EMPD patients have gained much attention. These findings highlight the importance of genetic alterations in the tumorigenesis of this skin cancer. Genetic tests and functional analysis of mismatch repair (MMR) genes were performed in EMPD. The results showed that 8 of 20 cases with germline MMR genes mutations and 5 of them exhibited microsatellite instability (MSI). Immunohistochemical staining showed that the tumor tissues from 20 patients had the normal expression of MLH1 but 5 cases had the reduced expression of MSH2. There is a nearly significant correlation between MSI and germline mutations. In 172 cases, rates of germline and somatic mutations were 34.3% and 13.4%, respectively. The mutations of MLH1 V384D (15.7%), R217C (4.1%), and I219V (5.2%) were common in this cancer. In addition, the yeast 2-hybrid and immunoprecipitation assays exhibited reduced interaction between MLH1 and PMS2 in MLH1 V384D and R217C but not I219V. Moreover, MLH1 V384D and R217C had impaired MMR activity compared with the wild-type and I219V mutation by an in vitro MMR assay. The germline mutations in MMR genes are involved in the pathogenesis of EMPD and partially explain the genetic abnormalities for this disease.
authors.affiliation: Departments of *Laboratory Medicine †Dermatology **Central Laboratory ††Urology, Huashan Hospital Departments of ‡Pathology ¶Laboratory Medicine ∥Microbiology, Huashan Hospital North §Department of Microbiology, Children's Hospital #Department of Laboratory Medicine, The Fifth People's Hospital of Shanghai, Shanghai Medical School, Fudan University, Shanghai, P.R. China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Kang
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.forename: Yingfeng
authors.initials: Y
authors.lastname: Zhu
authors.forename: Pan
authors.initials: P
authors.lastname: Fu
authors.forename: Qiao-An
authors.initials: QA
authors.lastname: Zhang
authors.forename: Tingting
authors.initials: T
authors.lastname: Hu
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Li
authors.forename: Qunfeng
authors.initials: Q
authors.lastname: Zhang
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Wu
authors.forename: Xinju
authors.initials: X
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.forename: Jinhua
authors.initials: J
authors.lastname: Xu
authors.forename: Zujun
authors.initials: Z
authors.lastname: Fang
authors.forename: Ming
authors.initials: M
authors.lastname: Guan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D053843:DNA Mismatch Repair / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005455:Fluorescent Antibody Technique; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1 / Q000235:genetics*; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D010145:Paget Disease, Extramammary / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics*
chemical_list: C501486:MLH1 protein, human; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein