title: Multiple epithelial and nonepithelial tumors in hereditary nonpolyposis colorectal cancer: characterization of germline and somatic mutations of the MSH2 gene and heterogeneity of replication error phenotypes.
abstract: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal inherited cancer syndrome characterized by germline plus somatic mutations of DNA mismatch repair genes and familial clustering of cancers of colorectum and other visceral organs. So far, to our knowledge, there has been no proof of nonepithelial tumors in association with HNPCC. Here we report on a MSH2 frameshift HNPCC family with a carrier found to have multiple primary tumors, including endometrial hyperplasia, ovarian adenocarcinoma, skin cavernous hemangioma, and skin dermatofibrosarcoma protuberans (DFSP). We studied the replication error (RER) phenotype in noncoding (Bat-26, Bat-25, D2S123, D5S346, and D17S250) and coding (MSH3, MSH6, BAX, and TGFBR2 genes) DNA sequences, and characterized the germline and somatic mutations of the MSH2 gene in the tumors described above and in endometrial carcinomas from two of her affected siblings. RER was observed in an order of hyperplasic endometrium (6/10 markers), ovarian carcinoma (5/10 markers), endometrial carcinomas (4/9 and 3/10), DFSP (2/9 markers), and cavernous hemangioma (2/10 markers). All the tumors showed the same germline mutation of G5-->G6 frameshift at 183-187 and polymorphism of C1168T in a heterozygous pattern. In an endometrial carcinoma, deletion of the second allele of MSH2 was evident. Heterogeneous RER patterns were noted in multiple primary tumors of the same individual and in premalignant and malignant endometrial tumors from different individuals. The study demonstrated the two hits of the hMSH(2) gene as well as intra- and interindividual variations of RER phenotypes in HNPCC. The first characterized nonepithelial tumors in HNPCC seem to carry a limited panel of RER, including a framesift at the (A)(10) tract of TGFBR2.
authors.affiliation: Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, 325, section 2, Chengong Road, Taipei 114, Taiwan, Republic of China.
authors.forename: Rui-Len
authors.initials: RL
authors.lastname: Huang
authors.forename: Chung-Faye
authors.initials: CF
authors.lastname: Chao
authors.forename: Dah-Ching
authors.initials: DC
authors.lastname: Ding
authors.forename: Cheng-Ping
authors.initials: CP
authors.lastname: Yu
authors.forename: Cheng-Chang
authors.initials: CC
authors.lastname: Chang
authors.forename: Hung-Chen
authors.initials: HC
authors.lastname: Lai
authors.forename: Mu-Hsien
authors.initials: MH
authors.lastname: Yu
authors.forename: Hang-Seng
authors.initials: HS
authors.lastname: Liu
authors.forename: Tang-Yuan
authors.initials: TY
authors.lastname: Chu
mesh_terms: D000328:Adult; D020137:Base Pair Mismatch; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000473:pathology*; D004261:DNA Replication / Q000235:genetics*; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology; D008297:Male; D051718:MutS Homolog 2 Protein; D009154:Mutation / Q000235:genetics*; D016609:Neoplasms, Second Primary / Q000235:genetics; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein