title: Loss of CDX2 expression and microsatellite instability are prominent features of large cell minimally differentiated carcinomas of the colon.
abstract: Most large bowel cancers are moderately to well-differentiated adenocarcinomas comprised chiefly or entirely of glands lined by tall columnar cells. We have identified a subset of poorly differentiated colon carcinomas with a distinctive histopathological appearance that we term large cell minimally differentiated carcinomas (LCMDCs). These tumors likely include a group of poorly differentiated carcinomas previously described by others as medullary adenocarcinomas. To better understand the pathogenesis of these uncommon neoplasms, we compared molecular features of 15 LCMDCs to those present in 25 differentiated adenocarcinomas (DACs) of the colon. Tumors were examined for alterations commonly seen in typical colorectal carcinomas, including increased p53 and beta-catenin immunoreactivity, K-ras gene mutations, microsatellite instability, and loss of heterozygosity of markers on chromosomes 5q, 17p, and 18q. In addition, tumors were evaluated by immunohistochemistry for CDX2, a homeobox protein whose expression in normal adult tissues is restricted to intestinal and colonic epithelium. Markedly reduced or absent CDX2 expression was noted in 13 of 15 (87%) LCMDCs, whereas only 1 of the 25 (4%) DACs showed reduced CDX2 expression (P < 0.001). Nine of 15 (60%) LCMDCs had the high-frequency microsatellite instability phenotype, but only 2 of 25 (8%) DACs had the high-frequency microsatellite instability phenotype (P = 0.002). Our findings provide support for the hypothesis that the molecular pathogenesis of LCMDCs is distinct from that of most DACs. CDX2 alterations and DNA mismatch repair defects have particularly prominent roles in the development of LCMDCs.
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: T
authors.initials: T
authors.lastname: Hinoi
authors.forename: M
authors.initials: M
authors.lastname: Tani
authors.forename: P C
authors.initials: PC
authors.lastname: Lucas
authors.forename: K
authors.initials: K
authors.lastname: Caca
authors.forename: R L
authors.initials: RL
authors.lastname: Dunn
authors.forename: E
authors.initials: E
authors.lastname: Macri
authors.forename: M
authors.initials: M
authors.lastname: Loda
authors.forename: H D
authors.initials: HD
authors.lastname: Appelman
authors.forename: K R
authors.initials: KR
authors.lastname: Cho
authors.forename: E R
authors.initials: ER
authors.lastname: Fearon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000071616:CDX2 Transcription Factor; D018287:Carcinoma, Large Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D003598:Cytoskeletal Proteins / Q000032:analysis; D004268:DNA-Binding Proteins; D005260:Female; D011905:Genes, ras / Q000235:genetics; D018398:Homeodomain Proteins / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009154:Mutation; D009363:Neoplasm Proteins / Q000032:analysis; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000032:analysis; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D051176:beta Catenin
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071616:CDX2 Transcription Factor; C495270:CTNNB1 protein, human; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein