Loss of CDX2 expression and microsatellite instability are prominent features of large cell minimally differentiated carcinomas of the colon.

TitleLoss of CDX2 expression and microsatellite instability are prominent features of large cell minimally differentiated carcinomas of the colon.
Publication TypeJournal Article
Year of Publication2001
AuthorsHinoi T, Tani M, Lucas PC, Caca K, Dunn RL, Macrì E, Loda M, Appelman HD, Cho KR, Fearon ER
JournalAm J Pathol
Volume159
Issue6
Pagination2239-48
Date Published2001 Dec
ISSN0002-9440
KeywordsAdaptor Proteins, Signal Transducing, Adenocarcinoma, Adult, Aged, Aged, 80 and over, beta Catenin, Carcinoma, Large Cell, Carrier Proteins, CDX2 Transcription Factor, Chromosomes, Human, Pair 17, Chromosomes, Human, Pair 18, Chromosomes, Human, Pair 5, Colonic Neoplasms, Cytoskeletal Proteins, DNA-Binding Proteins, Female, Genes, ras, Homeodomain Proteins, Humans, Immunohistochemistry, Loss of Heterozygosity, Male, Microsatellite Repeats, Middle Aged, Mutation, MutL Protein Homolog 1, MutS Homolog 2 Protein, Neoplasm Proteins, Nuclear Proteins, Proto-Oncogene Proteins, Trans-Activators, Tumor Suppressor Protein p53
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.

DOI10.1016/S0002-9440(10)63074-X
Alternate JournalAm J Pathol
PubMed ID11733373
PubMed Central IDPMC1850596
Grant ListR01 CA082223 / CA / NCI NIH HHS / United States
R01CA82223 / CA / NCI NIH HHS / United States
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