title: Expression and mutation of SMAD4 in poorly differentiated carcinoma and signet-ring cell carcinoma of the colorectum.
abstract: Poorly differentiated adenocarcinoma (Por) and signet-ring cell carcinoma (Sig) are rare but highly malignant types of colorectal cancer. To explore their genetic backgrounds we investigated TGF-beta type II receptor (TGF-beta RII) and SMAD4 in the TGF-beta signaling pathway, and to identify their mutator phenotype we examined microsatellite instability (MSI) status. Loss of SMAD4 expression was significantly more frequent in Por (12 of 38; 31%) and Sig (4 of 5; 80%) tumors than in well (Well) and moderately differentiated (Mod) carcinomas (p = 0.04, 0.003, respectively). Mutation of the SMAD4 gene was detected in 2 of 26 Por tumors. MSI was positive in 14 of the 38 Por tumors and in 1 of the 5 Sig tumors, but in none of the Well or Mod tumors examined. We also found mutation of TGF-beta RII, a putative target of MSI, in 10 of 35 Por tumors (28.6%), but in none of 3 Sig tumors. As a whole, about 50% of the Por tumors and 80% of the Sig tumors showed abnormalities of either TGF-beta RII or SMAD4 expression. This suggests that disruption of the TGF-beta signaling pathway may play a central role in the pathogenesis of Por and Sig tumors of the colorectum.
authors.affiliation: Department of Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Seshimo
authors.forename: H
authors.initials: H
authors.lastname: Yamamoto
authors.forename: H
authors.initials: H
authors.lastname: Mishima
authors.forename: A
authors.initials: A
authors.lastname: Kurata
authors.forename: R
authors.initials: R
authors.lastname: Suzuki
authors.forename: K
authors.initials: K
authors.lastname: Ezumi
authors.forename: I
authors.initials: I
authors.lastname: Takemasa
authors.forename: M
authors.initials: M
authors.lastname: Ikeda
authors.forename: T
authors.initials: T
authors.lastname: Fukushima
authors.forename: T
authors.initials: T
authors.lastname: Tsujinaka
authors.forename: M
authors.initials: M
authors.lastname: Sekimoto
authors.forename: N
authors.initials: N
authors.lastname: Kikkawa
authors.forename: S
authors.initials: S
authors.lastname: Takenoshita
authors.forename: M
authors.initials: M
authors.lastname: Monden
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D018279:Carcinoma, Signet Ring Cell / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004273:DNA, Neoplasm; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D051901:Smad4 Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; D018125:Receptors, Transforming Growth Factor beta; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II