title: Loss of CDX2/CK20 expression is associated with poorly differentiated carcinoma, the CpG island methylator phenotype, and adverse prognosis in microsatellite-unstable colorectal cancer.
abstract: Several previous studies have demonstrated that the CDX2-negative (CDX2) and/or CK20-negative (CK20) phenotypes of colorectal cancers (CRCs) might be associated with high levels of microsatellite instability (MSI-H). The aim of this study was to investigate the clinicopathologic and molecular features of MSI-H CRCs with different CDX2/CK20 expression statuses. The CDX2 and CK20 expression statuses were immunohistochemically evaluated in 109 MSI-H CRC tissue samples, and the correlations of these statuses with clinicopathologic, molecular, and survival data were statistically analyzed. Of the 109 MSI-H CRCs, 15 were CDX2 (13.8%), and 19 were CK20 (17.4%). The simultaneous loss of CDX2 and CK20 expression (CDX2/CK20) was observed in 9 cases (8.3%). CDX2 loss was correlated with lymph node metastasis, poor differentiation, MLH1 loss, the mutation of BRAF, and CpG island methylator phenotype-high (CIMP-H) status. Right-sided tumor location, nodal metastasis, poor differentiation, and CIMP-H status were significant characteristics of CK20 tumors. The CDX2/CK20 phenotype was associated with older age (above 56 y), higher stage (stage III or IV), deep invasion (pT3 or pT4), lymph node metastasis (pN1 or pN2), poor differentiation (nonmedullary/non-signet ring cell type), the mutation of BRAF, and CIMP-H status among MSI-H CRCs. Patients with CDX2/CK20 tumors exhibited worse overall and disease-free survival compared with the patients with CDX2 and/or CK20 tumors (P<0.001). In the multivariate analysis for disease-free survival, the CDX2/CK20 phenotype was an independent prognostic factor for MSI-H CRC (P=0.030, hazard ratio=3.288). The CDX2/CK20 phenotype defines a distinct subgroup of MSI-H CRCs with poor differentiation, CIMP-H status, and unfavorable prognosis.
authors.affiliation: *Department of Pathology ‡Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine †Department of Pathology, SMG-SNU Boramae Medical Center, Seoul, Republic of Korea.
authors.forename: Jung Ho
authors.initials: JH
authors.lastname: Kim
authors.forename: Ye-Young
authors.initials: YY
authors.lastname: Rhee
authors.forename: Jeong Mo
authors.initials: JM
authors.lastname: Bae
authors.forename: Nam-Yun
authors.initials: NY
authors.lastname: Cho
authors.forename: Gyeong Hoon
authors.initials: GH
authors.lastname: Kang
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D000071616:CDX2 Transcription Factor; D002454:Cell Differentiation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D018398:Homeodomain Proteins / Q000032:analysis / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D053554:Keratin-20 / Q000032:analysis / Q000096:biosynthesis*; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D010641:Phenotype; D011379:Prognosis; D046888:Tissue Array Analysis; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; D053554:Keratin-20