Possible role of Cdx2 in the serrated pathway of colorectal cancer characterized by BRAF mutation, high-level CpG Island methylator phenotype and mismatch repair-deficiency

Dawson, Heather; Galván Hernández, José Alberto; Helbling, Melina; Müller, Dominique-Elisabeth; Karamitopoulou, Evanthia; Kölzer, Viktor; Economou, Mary; Hammer, Caroline; Lugli, Alessandro; Zlobec, Inti (2014). Possible role of Cdx2 in the serrated pathway of colorectal cancer characterized by BRAF mutation, high-level CpG Island methylator phenotype and mismatch repair-deficiency. International journal of cancer, 134(10), pp. 2342-2351. Wiley-Blackwell 10.1002/ijc.28564

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Colorectal cancer is a heterogeneous disease at the histomorphological, clinical and molecular level. Approximately 20% of cases may progress through the "serrated" pathway characterized by BRAF mutation and high-level CpG Island Methylator Phenotype (CIMP). A large subgroup are additionally microsatellite instable (MSI) and demonstrate significant loss of tumor suppressor Cdx2. The aim of this study is to determine the specificity of Cdx2 protein expression and CpG promoter hypermethylation for BRAF(V600E) and high-level CIMP in colorectal cancer. Cdx2, Mlh1, Msh2, Msh6, and Pms2 were analyzed by immunohistochemistry using a multi-punch tissue microarray (TMA; n = 220 patients). KRAS and BRAF(V600E) mutation analysis, CDX2 methylation and CIMP were investigated. Loss of Cdx2 was correlated with larger tumor size (P = 0.0154), right-sided location (P = 0.0014), higher tumor grade (P < 0.0001), more advanced pT (P = 0.0234) and lymphatic invasion (P = 0.0351). Specificity was 100% for mismatch repair (MMR)-deficiency (P < 0.0001), 92.2% (P < 0.0001) for BRAF(V600E) and 91.8% for CIMP-high. Combined analysis of BRAF(V600E) /CIMP identified Cdx2 loss as sensitive (80%) and specific (91.5%) for mutation/high status. These results were validated on eight well-established colorectal cancer cell lines. CDX2 methylation correlated with BRAF(V600E) (P = 0.0184) and with Cdx2 protein loss (P = 0.0028). These results seem to indicate that Cdx2 may play a role in the serrated pathway to colorectal cancer as underlined by strong relationships with BRAF(V600E) , CIMP-high and MMR-deficiency. Whether this protein can only be used as a "surrogate" marker, or is functionally involved in the progression of these tumors remains to be elucidated.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Autopsy

UniBE Contributor:

Dawson, Heather; Galván Hernández, José Alberto; Helbling, Melina; Müller, Dominique-Elisabeth; Karamitopoulou, Evanthia; Kölzer, Viktor; Economou, Mary; Hammer, Caroline; Lugli, Alessandro and Zlobec, Inti

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0020-7136

Publisher:

Wiley-Blackwell

Language:

English

Submitter:

Andrea Arnold

Date Deposited:

02 Apr 2014 13:51

Last Modified:

26 Apr 2017 02:28

Publisher DOI:

10.1002/ijc.28564

PubMed ID:

24166180

Uncontrolled Keywords:

BRAF, CIMP, Cdx2, colorectal cancer, serrated pathway

BORIS DOI:

10.7892/boris.45983

URI:

https://boris.unibe.ch/id/eprint/45983

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