Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer

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Bruun , J , Sveen , A , Barros , R , Eide , P W , Eilertsen , I , Kolberg , M , Pellinen , T , David , L , Svindland , A , Kallioniemi , O , Guren , M G , Nesbakken , A , Almeida , R & Lothe , R A 2018 , ' Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer ' , Molecular oncology , vol. 12 , no. 9 , pp. 1639-1655 . https://doi.org/10.1002/1878-0261.12347

Title: Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer
Author: Bruun, Jarle; Sveen, Anita; Barros, Rita; Eide, Peter W.; Eilertsen, Ina; Kolberg, Matthias; Pellinen, Teijo; David, Leonor; Svindland, Aud; Kallioniemi, Olli; Guren, Marianne G.; Nesbakken, Arild; Almeida, Raquel; Lothe, Ragnhild A.
Contributor organization: Institute for Molecular Medicine Finland
University of Helsinki
Doctoral Programme in Integrative Life Science
Olli-Pekka Kallioniemi / Principal Investigator
Precision Systems Medicine
Date: 2018-09
Language: eng
Number of pages: 17
Belongs to series: Molecular oncology
ISSN: 1878-0261
DOI: https://doi.org/10.1002/1878-0261.12347
URI: http://hdl.handle.net/10138/243771
Abstract: We aimed to refine the value of CDX2 as an independent prognostic and predictive biomarker in colorectal cancer (CRC) according to disease stage and chemotherapy sensitivity in preclinical models. CDX2 expression was evaluated in 1045 stage I-IV primary CRCs by gene expression (n = 403) or immunohistochemistry (n = 642) and in relation to 5-year relapse-free survival (RFS), overall survival (OS), and chemotherapy. Pharmacogenomic associations between CDX2 expression and 69 chemotherapeutics were assessed by drug screening of 35 CRC cell lines. CDX2 expression was lost in 11.6% of cases and showed independent poor prognostic value in multivariable models. For individual stages, CDX2 was prognostic only in stage IV, independent of chemotherapy. Among stage I-III patients not treated in an adjuvant setting, CDX2 loss was associated with a particularly poor survival in the BRAF-mutated subgroup, but prognostic value was independent of microsatellite instability status and the consensus molecular subtypes. In stage III, the 5-year RFS rate was higher among patients with loss of CDX2 who received adjuvant chemotherapy than among patients who did not. The CDX2-negative cell lines were significantly more sensitive to chemotherapeutics than CDX2-positive cells, and the multidrug resistance genes MDR1 and CFTR were significantly downregulated both in CDX2-negative cells and in patient tumors. Loss of CDX2 in CRC is an adverse prognostic biomarker only in stage IV disease and appears to be associated with benefit from adjuvant chemotherapy in stage III. Early-stage patients not qualifying for chemotherapy might be reconsidered for such treatment if their tumor has loss of CDX2 and mutated BRAF.
Subject: CDX2
colorectal cancer
drug sensitivity
pharmacogenomics
predictive biomarker
prognostic biomarker
COLON-CANCER
MOLECULAR SUBTYPES
CELL-LINES
MICROSATELLITE INSTABILITY
MULTIDRUG-RESISTANCE
MISMATCH REPAIR
GASTRIC-CANCER
STAGE-II
EXPRESSION
MARKER
3122 Cancers
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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