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

Jarle Bruun, Anita Sveen, Rita Barros, Peter W. Eide, Ina Eilertsen, Matthias Kolberg, Teijo Pellinen, Leonor David, Aud Svindland, Olli Kallioniemi, Marianne G. Guren, Arild Nesbakken, Raquel Almeida, Ragnhild A. Lothe

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1639-1655
Number of pages17
JournalMolecular oncology
Volume12
Issue number9
DOIs
StatePublished - Sep 2018

Fingerprint

Pharmacogenetics
Colorectal Neoplasms
Drug Therapy
Adjuvant Chemotherapy
Survival
Biomarkers
MDR Genes
Recurrence
Cell Line
Microsatellite Instability
Preclinical Drug Evaluations
Neoplasms
Down-Regulation
Survival Rate
Immunohistochemistry
Gene Expression

Keywords

  • CDX2
  • colorectal cancer
  • drug sensitivity
  • pharmacogenomics
  • predictive biomarker
  • prognostic biomarker

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Oncology
  • Cancer Research

Cite this

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

In: Molecular oncology, Vol. 12, No. 9, 09.2018, p. 1639-1655.

Research output: Contribution to journalArticle

Bruun, J, Sveen, A, Barros, R, Eide, PW, Eilertsen, I, Kolberg, M, Pellinen, T, David, L, Svindland, A, Kallioniemi, O, Guren, MG, Nesbakken, A, Almeida, R & Lothe, RA 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
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. / Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer. In: Molecular oncology. 2018 ; Vol. 12, No. 9. pp. 1639-1655.
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AU - Eilertsen, Ina

AU - Kolberg, Matthias

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AU - Kallioniemi, Olli

AU - Guren, Marianne G.

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