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Expression Analysis of Aldehyde Dehydrogenase 1A1 (ALDH1A1) in Colon and Rectal Cancer in Association with Prognosis and Response to Chemotherapy

  • Healthcare Policy and Outcomes
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Abstract

Background

Aldehyde dehydrogenase 1A1 (ALDH1A1) has been described as a cancer stem cell marker and as a regulator of cellular chemoresistance. Therefore, ALDH1A1 has been suggested as potential biomarker to stratify patients into different risk categories for a “personalized” therapy approach. We have investigated the prognostic role of ALDH1A1 in primary colorectal cancer and its value in predicting response to chemotherapy in metastatic colorectal cancer.

Methods

Immunostaining against ALDH1A1 was performed on a paraffin-embedded tissue microarray including 659 primary colon cancer samples and 338 rectal cancer samples. Likewise, tissue of 44 palliatively resected colorectal liver metastases on whole-mount tissue slides was immunostained against ALDH1A1. Cytoplasmic, nuclear, and stromal expression of ALDH1A1 was assessed and merged with histopathological and clinical data.

Results

Univariate and multivariate analysis revealed that cytoplasmic and stromal expression of ALDH1A1 is not significantly associated with prognosis either in colon or in rectal cancer. Furthermore, cytoplasmic expression of ALDH1A1 does not predict response to palliative chemotherapy in patients with metastatic diseases. Intriguingly, as a novel finding, nuclear expression of ALDH1A1 was observed in a small subgroup of patients with colon cancer and rectal cancer. In colon cancer, nuclear expression was significantly associated with shortened overall survival by univariate and multivariate analysis.

Conclusions

Immunohistochemical expression analysis of ALDH1A1 in colon cancer is useful for the detection of nuclear expression in a small subpopulation of patients and is associated with shorter survival. Cytoplasmic expression fails to be of clinical relevance as prognostic or predictive marker in colorectal cancer.

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Acknowledgment

We are grateful to study participants and the interviewers who collected the data of the DACHS study. We would like to thank the following hospitals and cooperating institutions which recruited patients for this study: Chirurgische Universitätsklinik Heidelberg, Klinik am Gesundbrunnen Heilbronn, Sankt Vincentiuskrankenhaus Speyer, Sankt Josefskrankenhaus Heidelberg, Chirurgische Universitätsklinik Mannheim, Diakonissenkrankenhaus Speyer, Krankenhaus Salem Heidelberg, Kreiskrankenhaus Schwetzingen, Sankt Marien- und Sankt Annastiftkrankenhaus Ludwigshafen, Klinikum Ludwigshafen, Stadtklinik Frankenthal, Diakoniekrankenhaus Mannheim, Kreiskrankenhaus Sinsheim, Klinikum am Plattenwald Bad Friedrichshall, Kreiskrankenhaus Weinheim, Kreiskrankenhaus Eberbach, Kreiskrankenhaus Buchen, Kreiskrankenhaus Mosbach, Enddarmzentrum Mannheim, Kreiskrankenhaus Brackenheim, Cancer Registry of Rhineland-Palatinate, Mainz. We are also very grateful for the support of the pathologies in the provision of tumor samples: Institut für Pathologie, Universitätsklinik Heidelberg; Institut für Pathologie, Klinikum Heilbronn; Institut für Angewandte Pathologie, Speyer; Pathologisches Institut, Universitätsklinikum Mannheim; Institut für Pathologie, Klinikum Ludwigshafen; Institut für Pathologie, Klinikum Stuttgart; Institut für Pathologie, Klinikum Ludwigsburg. We would like to thank Ute Handte-Daub, Petra Bächer, Bettina Walter, and Barbara Schreiber for their excellent technical assistance.

Grant Support

Clinical Research Unit KFO 227 “Colorectal cancer: From primary tumor progression towards metastases” funded by the German Research foundation (DFG). The DACHS study was supported by grants from the German Research Council (Deutsche Forschungsgemeinschaft, grant numbers BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, and CH 117/1-1), and the German Federal Ministry of Education and Research (grant No. 01KH0404 and 01ER0814).

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Authors and Affiliations

  1. Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany

    Christoph Kahlert MD, Eva Gaitzsch BA (hons), Gunnar Steinert PhD, Nuh Rahbari MD, Thomas Schmidt MD, Fee Klupp MD, Moritz Koch MD, Markus Büchler MD & Juergen Weitz MD, MSc

  2. Institute of Pathology, University of Heidelberg, Heidelberg, Germany

    Carolin Mogler MD & Esther Herpel MD

  3. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany

    Michael Hoffmeister PhD, MSc, Lina Jansen PhD, MSc & Hermann Brenner MD, MPH

  4. Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany

    Axel Benner MSc

  5. Unit of Genetic Epidemiology, Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany

    Jenny Chang-Claude PhD, MHS

  6. Medical Oncology, National Center for Tumor Diseases and Hamamatsu Tissue Imaging and Analysis (TIGA) Center, Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany

    Niels Grabe MD, Bernd Lahrmann MSc & Niels Halama MD

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  1. Christoph Kahlert MD
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  2. Eva Gaitzsch BA (hons)
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  6. Michael Hoffmeister PhD, MSc
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  7. Lina Jansen PhD, MSc
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  8. Axel Benner MSc
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  9. Hermann Brenner MD, MPH
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  10. Jenny Chang-Claude PhD, MHS
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  11. Nuh Rahbari MD
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  12. Thomas Schmidt MD
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  15. Bernd Lahrmann MSc
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  16. Moritz Koch MD
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  17. Niels Halama MD
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  18. Markus Büchler MD
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  19. Juergen Weitz MD, MSc
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Corresponding author

Correspondence to Christoph Kahlert MD.

Additional information

Christoph Kahlert and Eva Gaitzsch contributed equally to this work.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 15 kb)

Supplementary material 2 (TIFF 1403 kb)

Supplementary Figure 2: Kaplan-Meier survival curves for stromal staining (TIFF 60 kb)

10434_2012_2518_MOESM4_ESM.tif

Supplementary Figure 3: Kaplan–Meier curves displaying (A) overall survival and (B) progression-free survival in colorectal liver metastases with cyptoplasmic expression of ALDH1A1. (TIFF 36 kb)

Supplementary material 5 (TIFF 232 kb)

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Kahlert, C., Gaitzsch, E., Steinert, G. et al. Expression Analysis of Aldehyde Dehydrogenase 1A1 (ALDH1A1) in Colon and Rectal Cancer in Association with Prognosis and Response to Chemotherapy. Ann Surg Oncol 19, 4193–4201 (2012). https://doi.org/10.1245/s10434-012-2518-9

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  • DOI: https://doi.org/10.1245/s10434-012-2518-9

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