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Tumor response is predicted by patient genetic profile in rectal cancer patients treated with neo-adjuvant chemo-radiotherapy

The Pharmacogenomics Journal volume 11, pages 214–226 (2011)Cite this article

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Abstract

The aim of the study was the identification of a pharmacogenetic profile predictive of the tumor regression grade (TRG), considered as tumor response parameter, after neo-adjuvant treatment in rectal cancer patients. A total of 238 rectal cancer patients treated in a neo-adjuvant setting by a fluoropyrimidines-based chemo-radiotherapy (RT) were genotyped for 25 genetic polymorphisms in 16 genes relevant for treatment-associated pathways. Two polymorphisms were associated with TRG in a multivariate analysis: hOGG1-1245C>G, which can affect radiosensitivity and MTHFR-677C>T, which is involved in fluoropyrimidines action. Patients bearing at least one variant allele had a lower chance to get TRG⩽2 (OR=0.46 95% CI 0.23–0.90, P=0.024; and OR=0.48 95% CI 0.24–0.96, P=0.034; respectively). An association trend was observed for ABCB1-3435C>T, which is responsible for the multi-drug resistance (odds ratio (OR)=1.96, 95% confidence interval (CI) 0.98–3.95, P=0.057). Exploratory classification and regression tree (CART) analysis highlighted high-order gene–gene and gene–environment interactions and a genetic signature associated with differential response, with hOGG1-1245C>G as the most predictive factor. Other significant variables were: ABCB1-3435C>T, MTHFR-677C>T, ERCC1-8092C>A, ABCC2-1249G>A, XRCC1-28152G>A, XRCC3-4541A>G and patients gender. On the basis of CART results, patients were categorized into three groups according to tumor response probability: intermediate and high profiles had a higher probability to get TRG⩽2 as compared with low profiles (OR=4.12 95% CI 1.46–11.65, P<0.001 and OR=12.44, 95% CI 5.52–28.04, P<0.0001, respectively). This study evidences a major role of hOGG1-1245C>G and MTHFR-677C>T polymorphisms in the tumor response of rectal cancer patients treated with chemo-RT in neo-adjuvant setting, and shows the relevance of gene–gene and gene–environment interactions for complex phenotypes as tumor response.

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Acknowledgements

This study was supported by the Italian Ministry of Health grant (Programma speciale ex. art.12, 2005 and Ricerca Finalizzata RO Strategici 11/07) and AIRC (Associazione Italiana per la Ricerca sul Cancro). Samples were provided by Clinica Chirurgica II Tissue Biobank and CRO Biobank.

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Authors and Affiliations

  1. Experimental and Clinical Pharmacology Unit, CRO-National Cancer Institute, Aviano, Italy

    E Cecchin, E De Mattia, P Biason, M Visentin & G Toffoli

  2. Clinica Chirurgica II Unit, Padova University, Padova, Italy

    M Agostini, S Pucciarelli, M L Friso & D Nitti

  3. Radiation Oncology Unit, CRO-National Cancer Institute, Aviano, Italy

    A De Paoli

  4. Pathology Unit, CRO-National Cancer Institute, Aviano, Italy

    V Canzonieri

  5. Surgical Oncology Unit, CRO-National Cancer Institute, Aviano, Italy

    R Sigon

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Cecchin, E., Agostini, M., Pucciarelli, S. et al. Tumor response is predicted by patient genetic profile in rectal cancer patients treated with neo-adjuvant chemo-radiotherapy. Pharmacogenomics J 11, 214–226 (2011). https://doi.org/10.1038/tpj.2010.25

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