Wild-type APC predicts poor prognosis in microsatellite-stable proximal colon cancer

Robert N. Jorissen, Michael Christie, Dmitri Mouradov, Anuratha Sakthianandeswaren, Shan Li, Christopher G. Love, Zhengzhou Xu, Peter L. Molloy, Ian T. Jones, Stephen J. McLaughlin, Robyn L. Ward, Nicholas Hawkins, Andrew R. Ruszkiewicz, James W. Moore, Antony Wilks Burgess, Dana A. Busam, Qi Zhao, Robert L. Strausberg, Lara R. Lipton, Jayesh R. DesaiPeter Gibbs, Oliver M. Sieber

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Abstract

Background:APC mutations (APC-mt) occur in ∼70% of colorectal cancers (CRCs), but their relationship to prognosis is unclear.Methods:APC prognostic value was evaluated in 746 stage I-IV CRC patients, stratifying for tumour location and microsatellite instability (MSI). Microarrays were used to identify a gene signature that could classify APC mutation status, and classifier ability to predict prognosis was examined in an independent cohort.Results:Wild-type APC microsatellite stable (APC-wt/MSS) tumours from the proximal colon showed poorer overall and recurrence-free survival (OS, RFS) than APC-mt/MSS proximal, APC-wt/MSS distal and APC-mt/MSS distal tumours (OS HR≥1.79, P≤0.015; RFS HR≥1.88, P≤0.026). APC was a stronger prognostic indicator than BRAF, KRAS, PIK3CA, TP53, CpG island methylator phenotype or chromosomal instability status (P≤0.036). Microarray analysis similarly revealed poorer survival in MSS proximal cancers with an APC-wt-like signature (P=0.019). APC status did not affect outcomes in MSI tumours. In a validation on 206 patients with proximal colon cancer, APC-wt-like signature MSS cases showed poorer survival than APC-mt-like signature MSS or MSI cases (OS HR≥2.50, P≤0.010; RFS HR≥2.14, P≤0.025). Poor prognosis APC-wt/MSS proximal tumours exhibited features of the sessile serrated neoplasia pathway (P≤0.016).Conclusions:APC-wt status is a marker of poor prognosis in MSS proximal colon cancer.

Original languageEnglish
Pages (from-to)979-988
Number of pages10
JournalBritish Journal of Cancer
Volume113
Issue number6
DOIs
Publication statusPublished - 2015

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    Jorissen, R. N., Christie, M., Mouradov, D., Sakthianandeswaren, A., Li, S., Love, C. G., Xu, Z., Molloy, P. L., Jones, I. T., McLaughlin, S. J., Ward, R. L., Hawkins, N., Ruszkiewicz, A. R., Moore, J. W., Burgess, A. W., Busam, D. A., Zhao, Q., Strausberg, R. L., Lipton, L. R., ... Sieber, O. M. (2015). Wild-type APC predicts poor prognosis in microsatellite-stable proximal colon cancer. British Journal of Cancer, 113(6), 979-988. https://doi.org/10.1038/bjc.2015.296