TY - JOUR
T1 - Wild-type APC predicts poor prognosis in microsatellite-stable proximal colon cancer
AU - Jorissen, Robert N.
AU - Christie, Michael
AU - Mouradov, Dmitri
AU - Sakthianandeswaren, Anuratha
AU - Li, Shan
AU - Love, Christopher G.
AU - Xu, Zhengzhou
AU - Molloy, Peter L.
AU - Jones, Ian T.
AU - McLaughlin, Stephen J.
AU - Ward, Robyn L.
AU - Hawkins, Nicholas
AU - Ruszkiewicz, Andrew R.
AU - Moore, James W.
AU - Burgess, Antony Wilks
AU - Busam, Dana A.
AU - Zhao, Qi
AU - Strausberg, Robert L.
AU - Lipton, Lara R.
AU - Desai, Jayesh R.
AU - Gibbs, Peter
AU - Sieber, Oliver M.
PY - 2015/9/15
Y1 - 2015/9/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84941878434&partnerID=8YFLogxK
U2 - 10.1038/bjc.2015.296
DO - 10.1038/bjc.2015.296
M3 - Article
SN - 0007-0920
VL - 113
SP - 979
EP - 988
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 6
ER -
