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
AU - Xu, Zheng Zhou
AU - Molloy, Peter L.
AU - Jones, Ian T.
AU - McLaughlin, Stephen
AU - Ward, Robyn L.
AU - Hawkins, Nicholas J.
AU - Ruszkiewicz, Andrew R.
AU - Moore, James
AU - Burgess, Antony W.
AU - Busam, Dana
AU - Zhao, Qi
AU - Strausberg, Robert L.
AU - Lipton, Lara
AU - Desai, Jayesh
AU - Gibbs, Peter
AU - Sieber, Oliver M.
N1 - Funding Information:
We thank all individuals who participated in this study and colleagues who undertook sample and clinical data collection. We acknowledge the Victorian Cancer Biobank for the provision of specimens and BioGrid Australia for providing clinical data. This work was supported by a Cancer Australia Project Grant (APP1030098), a Cancer Council Victoria Grant-in-Aid (APP1060964), Ludwig Institute for Cancer Research, a Cancer Council Victoria Postgraduate Cancer Research Scholarship to MC and a National Health and Medical Research Council of Australia (NHMRC) R.D. Wright Biomedical Career Development Fellowship to OMS (APP1062226). This study was supported in part by the Victorian Government’s Operational Infrastructure Support Program.
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 - https://www.scopus.com/pages/publications/84941878434
U2 - 10.1038/bjc.2015.296
DO - 10.1038/bjc.2015.296
M3 - Article
C2 - 26305864
AN - SCOPUS:84941878434
SN - 0007-0920
VL - 113
SP - 979
EP - 988
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 6
ER -