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

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.