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

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.

Association between mutations of critical pathway genes and survival outcomes according to the tumor location in colorectal cancer

“…Wild-type APC was a negative prognostic factor in MSS proximal colon cancer but not in distal colon cancer. 45 APC is the most important gene in the WNT pathway, and this result is similar to our data showing that a mutation in the WNT pathway was a positive prognostic factor in proximal tumors. In addition, there is a report showing that a KRAS mutation is a negative prognostic factor in distal colon cancer but not proximal colon cancer.…”

“…Moreover, there is evidence showing that the prognostic effect of a gene mutation may be different according to the tumor location. Wild‐type APC was a negative prognostic factor in MSS proximal colon cancer but not in distal colon cancer . APC is the most important gene in the WNT pathway, and this result is similar to our data showing that a mutation in the WNT pathway was a positive prognostic factor in proximal tumors.…”

Colorectal cancer mutations are associated with survival and recurrence after pulmonary metastasectomy

“…In the analysis for disease recurrence of any kind after PM, TP53 and RAS mutations were associated with shorter DFI. This finding is consistent with prior investigations reporting improved outcomes in patients with mutant APC, compared with wild‐type . Others have demonstrated instability in APC mutant hepatocytes, at first resulting in cellular proliferation, though later increased apoptosis is seen .…”

Lymphocytic response to tumour and deficient DNA mismatch repair identify subtypes of stage II/III colorectal cancer associated with patient outcomes

“…Lastly, other molecular events or epidemiological factors within the TIL/MMR subtypes may impact prognosis or chemosensitivity, which could contribute to the observed subtype-specific survival differences. Evidence supports potential roles for APC mutation,44 chromosome instability,45 tumour-associated stroma,24 body mass index,46 smoking47 and aspirin,48 among other factors.…”