Abstract
BackgroundCaudal‐related homeobox transcription factor 2 (CDX2) is an intestine‐specific transcription factor implicated in tumour differentiation, proliferation, cell adhesion and migration. Negative CDX2 status (CDX2−) is associated with worse prognosis in colorectal cancer and may identify high‐risk stage II disease that benefits from adjuvant chemotherapy. This observational study investigated whether CDX2− is associated with prognosis or response to chemotherapy in the mismatch repair‐deficient (dMMR) phenotype of colorectal cancer.MethodsPatients with resectable dMMR colorectal cancer were eligible for inclusion. The prognostic and predictive value of CDX2 expression on the presence of lymph node metastasis (LNM) and survival was investigated. CDX2 status was determined via immunohistochemistry using the Leica Bond™ CDX2 (clone EP25) ready‐to‐use primary antibody.ResultsSome 235 of 238 consecutive dMMR tumours were assessed for CDX2 status. CDX2− was observed in 15·7 per cent of colorectal cancer. Interobserver agreement was excellent (κ = 0·863; P < 0·001). CDX2− was significantly associated with female sex, increased size, advanced stage, worse conventional and poorly differentiated cluster (PDC) grade, mucinous morphology, perineural and lymphovascular invasion, and pN status (all P ≤ 0·038). CDX2− was not associated with LNM or survival in multivariable analysis. Independent predictors of LNM were PDC grade (odds ratio (OR) 4·12, 95 per cent c.i. 1·76 to 9·63; P = 0·001) and extramural venous invasion (OR 3·79, 1·62 to 8·85; P = 0·002). Budding (hazard ratio (HR) 2·79, 95 per cent c.i. 1·60 to 4·87; P < 0·001), pT status (HR 3·59, 1·29 to 10·01; P = 0·015) and adjuvant chemotherapy (HR 2·07, 1·15 to 3·74; P = 0·016) were independently associated with worse disease‐free survival.ConclusionCDX2− does not confer a worse prognosis in the dMMR phenotype of colorectal cancer. The MMR status of patients with colorectal cancer should be determined before assessing CDX2 status.
Highlights
Molecular profiles of colorectal cancers have been characterized in detail in recent years[1], for practical purposes there are two main molecular subtypes: those with microsatellite instability (MSI) (15–20 per cent) where errors in replication go unchecked due to deficient DNA mismatch repair, and mismatch repair (MMR)-proficient tumours (80–85 per cent)[2].The majority of dMMR cancer is sporadic and caused by MLH1 promoter hypermethylation, occurring on a background of global gene promoter hypermethylation known as the CpG island methylator phenotype (CIMP)[3]
No further tissue was available for Caudal-related homeobox transcription factor 2 (CDX2) analysis on three dMMR slides that had been referred from external institutions for MMR testing
In this study CDX2− status in dMMR colorectal cancer was associated with a number of adverse prognostic variables such as stage, conventional WHO grade, poorly differentiated cluster (PDC) grade, PNI and LVI, but not with survival
Summary
The majority of dMMR cancer is sporadic and caused by MLH1 promoter hypermethylation, occurring on a background of global gene promoter hypermethylation known as the CpG island methylator phenotype (CIMP)[3] Such tumours are usually diagnosed at advanced age with a female preponderance, are associated with BRAF mutation, and originate from sessile serrated lesions (SSLs)[2]. Negative CDX2 status (CDX2−) is associated with worse prognosis in colorectal cancer and may identify high-risk stage II disease that benefits from adjuvant chemotherapy. This observational study investigated whether CDX2− is associated with prognosis or response to chemotherapy in the mismatch repair-deficient (dMMR) phenotype of colorectal cancer. The MMR status of patients with colorectal cancer should be determined before assessing CDX2 status
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