Highlights d Proteogenomic characterization reveals the functional impact of genomic alterations d Phosphoproteomics uncovers putative therapeutic targets downstream of KRAS d Multiomics links endothelial cell remodeling and glycolysis to immune exclusion d Proteomics and glycoproteomics reveal candidates for early detection or intervention

Tumour budding or dedifferentiation at the invasive margin of colorectal cancer (CRC) is an important prognostic marker and linked mechanistically to dysregulation of Wnt pathway signalling. Since budding is observed in only 40% of CRCs, we hypothesized that Wnt pathway dysregulation may be a necessary but insufficient explanation for budding and that buds may be destroyed selectively by tumour immune mechanisms. Twenty potential markers of tumour budding were evaluated in tissue microarrays (TMAs) obtained from the main tumour body of 1164 DNA mismatch repair-proficient CRCs and the findings were correlated with tumour budding, lymphocytic infiltration and survival. Loss of expression of E-cadherin and APAF-1 were independent predictors of budding (sensitivity 70.3% and specificity 48.2% when one or the other was lost). Peritumoural lymphocytes (PTLs) were observed more frequently in CRCs with loss of either E-cadherin or APAF-1 that were budding-negative. PTLs and tumour-infiltrating lymphocytes (TILs) were strongly correlated. The absence of TILs increased the adverse prognostic impact of E-cadherin and APAF-1 loss. Co-occurrence of E-cadherin loss, APAF-1 loss and low TIL counts in CRCs was an independent prognostic factor. The findings were verified in whole tissue sections from 88 CRCs with known KRAS mutation status (which was not associated with budding). Loss of E-cadherin and APAF-1 within the main body of CRCs are independent predictors of tumour budding. The prognostic benefit of lymphocytic infiltration may be explained by the immune destruction of budding cells.

In this randomized trial, VCE or HD-WLE is not inferior to dye spraying colonoscopy for detection of colonic neoplastic lesions during surveillance colonoscopy. In fact, in this study HD-WLE alone was sufficient for detection of dysplasia, adenocarcinoma or all neoplastic lesions.

Increasing nuclear beta-catenin expression and loss of membranous E-cadherin are independent, adverse prognostic factors in MMR-proficient and MLH1- CRC.

Raf-1 kinase inhibitor protein (RKIP) is known as a critical down-regulator of the mitogen-activated protein kinase signaling pathway and a potential molecular determinant of malignant metastasis. The aim of this study was to determine the prognostic significance of RKIP expression in colorectal cancer (CRC). Immunohistochemical staining for RKIP was performed on a tissue microarray comprising 1,197 mismatch repair (MMR)-proficient and 141 MMRdeficient CRCs. The association of RKIP with clinicopathologic features was analyzed. Loss of cytoplasmic RKIP was associated with distant metastasis (P = .038), higher N stage (P = .032), vascular invasion (P = .01), and worse survival (P = .001) in the MMR-proficient group. In MMR-deficient CRCs, loss of cytoplasmic RKIP was associated with distant metastasis (P = .043) and independently predicted worse survival (P = .004). Methylation analysis of 28 cases showed that loss of RKIP expression is unlikely to be due to promoter methylation.Loss of RKIP expression is a marker of tumor progression and distant metastasis in MMR-proficient and MMR-deficient CRCs.

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Mammalian Sterile20-like kinase 1 (Mst1) is a member of the yeast Ste20-related kinase family known to be involved in the process of apoptosis initiated by a variety of stimuli. The aim of this study was to determine the prognostic significance of Mst1 expression in colorectal cancer. A series of 1197 mismatch-repair-proficient colorectal cancers retrieved from a tissue microarray were randomized into two study groups. On the first group (n ¼ 599) receiver operating characteristic curves were used to determine the most clinically useful cutoffs to describe Mst1 expression with respect to T stage, N stage, tumor grade, vascular invasion and overall survival. The association of Mst1 expression and each outcome was immunohistochemically evaluated on the second study group (n ¼ 598) as well as on a third study group comprising 141 mismatch-repair-deficient colorectal cancers. A univariate analysis in the second study group showed that loss of cytoplasmic Mst1 was associated with higher T stage (P ¼ 0.001), higher N stage (P ¼ 0.029), vascular invasion (P ¼ 0.017) and overall survival (P ¼ 0.014). Nuclear Mst1 expression was not significantly associated with N stage, T stage or vascular invasion but was associated with tumor grade. In mismatch-repair-deficient colorectal cancers, loss of cytoplasmic Mst1 was associated with higher N stage (P ¼ 0.019) and shortened survival (P ¼ 0.0001). In a multivariate analysis, loss of cytoplasmic Mst1 was an independent adverse prognostic factor in this group of patients. Methylation analysis on 32 cases showed that the loss of cytoplasmic Mst1 expression is not likely due to promoter methylation. In summary, loss of cytoplasmic Mst1 expression is a marker of tumor progression in mismatchrepair-proficient as well as mismatch-repair-deficient colorectal cancers. These results are suggestive of a tumor suppressor role for Mst1 in human colorectal cancer.

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