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The consensus molecular subtype (CMS) classification divides colon tumors into four subtypes holding promise as a predictive biomarker. However, the effect of adjuvant chemotherapy on recurrence free survival (RFS) per CMS in stage III patients remains inadequately explored. With this intention, we selected stage III colon cancer (CC) patients from the MATCH cohort (n = 575) and RadboudUMC (n = 276) diagnosed between 2005 and 2018. Patients treated with and without adjuvant chemotherapy were matched based on tumor location, T- and N-stage (n = 522). Tumor material was available for 464 patients, with successful RNA extraction and CMS subtyping achieved in 390 patients (surgery alone group: 192, adjuvant chemotherapy group: 198). In the overall cohort, CMS4 was associated with poorest prognosis (HR 1.55; p = .03). Multivariate analysis revealed favorable RFS for the adjuvant chemotherapy group in CMS1, CMS2, and CMS4 tumors (HR 0.19; p = .01, HR 0.27; p < .01, HR 0.19; p < .01, respectively), while no significant difference between treatment groups was observed within CMS3 (HR 0.68; p = .51). CMS subtyping in this non-randomized cohort identified patients with poor prognosis and patients who may not benefit significantly from adjuvant chemotherapy., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

In colorectal cancer, the molecular alterations that lead to metastasis are not clearly established, probably because of their high genetic complexity. To identify combinations of genetic changes involved in tumor progression and metastasis, we focused on chromosome instable (CIN) colon cancers. We compared by allelotyping of 33 microsatellites, the genomic alterations of 38 primary colon tumors with the synchronously resected matched liver metastases (CLM). We observed that (i) the number of patients with alterations at certain loci did not differ significantly between the whole primary tumor and the paired CLM, (ii) a group of patients had fewer alterations in the metastasis when compared with the matched primary tumor. A 2-way hierarchical unsupervised clustering of the allelotyping data revealed 2 tumor subtypes that have different levels of CIN (CIN-High, CIN-Low). Both subtypes have a minimal common set of alterations at chromosomes 8p, 17p and 18q, but does not include alteration at 5q or mutation at K-Ras. These 2 subtypes were also observed using a collection of 104 independent primary CIN colon tumors. In addition, we found a third subtype, consisting of tumors with a very low number of alterations not associated with specific loci (CIN-Very Low). We found that colon carcinogenesis may require a minimal set of alterations and that, in contrast to the current hypothesis, the level of CIN does not correlate with tumor progression. Therefore, our results suggest that metastasis potential could be present at very early stages of tumor development.

Protein expression profiling has been increasingly used to discover and characterize biomarkers that can be used for diagnostic, prognostic or therapeutic purposes. Most proteomic studies published to date have identified relatively abundant host response proteins as candidate biomarkers, which are often dismissed because of an apparent lack of specificity. We demonstrate that 2 host response proteins previously identified as candidate markers for early stage ovarian cancer, transthyretin and inter-alpha trypsin inhibitor heavy chain 4 (ITIH4), are posttranslationally modified. These modifications include proteolytic truncation, cysteinylation and glutathionylation. Assays using Surface Enhanced Laser Desorption/Ionization Time of Flight Mass Spectrometry (SELDI-TOF-MS) may provide a means to confer specificity to these proteins because of their ability to detect and quantitate multiple posttranslationally modified forms of these proteins in a single assay. Quantitative measurements of these modifications using chromatographic and antibody-based ProteinChip array assays reveal that these posttranslational modifications occur to different extents in different cancers and that multivariate analysis permits the derivation of algorithms to improve the classification of these cancers. We have termed this process host response protein amplification cascade (HRPAC), since the process of synthesis, posttranslational modification and metabolism of host response proteins amplifies the signal of potentially low-abundant biologically active disease markers such as enzymes., ((c) 2005 Wiley-Liss, Inc.)

In 584 consecutive patients with no previous history of cancer or polypectomy, 769 adenomas were excised endoscopically and classified retrospectively according to the following parameters: macroscopic growth pattern, size, histological type, grade of dysplasia, anatomical site, presence of adenocarcinoma (ADK), number of adenomas and sex and age of the patient. A multivariate logistic analysis confirmed that size and histological type are the 2 most important predictors of ADK, both in solitary and in multiple adenomas. Adenomas located in the sigmoid portion and in the rectum have an increased probability of ADK, independent of size and histology. Multiple polyps, when compared to solitary polyps, were more frequent in males (p less than 0.01) and were more often larger than 2 cm. Significant similarities in histology, morphology and degree of dysplasia were observed among multiple adenomas from the same patient.

Monoclonal antibodies have been generated using membrane-enriched extracts of human metastatic mammary carcinoma lesions (Colcher et al., 1981), some of which demonstrated binding to the surface of human colon carcinoma cell lines. We report here an analysis of the reactivity of three of these monoclonal antibodies with formalin fixed tissue sections of human colon adenocarcinomas and adenomas. The three monoclonals employed were B72.3, which is reactive with a 220-400 kdal high molecular weight glycoprotein complex; B6.2, reactive with a 90 kdal glycoprotein, and B1.1, which is reactive with the 180 kdal glycoprotein CEA. B1.1 was least selective in its reactivity to colon carcinoma versus adenoma lesions. When 10 micrograms/ml of purified B1.1 IgG were used per slide, 94% (15 of 16) of carcinomas and 83% (15 of 18) adenomas showed reactivity. Monoclonal B72.3 demonstrated the most selective reactivity for carcinomas. Eighty-two percent (14 of 17) of carcinomas were positive while none of 18 adenomas examined showed reactivity with more than a few percent of adenoma cells positive. When a low concentration of purified B72.3 immunoglobulin was used per slide, 8 of 16 carcinomas and none of 46 adenomas or normal colon epithelium samples scored positive. Monoclonal B72.3 also reacted with cells in areas of "atypia" within adenomas. The reactivity of monoclonal B6.2 was intermediate as compared to B1.1 and B72.3 in its selectivity of reactivity for carcinoma cells. A heterogeneity in the populations of tumor cells showing reactivity with the three monoclonals was observed within many of the tumor masses. Both colon adenocarcinomas and adenomas can now be placed in several distinct groups based on their expression of antigens reactive with the three monoclonal antibodies employed.