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Interconnectivity between molecular subtypes and tumor stage in colorectal cancer.

ABSTRACT: BACKGROUND:There are profound individual differences in clinical outcomes between colorectal cancers (CRCs) presenting with identical stage of disease. Molecular stratification, in conjunction with the traditional TNM staging, is a promising way to predict patient outcomes. We investigated the interconnectivity between tumor stage and tumor biology reflected by the Consensus Molecular Subtypes (CMSs) in CRC, and explored the possible value of these insights in patients with stage II colon cancer. METHODS:We performed a retrospective analysis using clinical records and gene expression profiling in a meta-cohort of 1040 CRC patients. The interconnectivity of tumor biology and disease stage was assessed by investigating the association between CMSs and TNM classification. In order to validate the clinical applicability of our findings we employed a meta-cohort of 197 stage II colon cancers. RESULTS:CMS4 was significantly more prevalent in advanced stages of disease (stage I 9.8% versus stage IV 38.5%, p?

SUBMITTER: Coebergh van den Braak RRJ

PROVIDER: S-EPMC7473811 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Interconnectivity between molecular subtypes and tumor stage in colorectal cancer.

Coebergh van den Braak R R J RRJ Ten Hoorn S S Sieuwerts A M AM Tuynman J B JB Smid M M Wilting S M SM Martens J W M JWM Punt C J A CJA Foekens J A JA Medema J P JP IJzermans J N M JNM Vermeulen L L

BMC cancer 20200904 1

<h4>Background</h4>There are profound individual differences in clinical outcomes between colorectal cancers (CRCs) presenting with identical stage of disease. Molecular stratification, in conjunction with the traditional TNM staging, is a promising way to predict patient outcomes. We investigated the interconnectivity between tumor stage and tumor biology reflected by the Consensus Molecular Subtypes (CMSs) in CRC, and explored the possible value of these insights in patients with stage II colo ...[more]

PMID: 32887573

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Project description:Background and aimsColorectal cancer (CRC) is a heterogeneous disease that can develop via several pathways. Different CRC subtypes, identified based on tumor markers, have been proposed to reflect these pathways. We evaluated the significance of these previously proposed classifications to survival.MethodsParticipants in the population-based Seattle Colon Cancer Family Registry were diagnosed with invasive CRC from 1998 through 2007 in western Washington State (N = 2706), and followed for survival through 2012. Tumor samples were collected from 2050 participants and classified into 5 subtypes based on combinations of tumor markers: type 1 (microsatellite instability [MSI]-high, CpG island methylator phenotype [CIMP] -positive, positive for BRAF mutation, negative for KRAS mutation); type 2 (microsatellite stable [MSS] or MSI-low, CIMP-positive, positive for BRAF mutation, negative for KRAS mutation); type 3 (MSS or MSI low, non-CIMP, negative for BRAF mutation, positive for KRAS mutation); type 4 (MSS or MSI-low, non-CIMP, negative for mutations in BRAF and KRAS); and type 5 (MSI-high, non-CIMP, negative for mutations in BRAF and KRAS). Multiple imputation was used to impute tumor markers for those missing data on 1-3 markers. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of subtypes with disease-specific and overall mortality, adjusting for age, sex, body mass, diagnosis year, and smoking history.ResultsCompared with participants with type 4 tumors (the most predominant), participants with type 2 tumors had the highest disease-specific mortality (HR = 2.20, 95% CI: 1.47-3.31); subjects with type 3 tumors also had higher disease-specific mortality (HR = 1.32, 95% CI: 1.07-1.63). Subjects with type 5 tumors had the lowest disease-specific mortality (HR = 0.30, 95% CI: 0.14-0.66). Associations with overall mortality were similar to those with disease-specific mortality.ConclusionsBased on a large, population-based study, CRC subtypes, defined by proposed etiologic pathways, are associated with marked differences in survival. These findings indicate the clinical importance of studies into the molecular heterogeneity of CRC.

Project description:The backbone of all colorectal cancer classifications including the consensus molecular subtypes (CMS) highlights microsatellite instability (MSI) as a key molecular pathway. Although mucinous histology (generally defined as >50% extracellular mucin-to-tumor area) is a "typical" feature of MSI, it is not limited to this subgroup. Here, we investigate the association of CMS classification and mucin-to-tumor area quantified using a deep learning algorithm, and the expression of specific mucins in predicting CMS groups and clinical outcome. A weakly supervised segmentation method was developed to quantify extracellular mucin-to-tumor area in H&E images. Performance was compared to two pathologists' scores, then applied to two cohorts: (1) TCGA (n = 871 slides/412 patients) used for mucin-CMS group correlation and (2) Bern (n = 775 slides/517 patients) for histopathological correlations and next-generation Tissue Microarray construction. TCGA and CPTAC (n = 85 patients) were used to further validate mucin detection and CMS classification by gene and protein expression analysis for MUC2, MUC4, MUC5AC and MUC5B. An excellent inter-observer agreement between pathologists' scores and the algorithm was obtained (ICC = 0.92). In TCGA, mucinous tumors were predominantly CMS1 (25.7%), CMS3 (24.6%) and CMS4 (16.2%). Average mucin in CMS2 was 1.8%, indicating negligible amounts. RNA and protein expression of MUC2, MUC4, MUC5AC and MUC5B were low-to-absent in CMS2. MUC5AC protein expression correlated with aggressive tumor features (e.g., distant metastases (p = 0.0334), BRAF mutation (p < 0.0001), mismatch repair-deficiency (p < 0.0001), and unfavorable 5-year overall survival (44% versus 65% for positive/negative staining). MUC2 expression showed the opposite trend, correlating with less lymphatic (p = 0.0096) and venous vessel invasion (p = 0.0023), no impact on survival.The absence of mucin-expressing tumors in CMS2 provides an important phenotype-genotype correlation. Together with MSI, mucinous histology may help predict CMS classification using only histopathology and should be considered in future image classifiers of molecular subtypes.

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Interconnectivity between molecular subtypes and tumor stage in colorectal cancer.

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Interconnectivity between molecular subtypes and tumor stage in colorectal cancer.

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