Mapping clinicopathological entities within colorectal mucinous adenocarcinomas: a hierarchical clustering approach

Abstract

The aim of this study was to interrogate the heterogeneity of colorectal mucinous adenocarcinomas. This study is based on hierarchical clustering approach combining clinicopathological and molecular patterns known to be relevant to oncogenesis and therapeutic management of patients with colorectal carcinoma, ie, microsatellite instability, O6-methylguanine-DNA methyltransferase (MGMT) status, KRAS, and BRAF mutations and wnt signaling pathway activation. Comparison of the study group of 60 mucinous adenocarcinomas defined according to World Health Organization classification with control group of 136 colorectal adenocarcinomas successively removed shows higher frequency of BRAF and KRAS mutations and microsatellite instability-high status and lower frequency of wnt signaling pathway activation in mucinous adenocarcinomas. Hierarchical clustering isolated three relevant clusters: (i) cluster of microsatellite stable mucinous adenocarcinomas (54%) with KRAS mutation, and frequent MGMT changes, more frequently located in the left colon, often associated with contiguous precursor adenoma; (ii) cluster of BRAF-mutated mucinous adenocarcinomas (28%) with either microsatellite instability-high or microsatellite stable status, occurring in elderly female patients, nearly all located in the right colon, having the signature of serrated pathway of carcinomas; and (iii) a heterogeneous cluster of microsatellite instability-high mucinous carcinomas (18%), including inherited colorectal carcinomas, displaying a high-grade histological pattern. Age, TNM stage, and BRAF mutation had prognostic value. Hierarchical clustering analysis led to the identification of several clinicopathological entities of colorectal mucinous adenocarcinomas with epidemiologic, prognostic, and therapy relevance. Both KRAS and BRAF mutations appear as drivers in the alternate oncogenetic pathways governing the development of sporadic colorectal mucinous adenocarcinomas.

Meta-analysis of the molecular associations of mucinous colorectal cancer

“…), of which 121 articles were found ineligible. The remaining 46 articles with information on 17 746 patients were deemed suitable for inclusion in the systematic review and meta‐analysis. All included studies had Newcastle–Ottawa scores of between 6 and 9.…”

“…Several studies have tried to determine the genetic aetiology of mucinous adenocarcinoma of the colon and rectum, with heterogeneous outcomes. Mutations in Kirsten rat sarcoma viral oncogene ( KRAS ) and v‐Raf murine sarcoma viral oncogene homologue B ( BRAF ), inherited defects or epigenetic silencing of mismatch repair (MMR) proteins resulting in microsatellite instability (MSI), and the presence of the CpG island methylator phenotype (CIMP) are the most commonly studied genetic aberrations. The presence or absence of each of these genetic markers may have therapeutic and/or prognostic implications for patients with colorectal cancer.…”

Associations among histological characteristics and patient outcomes in colorectal carcinoma with a mucinous component

“…Far fewer mCRC casesonly 24%had undergone molecular analysis for KRAS and BRAF mutational status. Recent studies have reported intriguing results regarding molecular findings in mCRC; most notably, Liddell et al 37 suggested that mCRC can be split into four distinct subtypes depending on clinical and molecular factors. Our lack of molecular data in most cases precluded us from evaluating our cases in a similar, statistically sound manner.…”

Mucinous adenocarcinoma of the colon and rectum: A genomic analysis

“…Some studies have attempted to unravel the genetic etiology of mucinous adenocarcinoma of the colon and rectum by predominantly focusing on mutations in Kirsten rat sarcoma viral oncogene ( KRAS) , v‐Raf murine sarcoma viral oncogene homolog B ( BRAF ), inherited defects or epigenetic silencing of mismatch repair (MMR) proteins resulting in microsatellite instability (MSI) and the presence of the CpG island methylator phenotype (CIMP) . Mucinous tumors have been shown to be associated with an increased rate of BRAF mutations, MSI and CIMP and negatively associated with altered TP53 expression but little else has been described about the genetic mechanisms of these tumors beyond this .…”

“…Some studies have attempted to unravel the genetic etiology of mucinous adenocarcinoma of the colon and rectum by predominantly focusing on mutations in Kirsten rat sarcoma viral oncogene (KRAS), v-Raf murine sarcoma viral oncogene homolog B (BRAF), inherited defects or epigenetic silencing of mismatch repair (MMR) proteins resulting in microsatellite instability (MSI) and the presence of the CpG island methylator phenotype (CIMP). [10][11][12][13][14][15][16] Mucinous tumors have been shown to be associated with an increased rate of BRAF mutations, MSI and CIMP and negatively associated with altered TP53 expression but little else has been described about the genetic mechanisms of these tumors beyond this. 17 This study provides a more in-depth explanation of the genomic aberrations in mucinous adenocarcinoma by focusing on a greater number of genes and by providing analyses on copy number alteration (CNA) and oncogenic signaling pathways in an attempt to discern the molecular mechanisms driving the mucinous phenotype.…”