Molecular pathology of colorectal cancer

Abstract

SummaryColorectal cancer (CRC) is a molecularly heterogeneous disease arising from gradual accumulation of genetic and epigenetic changes. In the last decade, great efforts have been made to classify CRC according to molecular features. This has led to several proposals of molecular subtyping. Recently, consensus molecular subtypes (CMS) have been proposed based on the integration of previously existing categorizations and additional comprehensive molecular studies. Microsatellite instability (MSI) is a highly specific molecular feature in CRC with a therapeutic impact, for example for immunotherapy. MSI is recognized as a separate CMS subtype. Beyond MSI, molecular subtyping may also be helpful for further differentiating CRC into prognostically distinct groups and for identifying new treatment targets, particularly for CMS with more aggressive behavior and resistance to conventional systemic treatment. Molecular subtypes may also exhibit distinctive morphological features, which may open the horizon for morphomolecular diagnostics based on digital pathology and machine learning. This review article summarizes current aspects of the molecular pathology of CRC with a focus on molecular subtyping in the context of pathological features and therapeutic applications.

WITHDRAWN: The Molecular Signature Associated with Oxaliplatin Induced Peripheral Neuropathy in Colorectal Cancer

“…It is a major public health concern being the second leading cause of cancer-related deaths and is the third most prevalent cancer worldwide (6). CRC has also been divided into two classes by the Cancer Genome Atlas (TCGA) project i.e., hypermutated tumors (16%) and non-hypermutated tumors (84%) (7). As per the GLOBOCAN statistics, the total new cases and the number of deaths estimated in 2020 were 1,931,590 and 935,173, respectively, across all ages in both sexes (8).…”

Evaluation of the Immunohistochemical Scoring System of CDX2 Expression as a Prognostic Biomarker in Colon Cancer

“…As outlined in the current literature, the onset of CRC unveils two predominant molecular pathways: the conventional adenoma-carcinoma route and the serrated alternative pathway, each originating from distinct precancerous lesions [5,13,14]. In these pathways, a cascade of distinct genetic mutations unfolds, including alterations in the APC gene, associated with conventional adenomatous polyps, and mutations in the BRAF gene, linked to serrated polyps [12][13][14][15]. Additionally, three carcinogenic mechanisms have been described, with chromosomal instability (CIN) being the most common, frequently implicated in the adenoma-carcinoma molecular pathway [13].…”

“…Additionally, three carcinogenic mechanisms have been described, with chromosomal instability (CIN) being the most common, frequently implicated in the adenoma-carcinoma molecular pathway [13]. This mechanism is marked by a plethora of chromosomal irregularities stemming from mutations in key suppressor genes such as APC, SMAD4, and TP53, as well as mutations in the oncogene KRAS, which intricately interact with the Wnt and MAPK signaling pathways [5,[12][13][14][15]. The second mechanism involves the Mismatch Repair (MMR) system and is commonly linked with the serrated molecular pathway [12,13].…”

“…When a mutation arises in one of the genes responsible for synthesizing the four MMR proteins, the system undergoes inefficiency (dMMR), frequently via epigenetic mechanisms, resulting in the accumulation of errors like insertion-deletion loops or mispairing of DNA bases, a phenomenon termed high microsatellite instability (MSI-H) [5,[12][13][14]. Due to the expression of mutational neoantigens, the dMMR/MSI-H phenotype frequently associates with a vigorous immune response marked by an abundance of tumor-infiltrating lymphocytes (TILs) [12,15,18,19]. The third mechanism involves the hypermethylation of genetic promoter regions rich in CpG islands (CIMP) and is commonly associated with the serrated pathway, along with mutations in the APC, MLH1, and/or CDX2 genes [4,12,14,20,21].…”

“…In CRC, genetic and molecular biomarkers play a pivotal role across all stages, furnishing vital insights into potential genetic susceptibility to cancer (e.g., Lynch syndrome or familial adenomatous polyposis), disease prognosis (risk of recurrence or tumor progression), and/or therapeutic effectiveness [24]. Among the essential biomarkers in CRC management, seamlessly integrated into routine medical practice as per the latest ESMO and NCCN guidelines, lies the assessment of MMR/MSI status, offering valuable insights into prognosis, therapeutic efficacy, and genetic susceptibility to cancer such as Lynch syndrome [10,11,15]. In advanced CRC, the evaluation of RAS genes' (NRAS, KRAS) mutational status is recommended for predicting therapeutic response, while the assessment of the BRAF gene's mutational status is conducted for prognostic purposes [3,10,15].…”