Abstract
Simple SummaryColorectal cancer (CRC) is one of the most common malignancies worldwide. Next-generation sequencing technologies have identified new candidate genes and deepened the knowledge of the molecular mechanisms underlying the progression of colonic adenomas towards CRC. The main genetic, epigenetic, and molecular alterations driving the onset and progression of CRC in both hereditary and sporadic settings have also been investigated. The evaluation of the CRC risk based on the molecular characterization of early pre-cancerous lesions may contribute to the development of targeted preventive strategies development, help define specific risk profiles, and identify patients who will benefit from targeted endoscopic surveillance.Colorectal cancer (CRC) develops through a multi-step process characterized by the acquisition of multiple somatic mutations in oncogenes and tumor-suppressor genes, epigenetic alterations and genomic instability. These events lead to the progression from precancerous lesions to advanced carcinomas. This process requires several years in a sporadic setting, while occurring at an early age and or faster in patients affected by hereditary CRC-predisposing syndromes. Since advanced CRC is largely untreatable or unresponsive to standard or targeted therapies, the endoscopic treatment of colonic lesions remains the most efficient CRC-preventive strategy. In this review, we discuss recent studies that have assessed the genetic alterations in early colorectal lesions in both hereditary and sporadic settings. Establishing the genetic profile of early colorectal lesions is a critical goal in the development of risk-based preventive strategies.
Highlights
In approximately 75–80% of cases, colorectal cancer (CRC) occurs sporadically, without a genetic predisposition
Three main genetic pathways for CRC development have been described: (i) the chromosomal instability pathway (CIN, ~80% of CRC cases), frequently observed in the conventional pathway and distal CRC, driven by chromosomal alterations/rearrangements, and mutations in known oncogenes (KRAS, BRAF, PIK3CA) and tumor suppressor genes (APC, SMAD4, TP53); (ii) the CpG island methylator phenotype (CIMP, ~15–30% of CRC cases) due to a diffuse CpG island methylation mostly observed in proximal CRC and frequent in the serrated pathway associated with BRAF mutations; iii) the microsatellite instability pathway (MSI, ~15% of CRC cases), in which the genomic instability is driven by germline (Lynch syndrome—LS) or sporadic inactivation of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) [19]
We focus on familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), and LS-derived adenomas as part of the hereditary setting, as well as conventional and serrated lesions in the sporadic setting
Summary
In approximately 75–80% of cases, colorectal cancer (CRC) occurs sporadically, without a genetic predisposition. Three main genetic pathways for CRC development have been described: (i) the chromosomal instability pathway (CIN, ~80% of CRC cases), frequently observed in the conventional pathway and distal CRC, driven by chromosomal alterations/rearrangements, and mutations in known oncogenes (KRAS, BRAF, PIK3CA) and tumor suppressor genes (APC, SMAD4, TP53); (ii) the CpG island methylator phenotype (CIMP, ~15–30% of CRC cases) due to a diffuse CpG island methylation mostly observed in proximal CRC and frequent in the serrated pathway associated with BRAF mutations; iii) the microsatellite instability pathway (MSI, ~15% of CRC cases), in which the genomic instability is driven by germline (Lynch syndrome—LS) or sporadic inactivation of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) [19]. The genetic basis for these syndromes is known, many studies conducted in recent years have characterized the somatic alterations that cause the progression of adenomas in these patients (Table 1)
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