The Molecular Hallmarks of the Serrated Pathway in Colorectal Cancer

Abstract

Colorectal cancer (CRC) is a leading cause of cancer death worldwide. It includes different subtypes that differ in their clinical and prognostic features. In the past decade, in addition to the conventional adenoma-carcinoma model, an alternative multistep mechanism of carcinogenesis, namely the “serrated pathway”, has been described. Approximately, 15 to 30% of all CRCs arise from neoplastic serrated polyps, a heterogeneous group of lesions that are histologically classified into three morphologic categories: hyperplastic polyps, sessile serrated adenomas/polyps, and the traditional serrated adenomas/polyps. Serrated polyps are characterized by genetic (BRAF or KRAS mutations) and epigenetic (CpG island methylator phenotype (CIMP)) alterations that cooperate to initiate and drive malignant transformation from normal colon mucosa to polyps, and then to CRC. The high heterogeneity of the serrated lesions renders their diagnostic and pathological interpretation difficult. Hence, novel genetic and epigenetic biomarkers are required for better classification and management of CRCs. To date, several molecular alterations have been associated with the serrated polyp-CRC sequence. In addition, the gut microbiota is emerging as a contributor to/modulator of the serrated pathway. This review summarizes the state of the art of the genetic, epigenetic and microbiota signatures associated with serrated CRCs, together with their clinical implications.

High microsatellite instability (MSI-H) is associated with distinct clinical and molecular characteristics and an improved survival in early Colon cancer (CC); real world data from the AIO molecular registry Colopredict Plus

“…In our population the incidence of a BRAF-MT was 20.1 %, in rightsided CCs 29.3 % (▶ Fig. 2A), supporting this thesis and in accord- ance with previous data [14]. Next to BRAF-MT, age leads to a higher frequency of DNA-methylation, provoking the equal effect of epigenetic gene silencing [34,35].…”

“…The PETACC-8 study reported a percentage of 38.9 % and the NO147 trial 50 % of right-sided cancers [21]. A potential reason for a higher incidence of right-sided CCs within increasing age and female gender may be that CCs develops via the serrated pathway and activating mutation (MT) of the BRAF gene preferentially on the right side of the colon [3,[13][14][15]. These lesions are prone to acquire CpG island methylations, which leads to gene silencing [13].…”

“…High microsatellite instability (MSI-H) is a well-known positive prognostic factor for CRC, especially in UICC stage II with an incidence of up to 22 % in early cancer [10][11][12]. In elderly CRC patients, right-sided and MSI-H CRC are more frequent because of its development via the serrated pathway and age-dependent increased DNA-methylation leading to MSI-H phenotypes [13][14][15][16]. To detect the MSI-H genotype cancer and normal tissue needs to be analyzed by immunohistochemistry (IHC) of the 4 MMR-proteins and additional fragment length analysis (FLA) of microsatellites [17,18].…”

Mitochondrial Respiration in KRAS and BRAF Mutated Colorectal Tumors and Polyps

“…In the current study, comparing all the distal and proximal tumors showed differences in K m (ADP) but not in V max values (Figure 2A). A study including 57,847 patients showed proximal patients had better outcomes than those with distal CRC in several subgroups including stage II disease, patients aged >70 years and mucinous adenocarcinoma [61]. Inside the KRAS mutated group, proximal and distal tumors were compared to see the potential effect of cancer location on metabolic changes.…”

Innate Lymphoid Cells in Colorectal Cancers: A Double-Edged Sword

“…Tumors are widely distributed from the proximal region of the colon to the rectum and each location is associated with different tumor-intrinsic characteristics (5). Most of these tumors arise from benign lesions called polyps, which progressively acquire genetic and epigenetic modifications to form malignant tumors and metastases (3,4,6,7). These include deletions, amplifications, mutations or methylation of the promoter of certain genes such as APC, SMAD4, TP53, BRAF, MYC, KRAS, PTEN, or MLH1 (3,4,8).…”