A clinicopathological and molecular analysis of 200 traditional serrated adenomas

Abstract

The traditional serrated adenoma is the least common colorectal serrated polyp. The clinicopathological features and molecular drivers of these polyps require further investigation. We have prospectively collected a cohort of 200 ordinary and advanced traditional serrated adenomas and performed BRAF and KRAS mutational profiling, CpG island methylator phenotype analysis, and immunohistochemistry for a panel of 7 antibodies (MLH1, b-catenin, p53, p16, Ki67, CK7, and CK20) on all cases. The mean age of the patients was 64 years and 50% were female. Of the polyps, 71% were distal. Advanced histology (overt dysplasia or carcinoma) was present in 19% of cases. BRAF mutation was present in 67% and KRAS mutation in 22%. BRAF mutant traditional serrated adenomas were more frequently proximal (39% versus 2%; Pr0.0001), were exclusively associated with a precursor polyp (57% versus 0%; Pr0.0001), and were more frequently CpG island methylator phenotype high (60% versus 16%; Pr0.0001) than KRAS mutant traditional serrated adenomas. Advanced traditional serrated adenomas retained MLH1 expression in 97%, showed strong p53 staining in 55%, and nuclear b-catenin staining in 40%. P16 staining was lost in the advanced areas of 55% of BRAF mutant traditional serrated adenomas compared with 10% of the advanced areas of KRAS mutant or BRAF/KRAS wildtype traditional serrated adenomas. BRAF and KRAS mutant traditional serrated adenomas are morphologically related but biologically disparate polyps with distinctive clinicopathological and molecular features. The overwhelming majority of traditional serrated adenomas retain mismatch repair enzyme function indicating a microsatellite-stable phenotype. Malignant progression occurs via TP53 mutation and Wnt pathway activation regardless of mutation status. However, CDKN2A (encoding the p16 protein) is silenced nearly exclusively in the advanced areas of the BRAF mutant traditional serrated adenomas. Thus, the BRAF mutant traditional serrated adenoma represents an important precursor of the aggressive BRAF mutant, microsatellite-stable subtype of colorectal carcinoma. The serrated neoplasia pathway accounts for 15 to 35% of colorectal carcinoma. 1-3 Well-established molecular drivers of this pathway are MAP kinase pathway activation, a critical early event resulting from either activating BRAF or KRAS mutation, 4 and the CpG island methylator phenotype, a coordinate methylation of CpG islands in the promoter regions of many genes that results in gene silencing. [4][5][6] The CpG island methylator phenotype is particularly relevant to carcinogenesis when affecting tumorsuppressor genes. 5 MLH1 is the best known of these, with silencing leading to microsatellite instability. This is frequently observed in the malignant transformation of sessile serrated adenomas. However, MLH1 methylation and microsatellite instability are not prerequisites of serrated neoplasia.

Heterogén vastagbéldaganat: a fogazott útvonalon kialakuló, sporadikus laesiók jelentősége a klinikai gyakorlatban

“…Fogazott és adenomatosus dysplasia is előfordulhat bennük, mely előbbire a BRAF-mutáció és CIMP-H, míg az utóbbira a KRAS-mutáció és CIMP-L jellemző [31]. A TP53-mutáció közel 50%-ban mutatható ki [32]. Immunhisztokémiailag a MUC2-, MUC5AC-és β-kateninexpresszió gyakori [32].…”

“…A TP53-mutáció közel 50%-ban mutatható ki [32]. Immunhisztokémiailag a MUC2-, MUC5AC-és β-kateninexpresszió gyakori [32].…”

Role of stem cells in large bowel carcinogenesis

“…Однако есть данные о том, что TSA в качестве предшественника могут иметь SSA/P или НР, в связи с чем возможна общность этих 2 зубчатых путей (рис. 1) [10,11].…”

Integrated Analysis of the Endoscopic, Pathological and Molecular Characteristics of Colorectal Tumorigenesis

“…In contrast to SSA/Ps, TSAs are thought to develop into microsatellite stable CRCs, though the underlying mechanism of tumor progression is not yet fully understood [11]. TSAs reportedly exhibit genetic and epigenetic characteristics distinct from those of SSA/Ps.…”