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Up to 30% of colorectal cancers (CRCs) develop from sessile serrated lesions (SSLs). Within the serrated neoplasia pathway, at least two principally distinct oncogenetic routes exist generating microsatellite‐stable and microsatellite‐instable CRCs, respectively. Aberrant DNA methylation (DNAm) is found early in the serrated pathway and might play a role in both oncogenetic routes. We studied a cohort of 23 SSLs with a small focus (<10 mm) of dysplasia or cancer, 10 of which were MLH1 deficient and 13 MLH1 proficient. By comparing, for each SSL, the methylation status of (1) the region of dysplasia or cancer (SSL‐D), (2) the nondysplastic SSL (SSL), and (3) adjacent normal mucosa, differentially methylated probes (DMPs) and regions (DMRs) were assessed both genome‐wide as well as in a tumor‐suppressor gene‐focused approach. By comparing DNAm of MLH1‐deficient SSL‐Ds with their corresponding SSLs, we identified five DMRs, including those annotating for PRDM2 and, not unexpectedly, MLH1. PRDM2 gene promotor methylation was associated with MLH1 expression status, as it was largely hypermethylated in MLH1‐deficient SSL‐Ds and hypomethylated in MLH1‐proficient SSL‐Ds. Significantly increased DNAm levels of PRDM2 and MLH1, in particular at 'critical' MLH1 probe sites, were to some extent already visible in SSLs as compared to normal mucosa (p = 0.02, p = 0.01, p < 0.0001, respectively). No DMRs, nor DMPs, were identified for SSLs destined to evolve into MLH1‐proficient SSL‐Ds. Our data indicate that, within both arms of the serrated CRC pathway, the majority of the epigenetic alterations are introduced early during SSL formation. Promoter hypermethylation of PRDM2 and MLH1 on the other hand specifically initiates in SSLs destined to transform into MLH1‐deficient CRCs suggesting that the fate of SSLs may not necessarily result from a stochastic process but possibly is already imprinted and predisposed. [ABSTRACT FROM AUTHOR]

Abstract Up to 30% of colorectal cancers (CRCs) develop from sessile serrated lesions (SSLs). Within the serrated neoplasia pathway, at least two principally distinct oncogenetic routes exist generating microsatellite‐stable and microsatellite‐instable CRCs, respectively. Aberrant DNA methylation (DNAm) is found early in the serrated pathway and might play a role in both oncogenetic routes. We studied a cohort of 23 SSLs with a small focus (

Around 15–30% of colorectal cancers (CRC) develop from sessile serrated lesions (SSLs). After many years of indolent growth, SSLs can develop dysplasia and rapidly progress to CRC through events that are only partially understood. We studied molecular events at the very early stages of progression of SSLs via the MLH1‐proficient and deficient pathways to CRC. We collected a cohort of rare SSLs with a small focus (<10 mm) of dysplasia or cancer from the pathology archives of three hospitals. Whole‐exome sequencing was performed on DNA from nonprogressed and progressed components of each SSL. Putative somatic driver mutations were identified in known cancer genes that were differentially mutated in the progressed component. All analyses were stratified by MLH1 proficiency. Forty‐five lesions with a focus dysplasia or cancer were included, of which 22 (49%) were MLH1‐deficient. Lesions had a median diameter of 10 mm (interquartile range [IQR] 8–15), while the progressed component had a median diameter of 3.5 mm (IQR 1.75–4.75). Tumor mutational burden (TMB) was high in MLH1‐deficient lesions (23.9 mutations per MB) as compared to MLH1‐proficient lesions (6.3 mutations per MB). We identified 34 recurrently mutated genes in MLH1‐deficient lesions. Most prominently, ACVR2A and RNF43 were affected in 18/22 lesions, with mutations clustered in three hotspots. Most lesions with RNF43 mutations had concurrent mutations in ZNRF3. In MLH1‐proficient lesions APC (10/23 lesions) and TP53 (6/23 lesions) were recurrently mutated. Our results show that the mutational burden is exceptionally high even in the earliest MLH1‐deficient lesions. We demonstrate that hotspot mutations in ACVR2A and in the RNF43/ZNRF3 complex are extremely common in the early progression of SSLs along the MLH1‐deficient serrated pathway, while APC and TP53 mutations are early events in the the MLH1‐proficient pathway. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Sessile serrated adenoma/polyps (SSA/Ps) are early precursor lesions in the serrated neoplasia pathway, which results in BRAF‐mutated colorectal carcinomas with not only high levels of microsatellite instability but also microsatellite stable. SSA/Ps with advanced histology, including cytological dysplasia or minimally invasive carcinomas, are important lesions because SSA/Ps are considered major contributors to "interval cancers" and these lesions can rapidly become dysplastic or invasive carcinomas. Clinicopathologically, SSA/Ps with dysplasia or invasive carcinoma were associated with advanced age, female sex, and proximal colon. Although SSA/Ps with submucosal invasive carcinoma were smaller and invaded less deeply into the submucosal layer than conventional tubular adenomas with submucosal invasive carcinoma, SSA/Ps with submucosal invasive carcinoma frequently had a mucinous component and exhibited a higher potential for lymphatic invasion and lymph node metastasis. In an SSA/P series, endoscopic characteristics, including (semi)pedunculated morphology, double elevation, central depression, and reddishness, may help accurately diagnose SSA/Ps with advanced histology. Removal of SSA/Ps with dysplasia or invasive carcinoma was recommended. Endoscopic treatment such as endoscopic mucosal resection or endoscopic submucosal dissection is useful for those lesions. However, surgical resection with lymph node dissection might be indicated when SSA/Ps with invasive carcinoma are endoscopically suspected, because these have the high risk of lymph node metastasis. Greater awareness may promote further research into improving the detection, recognition, and complete resection rates of SSA/Ps with dysplasia or invasive carcinoma and reduce the interval cancer rates. [ABSTRACT FROM AUTHOR]

The histopathological characteristics of colorectal submucosal invasive carcinoma arising in sessile serrated adenoma/polyp (SSA/P), a rare malignant tumour, have not yet been fully elucidated. To investigate the features of such, we retrospectively analysed 40 submucosal invasive carcinomas with SSA/P (CA-SSA/P) and compared them to 129 cases of submucosal invasive carcinoma with conventional tubular adenoma (CA-AD). We additionally performed hMLH1 immunostaining. CA-SSA/Ps were significantly smaller than CA-ADs (P < 0.001). Histologically, well to moderately differentiated adenocarcinoma was predominant in both CA-SSA/Ps and CA-ADs. No significant differences in depth of invasion were found between the two groups. However, lymphatic invasion was more often found in CA-SSA/Ps (30%) than in CA-ADs (13%; P = 0.028), as was lymph node metastasis (CA-SSA/Ps, 28%; CA-ADs, 7%; P = 0.011). Furthermore, mucinous component and serrated architecture were significantly more frequent in CA-SSA/Ps (30 and 63%) than in CA-ADs (5 and 18%; P < 0.001, respectively). Tumour-infiltrating lymphocytes and Crohn-like inflammatory reaction were also more frequently found in CA-SSA/Ps (70 and 30%) than in CA-ADs (31 and 9%; P ≤ 0.001, respectively), whereas the opposite was true of desmoplastic reaction (CA-SSA/Ps, 35%; CA-ADs, 67%; P < 0.001). Loss of hMLH1 expression was more frequent in CA-SSA/P cases (93%) than in CA-AD cases (5%; P < 0.001). In conclusion, CA-SSA/P lesions exhibit a higher potential for lymphatic invasion and lymph node metastasis and have distinct histopathological features, including mucinous component, serrated architecture, tumour-infiltrating lymphocytes, Crohn-like inflammatory reaction, and absence of desmoplastic reaction, compared to their conventional counterparts. [ABSTRACT FROM AUTHOR]

Human gut microbiota is being increasingly recognized as a player in colorectal cancers (CRCs). Evidence suggests that Fusobacterium nucleatum ( F. nucleatum) may contribute to disease progression and is associated with CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) in CRCs; however, to date, there are no reports about the relationship between F. nucleatum and molecular features in the early stage of colorectal tumorigenesis. Therefore, we investigated the presence of F. nucleatum in premalignant colorectal lesions. In total, 465 premalignant lesions (343 serrated lesions and 122 non-serrated adenomas) and 511 CRCs were studied. We determined the presence of F. nucleatum and analyzed its association with molecular features including CIMP, MSI and microRNA-31 status. F. nucleatum was detected in 24% of hyperplastic polyps, 35% of sessile serrated adenomas (SSAs), 30% of traditional serrated adenomas (TSAs) and 33% of non-serrated adenomas. F. nucleatum was more frequently detected in CIMP-high premalignant lesions than in CIMP-low/zero lesions ( p = 0.0023). In SSAs, F. nucleatum positivity increased gradually from sigmoid colon to cecum ( p = 0.042). F. nucleatum positivity was significantly higher in CRCs (56%) than in premalignant lesions of any histological type ( p < 0.0001). In conclusion, F. nucleatum was identified in premalignant colorectal lesions regardless of histopathology but was more frequently associated with CIMP-high lesions. Moreover, F. nucleatum positivity increased according to histological grade, suggesting that it may contribute to the progression of colorectal neoplasia. Our data also indicate that F. nucleatum positivity in SSAs may support the 'colorectal continuum' concept. [ABSTRACT FROM AUTHOR]

Background & Aims: Patients with serrated polyposis syndrome (SPS) are advised to undergo endoscopic surveillance for early detection of polyps and prevention of colorectal cancer (CRC). The optimal surveillance and treatment regimen is unknown. We performed a prospective study to evaluate a standardized endoscopic treatment protocol in a large cohort of patients with SPS. Methods: We followed a cohort of patients with SPS who received annual endoscopic surveillance at the Academic Medical Centre in Amsterdam, The Netherlands from January 2007 through December 2012. All patients underwent clearing colonoscopy with removal of all polyps ≥3 mm. After clearance, subsequent follow-up colonoscopies were scheduled annually. The primary outcomes measure was the incidence of CRC and polyps. Secondary outcomes were the incidence of complications and the rate of preventive surgery. Results: Successful endoscopic clearance of all polyps ≥3 mm was achieved in 41 of 50 (82%) patients. During subsequent annual surveillance, with a median follow-up time of 3.1 years (interquartile range, 1.5−4.3 years), CRC was not detected. The cumulative risks of detecting CRC, advanced adenomas, or large (≥10 mm) serrated polyps after 3 surveillance colonoscopies were 0%, 9%, 34%, respectively. Twelve patients (24%) were referred for preventive surgery; 9 at initial colonoscopy and 3 during surveillance. Perforations or severe bleeding did not occur. Conclusions: Annual surveillance with complete removal of all polyps ≥3 mm with timely referral of selected high-risk patients for prophylactic surgery prevents development of CRC in SPS patients without significant morbidity. Considering the substantial risk of polyp recurrence, close endoscopic surveillance in SPS seems warranted. www.trialregister.nl ID NTR2757. [Copyright &y& Elsevier]

Abstract: Serrated polyps represent a heterogeneous group of lesions, some of which have well-documented malignant potential. The histological classification of serrated polyps has evolved over the last two decades to recognize three major subtypes: hyperplastic polyp, sessile serrated adenoma/polyp and traditional serrated adenoma. Sessile serrated adenoma/polyp remains under-diagnosed while it represents up to 25% of all serrated polyps and is the precursor lesion to colorectal carcinoma evolving though the serrated neoplasia pathway with BRAF mutation and CpG island methylator phenotype. Pathologists need to be aware of the World Health Organisation criteria to correctly diagnose each entity as patient management guidelines are based upon the use of this classification. Serrated polyposis is an under-recognized syndrome with unknown genetic cause conferring an increased risk of colorectal carcinoma. Pathologists have a pivotal role in identifying these patients who should undergo yearly surveillance colonoscopy. [Copyright &y& Elsevier]

Approximately 30% of colorectal carcinomas develop via a serrated neoplasia pathway, named for the pattern of crypts in the precursor polyps. Molecular abnormalities consistently involve methylation of Cp G islands [ Cp G island methylator phenotype ( CIMP)] of low degree ( CIMP- L) or high degree ( CIMP- H), and activating mutations of the mitogen-activated protein kinase pathway components BRAF or KRAS. Microsatellite instability ( MSI) of a high level ( MSI- H) is often present, allowing for a molecular classification of serrated pathway carcinoma as: (i) BRAF mutant/ CIMP- H with either a) MSI- H or b) microsatellite stable ( MSS); and (ii) KRAS mutant/ CIMP- L/ MSS. Precursor polyps include sessile serrated adenoma ( SSA), characterized by proximal location, crypt architectural disturbance, and BRAF mutation. Microvesicular hyperplasic polyp ( MVHP) probably precedes the development of SSA, and borderline lesions between MVHP and SSA occur. Cytological dysplasia in SSA portends advanced genetic abnormality and a high risk of progression to carcinoma. The traditional serrated adenoma has a predilection for the left colon, tubulovillous architecture, eosinophilic cytoplasm, and frequent KRAS mutation. Serrated morphology carcinoma is a new World Health Organization subtype with well-differentiated, mucinous or trabecular patterns. It has frequent KRAS or BRAF mutations and a poor prognosis. This review provides an insight into the histology and molecular mechanisms driving these serrated pathway lesions. [ABSTRACT FROM AUTHOR]

Aim: To validate the utility of Annexin A10 as a surrogate marker of the serrated neoplasia pathway in invasive colorectal cancers (CRCs)., Methods: A total of 1133 primary CRC patients who underwent surgical resection at Seoul National University Hospital between January 2004 and December 2007 were enrolled. Expression of Annexin A10 was evaluated by immunohistochemistry using tissue microarray and paired to our findings on clinicopathologic and molecular characteristics of each individual. CpG island methylator phenotype was determined by MethyLight assay and microsatellite instability was determined by high performance liquid chromatography. KRAS and BRAF mutation status was evaluated by direct sequencing and allele-specific PCR. Univariate and stage-specific survival analyses were performed to reveal the prognostic value of Annexin A10 expression., Results: Annexin A10 expression was observed in 66 (5.8%) of the 1133 patients. Annexin A10 expression was more commonly found in females and was associated with proximal location, ulcerative gross type, advanced T category, N category and TNM stage. CRCs with Annexin A10 expression showed an absence of luminal necrosis, luminal serration and mucin production. CRCs with Annexin A10 expression were associated with CpG island methylator phenotype, microsatellite instability and BRAF mutation. In survival analysis, Annexin A10 expression was associated with poor overall survival and progression-free survival, especially in stage IV CRCs., Conclusion: Annexin A10 expression is associated with poor clinical behavior and can be used a supportive surrogate marker of the serrated neoplasia pathway in invasive CRCs.

Colorectal cancer (CRC) is a heterogeneous disease and each CRC possesses a unique molecular tumor profile. The main pathways of oncogenesis are the chromosomal instability, microsatellite instability and serrated neoplasia pathway. Sessile serrated adenomas/polyps (SSA/Ps) may be the precursor lesions of CRC arising via the serrated neoplasia pathway. This has led to a paradigm shift because all SSA/Ps should be detected and resected during colonoscopy. The ability to accurately detect and resect only those polyps with a malignant potential could result in safer and cost-effective practice. Optimization of the endoscopic classification systems is however needed to implement targeted prevention methods., (Copyright © 2015 Elsevier Inc. All rights reserved.)