Risk Factors in Serrated Pathway Lesions: N-Glycosylation Profile as a Potential Biomarker of Progression to Malignancy.

Introduction: The serrated pathway contributes to interval colorectal cancers, highlighting the need for new biomarkers to assess lesion progression risk. The ß1,6-GlcNAc branched N-glycans expression in CRC cells was associated with an invasive phenotype and with immune evasion. Therefore, this study aims to identify potential risk factors for progression of serrated lesions (SLs) to malignancy, analyzing the N-glycosylation profile of epithelial/infiltrating immune cells. Methods: A retrospective cohort study was performed with data from 53 colonoscopies (48 patients). Sixty-three serrated pathway lesions (SPLs) were characterized based on N-glycosylation profile (lectin histochemistry/flow cytometry) and MGAT5 expression. Statistical analysis was performed to search for associations between the glycoprofile and clinical variables from each patient. Results: Increased ß1,6-GlcNAc branched N-glycans expression in epithelial cells is found associated with age (p = 0.007 in SPL), smoking (p = 0.038 in SL), increased BMI (p = 0.036 in sessile serrated lesions [SSL]), and polyp dimensions ≥10 mm (p = 0.001 in SL), while increased expression of these structures on immune cells is associated with synchronous CA number (CD4+T cells: p = 0.016; CD8+T cells: p = 0.044 in SL) and female gender (p = 0.026 in SL). Moreover, a lower high-mannose N-glycans expression in immune cells is associated with smoking (p = 0.010 in SPL) and synchronous CA presence (p = 0.010 in SPL). Higher expression of these glycans is associated with female (p = 0.016 in SL) and male (p = 0.044 in SL) gender, left colon location (p = 0.028), dysplasia (p = 0.028), and adenocarcinoma (p = 0.010). Conclusions: We identified an association between an abnormal glycoprofile and several clinical risk factors, proposing the N-glycosylation profile as a potential biomarker of tumor progression in the serrated pathway. The N-glycosylation anatomopathological profile analysis could be further used to decide shorter interval follow-up in patients with SPL.

Introdução: A via serreada contribui para os cancros colorretais de intervalo, destacando a necessidade de novos biomarcadores para determinar o risco de progressão destas lesões. A expressão de ß1,6-GlcNAc N-glicanos ramificados foi associada a um fenótipo invasivo e a evasão imune. Assim, este estudo tem como objetivo identificar potenciais fatores de risco de progressão das lesões serreadas para malignidade, analisando o perfil de N-glicosilação das células epiteliais/células imunitárias. Métodos: Foi realizado um estudo retrospetivo com dados de 53 colonoscopias (48 doentes). 63 lesões da via serreada foram caracterizadas segundo o perfil de N-glicosilação (histoquímica de lectinas/citometria de fluxo) e expressão de MGAT5. A análise estatística foi realizada para encontrar associações entre o perfil de N-glicosilação e as variáveis clínicas de cada doente. Resultados: O aumento da expressão de ß1,6-GlcNAc N-glicanos ramificados nas células epiteliais encontra-se associado com a idade (p = 0.007 nas SPL), tabagismo (p = 0.038 nas SL), aumento do BMI (p = 0.036 nas SSL), e pólipos com dimensões ≥10 mm (p = 0.001 nas SL), enquanto que o aumento destas estruturas nas células imunitárias está associado com o número de CA síncronos (células TCD4+: p = 0.016; células TCD8+: p = 0.044 nas SL) e o género feminino (p = 0.026 nas SL). Além disso, uma diminuição da expressão de N-glicanos ricos em manose está associada ao tabagismo (p = 0.010 para SPL) e a presença de adenomas síncronos (p = 0.010 nas SPL). A expressão aumentada destas estruturas está associado com o género feminino (p = 0.016 nas SSL), género masculino (p = 0.044 nas SSL), localização no cólon esquerdo (p = 0.028), displasia (p = 0­028) e adenocarcinoma (p = 0.010). Discussão/Conclusão: Identificámos uma associação entre um perfil de glicosilação anormal e vários fatores de risco clínicos, propondo o perfil de N-glicosilação como um potencial biomarcador de progressão tumoral na via serreada. A análise anatomopatológica do perfil de N-glicosilação pode vir a ser usada para decidir intervalos de follow-up mais curtos em doentes com SPL.

How to "pick up" colorectal serrated lesions and polyps in daily histopathology practice: From terminologies to diagnostic pitfalls.

Over the last decade, our knowledge of colorectal serrated polyps and lesions has significantly improved due to numerous studies on this group of precursor lesions. Serrated lesions were misleading as benign before 2010, but they are currently reclassified as precancerous lesions that contribute to 30% of colorectal cancer through the serrated neoplasia pathway. The World Health Organization updated the classification for serrated lesions and polyps of the colon and rectum in 2019, which is more concise and applicable in daily practice. The responsible authors prescribe that "colorectal serrated lesions and polyps are characterized by a serrated (sawtooth or stellate) architecture of the epithelium." From a clinical standpoint, sessile serrated lesion (SSL) and SSL with dysplasia (SSLD) are the two most significant entities. Despite these advancements, the precise diagnosis of SSL and SSLD based mainly on histopathology remains challenging due to various difficulties. This review describes the nomenclature and the terminology of colorectal serrated polyps and lesions and highlights the diagnostic criteria and obstacles encountered in the histopathological diagnosis of SSL and SSLD.

Effect of computer aided detection device on the adenoma detection rate and serrated detection rate among trainee fellows.

Background and Aims: The utilization of artificial intelligence (AI) with computer-aided detection (CADe) has the potential to increase the adenoma detection rate (ADR) by up to 30% in expert settings and specialized centers. The impact of CADe on serrated polyp detection rates (SDR) and academic trainees ADR & SDR remains underexplored. We aim to investigate the effect of CADe on ADR and SDR at an academic center with various levels of providers' experience. Methods: A single-center retrospective analysis was conducted on asymptomatic patients between the ages of 45 and 75 who underwent screening colonoscopy. Colonoscopy reports were reviewed for 3 months prior to the introduction of GI Genius™ (Medtronic, USA) and 3 months after its implementation. The primary outcome was ADR and SDR with and without CADe. Results: Totally 658 colonoscopies were eligible for analysis. CADe resulted in statistically significant improvement in SDR from 8.92% to 14.1% (P = 0.037). The (ADR + SDR) with CADe and without CADe was 58% and 55.1%, respectively (P = 0.46). Average colonoscopy (CSC) withdrawal time was 17.33 min (SD 10) with the device compared with 17.35 min (SD 9) without the device (P = 0.98). Conclusion: In this study, GI Genius™ was associated with a statistically significant increase in SDR alone, but not in ADR or (ADR + SDR), likely secondary to the more elusive nature of serrated polyps compared to adenomatous polyps. The use of CADe did not affect withdrawal time.

Safety and efficacy of underwater endoscopic mucosal resection for 10-20 mm colorectal serrated lesions (SEA CLEAR study).

BACKGROUND AND AIMS: Colorectal serrated lesions (SLs) are precursors of colorectal carcinoma via the serrated neoplasia pathway. However, the success rate of endoscopic resection of large SLs is low. Therefore, this study aimed to determine the safety and efficacy of underwater endoscopic mucosal resection (UEMR) for SLs sized 10-20 mm. METHODS: This two-center prospective observational study included patients with at least one SL sized 10-20 mm. We resected the SLs by UEMR and performed tattooing at the resection site. Surveillance colonoscopy was performed 12 months postoperatively to evaluate local recurrence. The primary outcome was the complete resection rate of UEMR, which was defined as en bloc resection with no serrated tissue in the four marginal biopsies and histologically negative margins. RESULTS: UEMR was performed for 65 SLs in 58 patients, with a median lesion size of 14 mm. The en bloc, R0 resection, and complete resection rates were 87.7% (57/65), 61.5% (40/65), and 60.0% (39/65), respectively. Adverse events included 1 (1.5%) immediate bleeding and 1 (1.5%) delayed perforation. Surveillance colonoscopy was performed in 50 patients with 57 scars, and the rates of identification for tattoos and scars were 94.7% (54/57) and 100% (57/57), respectively. The recurrence rate was 5.3% (3/57), and all three recurrent lesions were completely resected endoscopically. CONCLUSIONS: This two-center prospective study demonstrated that UEMR for SLs sized 10-20 mm was comparable to previous conventional endoscopic mucosal resection outcomes.

Current sessile serrated lesion incidence: implications for future clinical practice.

BACKGROUND: Sessile serrated lesions (SSL) account for up to 30% of colorectal carcinoma pathogenesis. With multiple classification changes and improvements in colonoscopy equipment and technique, historical reporting may have underestimated the true incidence of SSLs. This study aimed to determine the incidence of SSLs in patients undergoing colonoscopic investigation in Canterbury, New Zealand over a 1-year period and describe their clinical and pathological characteristics. METHODS: Electronic records were searched to identify all lower endoscopy procedures with polypectomy performed from 1 January 2022 to 1 December 2022 (inclusive). Patients' electronic records were used to collect histological classification, location and size of each polyp removed during their procedure. The primary outcome was the number of procedures that had one or more SSL, adenoma or hyperplastic polyp identified. Secondary outcomes included histological classification, location and size of each polyp removed. RESULTS: There were 4346 procedures completed during the study period. Of these, 64.1% (2786) had a polypectomy and 18.6% (808) had at least one SSL excised. Individual polyp analysis was completed on 9166 polyps and found that 24.0% of polyps removed were SSLs and they were found predominately in the right colon (65.1% right colon, 32.6% left colon, 2.3% rectum). SSLs were typically <10 mm (84.8%). CONCLUSION: This study found a higher incidence of SSLs compared to previous research. These results raise questions regarding whether SLL rates have been historically underestimated, whether SSL detection rate should be included as a key performance indicator and raises further concerns regarding the use of computed tomography colonography as a screening tool.

Clinical and endoscopic characteristics of colorectal sessile serrated lesions with or without dysplasia/carcinoma: A systematic review and meta-analysis.

OBJECTIVE: We aimed to compare the clinical and endoscopic characteristics of sessile serrated lesions (SSLs) with dysplasia/carcinoma (SSLD/Cs) and SSLs without dysplasia in this systematic review and meta-analysis. METHODS: MEDLINE, EMBASE, and Cochrane Library databases and Clinicaltrials.gov were searched for relevant studies published up to August 28, 2023. The primary outcome was lesion size in SSLD/Cs and SSLs without dysplasia. The secondary outcomes included risk of dysplasia/carcinoma, morphology (classified based on the Paris classification), and lesion features such as mucus cap and nodules/protrusions in the two groups. RESULTS: Thirteen studies with 14 381 patients were included. The proportion of SSLD/Cs ≥10 mm was significantly higher than that of SSLs without dysplasia (odds ratio [OR] 3.82, 95% confidence interval [CI] 1.21-12.02, p = 0.02). There was no significant difference in the risk of dysplasia/carcinoma between the proximal (OR 0.80, 95% CI 0.57-1.14) and distal colon (OR 1.25, 95% CI 0.88-1.77, p = 0.21). The 0-Ip (OR 2.47, 95% CI 1.50-4.09) and 0-IIa + Is (OR 10.38, 95% CI 3.08-34.98) morphologies were more prevalent among SSLD/Cs, whereas the 0-IIa morphology (OR 0.38, 95% CI 0.22-0.65) was more prevalent among SSLs without dysplasia (all p < 0.001). Furthermore, mucus cap (OR 0.61, 95% CI 0.42-0.89, p = 0.01) was more common among SSLs without dysplasia, whereas nodules/protrusions (OR 7.80, 95% CI 3.07-19.85, p < 0.001) were more common in SSLD/Cs. CONCLUSION: SSLs >10 mm, 0-Ip or 0-IIa + Is morphologies, and those with nodules/protrusions are significantly associated with dysplasia/carcinoma.

Cold snare polypectomy: A closer look at the efficacy and limitations for polyps 10-20 mm in size.

Current guidelines recommend cold snare polypectomy for polyps less than 10 mm in size. Conversely, endoscopic mucosal resection is still the preferred technique for larger polyps. Concerns regarding cold snare polypectomy for larger polyps revolve around the difficulty in conducting en-bloc resection (resulting in piecemeal removal), and the potential for local residual polyp tissue and a high rate of recurrence. On the other hand, cold snare technique has the advantages of shortening procedure time, reducing delayed bleeding risks and lowering cost of treatment. Numerous ongoing and recent studies are focused on evaluating the risks and benefits of this technique for polyps larger than 10 mm, with the goal of providing clear guidelines in the near future. The aim of this editorial is to provide our readers with an overview regarding this subject and the latest developments surrounding it.

Analysis of Immunohistochemical Expression of BRAF (V600E) Mutation in Serrated Colorectal Polyps: A Study from Tertiary Hospital in Oman.

BACKGROUND AND AIM: Colorectal cancer (CRC) is considered one of the most common cancers in the world. Serrated polyps were found to be precursor lesions for CRC. BRAF mutation (V600E) has been strongly linked to the development of these lesions. No previous study concerning BRAF immunohistochemical expression in serrated polyps- was done in Oman. The primary objective of our study was to assess the prevalence of BRAF (V600E) mutation in serrated colorectal polyps in the Omani population. The secondary objectives were to assess the prevalence of serrated polyps and their characteristic features: type, site and size as well as the relationship between BRAF (V600E) mutation and polyp type, site and size. MATERIALS AND METHODS: Ninety-one hyperplastic polyps (HP) (76.5%), 24 sessile serrated lesions (SSL) (20.2%) and 4 cases of tubular adenomas with low grade dysplasia (3.4%) were studied for BRAF (V600E) immunohistochemical expression. No case of traditional serrated adenoma (TSA) was present. Control cases of craniopharyngioma and papillary thyroid carcinoma were included. RESULTS: BRAF (V600E) IHC was positive in 63 of the HP polyps (69.2%), 13 SSLs (54.2%) and none of the adenomatous polyps. The majority of positive polyps (75.0%) were ≤5 mm in size, 17.9% were 5-10 mm and 7.1% were ≥10 mm in size.  The majority of BRAF (V600E) positive polyps (68.1 %) were in the distal colon and 31.9 % were in the proximal colon. The majority of positive cases for BRAF (V600E) were showing multiple polyps (61.8 %). None of the tubular adenomas showed any BRAF (V600E) positivity. CONCLUSION: Serrated polyps are now well known for their potential to develop CRC. Immunohistochemistry is an easy and reproducible way to detect BRAF (V600E) mutation. Our study showed there is high prevalence (64.3%) of BRAF mutation in serrated polyps in the Omani population. The majority of these polyps- were HP and SSL; and ≤5 mm in size and located in the distal colon.

A practical guide to serrated appendiceal lesions.

Several neoplastic and non-neoplastic proliferations of the appendix can show varying degrees of serrated epithelial architecture. Of these, diffuse mucosal hyperplasia is most common, followed in frequency by low-grade mucinous and serrated neoplasms. It is important to distinguish serrated appendiceal neoplasms from their potential mimics because these entities may be managed differently. Diffuse mucosal hyperplasia is a non-neoplastic change that usually develops in the setting of resolving appendicitis and requires no further therapy or surveillance, and serrated neoplasms confined to the mucosa are adequately treated by appendectomy alone. On the other hand, low-grade appendiceal mucinous neoplasms may require surveillance, and those with extra-appendiceal spread differ from adenocarcinomas arising from serrated neoplasms with respect to both treatment and prognosis. Low-grade mucinous neoplasms in the peritoneum are frequently amenable to peritoneum-directed therapies alone, while adenocarcinomas derived from serrated neoplasms often spread to both regional lymph nodes and the peritoneum, potentially requiring right colectomy and systemic chemotherapy. The purpose of this review is to summarize the literature regarding the clinical and pathologic features of appendiceal lesions that show epithelial serration and provide the reader with helpful tips to distinguish serrated neoplasms from their mimics.

BRAF-mutant mismatch repair deficient invasive colon cancer regressing to sessile serrated lesion.

A 69-year-old female was presented with a history of sigmoid colon cancer, uterine cancer, and intrahepatic carcinomas. After computed tomography revealed a disseminated nodule located in the peritoneum, colonoscopy demonstrated a rather flat-to-slightly elevated lesion with a depressed area located in the ascending colon. The flat component showed color similar to its surrounding area, and the depressed area showed redness and an expanded appearance. We obtained a biopsy specimen from the depressed area, and microscopic examination revealed well-differentiated adenocarcinoma, which was immunohistochemically positive for BRAF V600E-mutated and PMS2 proteins, and showed loss of MSH2 and MSH6 protein expressions. These findings suggested the lesion to have transformed from a sessile serrated lesion (SSL) to mismatch repair (MMR) deficient colon cancer. The patient underwent surgical removal of the nodule, which interpreted as metastasis of intrahepatic cholangiocarcinoma histopathologically. After postoperative chemotherapy, the follow-up colonoscopy revealed only the flat portion of the lesion without depressed area. Consequently, we performed an endoscopic resection, and microscopic examination confirmed the existence of BRAF V600E-mutated protein-positive and MMR protein-retained SSL without residual carcinoma. This is the first report of BRAF-mutant and MMR-deficient colon cancer, in association with SSL, showing regression.

Histopathological comparison of colorectal neoplasia or polyps development between young adults and older adults: Our experience of 735 consecutive cases and 1269 polyps.

Objective: In recent decades, there has been an increase in early-onset colorectal cancer, the need to screen individuals younger than 50 years of age, and the presence of histopathological differences remains unclear. The objective of this study was to explore the occurrence of polyps in both young adults and older individuals and to examine their potential correlation with colorectal cancer. Methods: In this retrospective study conducted between July 1, 2018, and October 5, 2022, in the Pathology Laboratory, we designed a study based on the histopathological features of colorectal polyps evaluated by an experienced gastrointestinal pathologist based on the WHO 2019 classification. Results: We evaluated 735 consecutive patients who underwent colonoscopic polypectomy between July 2018 and October 2022. The prevalence of cases under the age of 50 was 13.9%, and adults over the age of 50 was 86.1%. A total of 1269 polyps were detected, 1215 (95.7%) were epithelial polyps and 145 (11.9%) were epithelial polyps under the age of 50. One hundred four conventional adenomas and four intramucosal carcinomas were detected in cases younger than 50 years. The patients in the low-risk adenoma group was 57%, and the rate of patients in the high-risk adenoma group was 14.9%. Overall, polyps were most common in the sigmoid colon and there was a statistically significant difference between detecting tubular adenomas in the sigmoid colon (P=0.04). Conclusions: Our current results confirm the detection of sporadic colorectal adenomas and advanced neoplasia in young adults.It is important to establish professional community guidelines for surveillance colonoscopy in these age groups.

Different modifiable risk factors for the development of non-advanced adenoma, advanced adenomatous lesion, and sessile serrated lesions, on screening colonoscopy.

The development of premalignant colorectal polyps is significantly influenced by various lifestyle and modifiable risk factors. In our study, we used a large cohort of 9025 patients, who underwent screening colonoscopies at a university hospital, to assess the risk factors associated with the development of three different colorectal cancer precursor lesions: non-advanced adenomas (NAs), advanced adenomatous lesions (ADLs), and sessile serrated lesions (SSLs). Among the participants, 3641 had NAs, 836 had ADLs, and 533 had SSLs. We identified obesity, current smoking, and appendicular skeletal muscle mass as modifiable lifestyle risk factors that increase the development of NAs and ADLs (all P < 0.05). Furthermore, we found a positive correlation between the degree of obesity and an increased risk of developing NAs and ADLs (all P for trend < 0.001), while non-smoking was associated with a decreased risk (P for trend < 0.001 and 0.003, respectively). Smoking was the only modifiable risk factor for developing SSLs (adjusted odds ratio [aOR] 1.58; 95% confidence interval [CI] 1.20-2.07), and the risk was even higher in patients with metabolic syndrome (aOR 1.71; 95% CI 1.05-2.77). Addressing modifiable lifestyle factors such as smoking and obesity could play an important role in reducing the risk of both non-advanced and advanced adenomatous lesions. Smoking cessation is especially important as it is a significant modifiable risk factor for sessile serrated lesions.

Endoscopic characteristics and performance of WASP classification in the diagnosis of colorectal sessile-serrated lesions in Vietnamese patients.

Background/Aims: Sessile-serrated lesions (SSLs) are challenging to detect due to their typically subtle appearance. The Workgroup serrAted polypS and Polyposis (WASP) classification was developed to diagnose SSLs endoscopically. This study aimed to evaluate the endoscopic characteristics of SSLs and the performance of the WASP classification in the Vietnamese population. Methods: This cross-sectional study was carried out on patients with lower gastrointestinal symptoms who underwent colonoscopy at a Vietnamese tertiary hospital. Univariate and multivariate analyses were performed to identify endoscopic features associated with SSLs. The performance of the WASP classification for diagnosing SSLs was assessed, and SSLs were diagnosed according to the 2019 World Health Organization (WHO) criteria. Results: There were 2489 patients, with a mean age of 52.1 ± 13.1 years and a female-to-male ratio of 1:1.1. A total of 121 specimens from 105 patients were diagnosed with SSLs. According to multivariate analysis, the endoscopic features significantly associated with SSLs were proximal location (odds ratio [OR]: 2.351; 95% confidence interval [CI]: 1.475-3.746), size >5 mm (OR: 2.447; 95% CI: 1.551-3.862), flat morphology (OR: 2.781; 95% CI: 1.533-5.044), irregular shape (OR: 4.516; 95% CI: 2.173-9.388), varicose microvascular vessels (OR: 5.030; 95% CI: 2.657-9.522), and dark spots inside the crypts (OR: 5.955; 95% CI: 3.291-10.776). The accuracy of the WASP classification for diagnosing SSLs was 94.0% (95% CI: 92.8%-95.0%). Conclusion: Proximal location, size >5 mm, flat morphology, irregular shape, varicose microvascular vessels, and dark spots inside the crypts were significantly associated with SSLs. The WASP classification had high accuracy in the diagnosis of SSLs.

Unmasking early colorectal cancer clues: in silico and in vitro investigation of downregulated IGF2, SOCS1, MLH1, and CACNA1G in SSA polyps.

BACKGROUND AND AIM: Colorectal cancer (CRC) originates from pre-existing polyps in the colon. The development of different subtypes of CRC is influenced by various genetic and epigenetic characteristics. CpG island methylator phenotype (CIMP) is found in about 15-20% of sporadic CRCs and is associated with hypermethylation of certain gene promoters. This study aims to find prognostic genes and compare their expression and methylation status as potential biomarkers in patients with serrated sessile adenomas/polyps (SSAP) and CRC, in order to evaluate which, one is a better predictor of disease. METHOD: This study employed a multi-phase approach to investigate genes associated with CRC and SSAP. Initially, two gene expression datasets were analyzed using R and Limma package to identify differentially expressed genes (DEGs). Venn diagram analysis further refined the selection, revealing four genes from the Weissenberg panel with significant changes. These genes, underwent thorough in silico evaluations. Once confirmed, they proceeded to wet lab experimentation, focusing on expression and methylation status. This comprehensive methodology ensured a robust examination of the genes involved in CRC and SSAP. RESULT: This study identified cancer-specific genes, with 8,351 and 1,769 genes specifically down-regulated in SSAP and CRC tissues, respectively. The down-regulated genes were associated with cell adhesion, negative regulation of cell proliferation, and drug response. Four highly downregulated genes in the Weissenberg panel, including CACNA1G, IGF2, MLH1, and SOCS1. In vitro analysis showed that they are hypermethylated in both SSAP and CRC samples while their expressions decreased only in CRC samples. CONCLUSION: This suggests that the decrease in gene expression could help determine whether a polyp will become cancerous. Using both methylation status and gene expression status of genes in the Weissenberg panel in prognostic tests may lead to better prognoses for patients.

Identification of Early Events in Serrated Pathway Colorectal Tumorigenesis by Using Digital Spatial Profiling.

INTRODUCTION: The colorectal serrated pathway involves precursor lesions known as sessile serrated lesions (SSL) and traditional serrated adenomas (TSA). Mutations in BRAF or KRAS are crucial early events in this pathway. Additional genetic and epigenetic changes contribute to the progression of these lesions into high-grade lesions and, eventually, invasive carcinoma. METHODS: We employed digital spatial profiling to investigate the transcriptional changes associated with SSL and TSA. The genes identified are confirmed by immunohistochemical (IHC) staining. Colorectal cancer (CRC) cell lines with CEACAM6 overexpression and knockdown were established to study the roles of CEACAM6 on tumorigenesis of CRC. RESULTS: Ten genes were upregulated in SSL and TSA, and seven were upregulated in both types of lesions. IHC staining confirmed overexpression of CEACAM6, LCN2, KRT19, and lysozyme in SSL and TSA. CEACAM6 expression is an early event in the serrated pathway but a late event in the conventional pathway. Using cell line models, we confirmed that CEACAM6 promotes CRC cells' proliferation, migration, and invasion abilities. CONCLUSION: These results highlight that the transcriptional changes in the early stages of tumorigenesis exhibit relative uniformity. Identifying these early events may hold significant promise in elucidating the mechanisms behind tumor initiation.

Predictors for dMMR colorectal cancer in patients with serrated lesions and polyps - A register-based cohort study.

BACKGROUND: Serrated lesions and polyps (SP) are precursors of up to 30 % of colorectal cancers (CRC) through the serrated pathway. This often entails early BRAF mutations and MLH1 hypermethylation leading to mismatch repair deficient (dMMR) CRC. We investigated predictors of dMMR CRC among patients with co-occurrence of CRC and SP to increase our knowledge on the serrated pathway. METHODS: We used data from The Danish Pathology Registry and Danish Colorectal Cancer Groups Database from the period 2010-2021 to investigate risk factors for development of dMMR CRC. We used logistic regression models to identify difference in risk factors of developing dMMR CRC in comparison to CRC with proficient MMR (pMMR). RESULTS: We included 3273 patients with a median age of 70.7 years [64.3,76.4] of which 1850 (56.5 %) were male. dMMR CRC was present in 592 patients (18.1 %), with loss of MLH1/PMS2 being most common. The risk of dMMR CRC was significantly higher in females OR 3.47 [2.87;4.20]. When adjusting for age, SP subtype, conventional adenomas (CA), anatomical location and lifestyle factors, female sex remained the strongest predictor OR 2.84 [2.27;3.56]. The presence of sessile serrated lesions with or without dysplasia was related to higher risk OR 1.60 [1.11;2.31] and OR 1.42 [1.11;1.82] respectively, while conventional adenomas constituted a lower risk OR 0.68 [0.55;0.84]. CONCLUSION: In conclusion we found several predictors of whom female sex had the strongest correlation with dMMR CRC in patients with SP.

Serrated polyposis syndrome: defining the epidemiology and predicting the risk of dysplasia.

BACKGROUND: Serrated polyposis syndrome is the most common polyposis syndrome that has neoplastic potential. However, the natural history, genetic basis, and risk of dysplasia and neoplasia of serrated polyposis syndrome are incompletely understood. The objective of this study is to define the epidemiology of serrated polyposis syndrome. Using this data, we aim to evaluate candidate variables for predicting the risk of dysplasia and neoplasia in sessile serrated lesions found in serrated polyposis syndrome patients. Finally, we aim to use this data to create and evaluate clinical prediction models for accuracy in predicting dysplastic sessile serrated lesions in serrated polyposis syndrome patients. METHODS: This was a regional Australian single-centre retrospective cohort study. Data was prospectively collected data from the clinical record database of a regional Australian gastroenterology practice. All patients undergoing colonoscopy at Port Macquarie Gastroenterology between January 2015 and September 2021 were screened for this study. Collected data included patient demographic, endoscopic, and histopathological findings. Clinical and endoscopic multivariate logistic regression models were created to predict dysplastic sessile serrated lesions. Model performance was examined using the area under the receiver operating curve. RESULTS: In total 8401 patients underwent a colonoscopy procedure during the study period. Serrated polyposis syndrome was diagnosed in 247, representing a prevalence of 2.94% (mean age 67.15 years, 62.75% female). Logistic regression identified; older age at serrated polyposis syndrome diagnosis, a personal history of colorectal cancer, size of the largest sessile serrated lesions removed, and total sessile serrated lesions count as predictors of dysplastic sessile serrated lesions. The clinical and endoscopic model had an area under the receiver operating curve of 0.75. CONCLUSION: Serrated polyposis syndrome is more common than previously described. The clinical and endoscopic variables identified in logistic regression have acceptable accuracy in predicting the risk of dysplasia, however other populations need to be studied to achieve generalisability and improve model performance.

TGFß-Responsive Stromal Activation Occurs Early in Serrated Colorectal Carcinogenesis.

Activated TGFß signaling in the tumor microenvironment, which occurs independently of epithelial cancer cells, has emerged as a key driver of tumor progression in late-stage colorectal cancer (CRC). This study aimed to elucidate the contribution of TGFß-activated stroma to serrated carcinogenesis, representing approximately 25% of CRCs and often characterized by oncogenic BRAF mutations. We used a transcriptional signature developed based on TGFß-responsive, stroma-specific genes to infer TGFß-dependent stromal activation and conducted in silico analyses in 3 single-cell RNA-seq datasets from a total of 39 CRC samples and 12 bulk transcriptomic datasets consisting of 2014 CRC and 416 precursor samples, of which 33 were serrated lesions. Single-cell analyses validated that the signature was expressed specifically by stromal cells, effectively excluding transcriptional signals derived from epithelial cells. We found that the signature was upregulated during malignant transformation and cancer progression, and it was particularly enriched in CRCs with mutant BRAF compared to wild-type counterparts. Furthermore, across four independent precursor datasets, serrated lesions exhibited significantly higher levels of TGFß-responsive stromal activation compared to conventional adenomas. This large-scale analysis suggests that TGFß-dependent stromal activation occurs early in serrated carcinogenesis. Our study provides novel insights into the molecular mechanisms underlying CRC development via the serrated pathway.

Effect of fecal immunochemical test cut-off levels on adenoma detection rate: a systematic review and meta-analysis.

BACKGROUND: Adenoma detection rate (ADR) is higher after a positive fecal immunochemical test (FIT) compared to direct screening colonoscopy. OBJECTIVE: This meta-analysis evaluated how ADR, the rates of advanced adenoma detection (AADR), colorectal cancer detection (CDR), and sessile serrated lesion detection (SSLDR) are affected by different FIT positivity thresholds. METHODS: We searched MEDLINE, EMBASE, CINAHL, and EBM Reviews databases for studies reporting ADR, AADR, CDR, and SSLDR according to different FIT cut-off values in asymptomatic average-risk individuals aged 50-74 years old. Data were stratified according to sex, age, time to colonoscopy, publication year, continent, and FIT kit type. Study quality, heterogeneity, and publication bias were assessed. RESULTS: Overall, 4280 articles were retrieved and fifty-eight studies were included (277,661 FIT-positive colonoscopies; mean cecal intubation 96.3%; mean age 60.8 years; male 52.1%). Mean ADR was 56.1% (95% CI 53.4 - 58.7%), while mean AADR, CDR, and SSLDR were 27.2% (95% CI 24.4 - 30.1%), 5.3% (95% CI 4.7 - 6.0%), and 3.0% (95% CI 1.7 - 4.6%), respectively. For each 20 µg Hb/g increase in FIT cut-off level, ADR increased by 1.54% (95% CI 0.52 - 2.56%, p < 0.01), AADR by 3.90% (95% CI 2.76 - 5.05%, p < 0.01) and CDR by 1.46% (95% CI 0.66 - 2.24%, p < 0.01). Many detection rates were greater amongst males and Europeans. CONCLUSIONS: ADRs in FIT-positive colonoscopies are influenced by the adopted FIT positivity threshold, and identified targets, importantly, proved to be higher than most current societal recommendations.

Serrated Polyps in Inflammatory Bowel Disease Indicate a Similar Risk of Metachronous Colorectal Neoplasia as in the General Population.

BACKGROUND: The risk of metachronous advanced neoplasia after diagnosing serrated polyps in patients with IBD is poorly understood. METHODS: A retrospective multicenter cohort study was conducted between 2010 and 2019 at three tertiary centers in Montreal, Canada. From pathology databases, we identified 1587 consecutive patients with serrated polyps (sessile serrated lesion, traditional serrated adenoma, or serrated epithelial change). We included patients aged 45-74 and excluded patients with polyposis, colorectal cancer, or no follow-up. The primary outcome was the risk of metachronous advanced neoplasia (advanced adenoma, advanced serrated lesion, or colorectal cancer) after index serrated polyp, comparing patients with and without IBD. RESULTS: 477 patients with serrated polyps were eligible (mean age 61 years): 37 with IBD, totaling 45 serrated polyps and 440 without IBD, totaling 586 serrated polyps. The median follow-up was 3.4 years. There was no difference in metachronous advanced neoplasia (HR 0.77, 95% CI 0.32-1.84), metachronous advanced adenoma (HR 0.54, 95% CI 0.11-2.67), and metachronous advanced serrated lesion (HR 0.76, 95% CI 0.26-2.18) risk. When comparing serrated polyps in mucosa involved or uninvolved with IBD, both groups had similar intervals from IBD to serrated polyp diagnosis (p > 0.05), maximal therapies (p > 0.05), mucosal inflammation, inflammatory markers, and fecal calprotectin (p > 0.05). CONCLUSION: The risk of metachronous advanced neoplasia after serrated polyp detection was similar in patients with and without IBD. Serrated polyps in IBD occurred independently of inflammation. This helps inform surveillance intervals for patients with IBD diagnosed with serrated polyps.