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Immune response during the progression of premalignant lesions and their molecular subtype to colorectal cancer (CRC) remains unclear. Using gene expression data from 135 normal (NLs), 176 conventional adenomas (AD), 42 serrated polyps (SER), and 2760 CRC samples, we estimated overall immune activity (ImmuneScore) and tumor-infiltrating lymphocyte (TIL) abundance using the xCell tool. We evaluated association of the ImmuneScore and TILs with CRC progression using adjusted multivariable regression models. Immunohistochemistry (IHC) staining for five immunological markers was conducted on NL, early- and late-stage AD, and carcinoma tissues from 75 study participants. The consensus molecular subtypes (CMS) of adenomas and carcinomas were classified using random forest methods, and the association of immune activity with CRC progression was assessed. Immune activity consistently decreased from NLs through premalignant lesions to adenocarcinoma, more prominently in AD than SER (AD vs. NL: odds ratio = 0.86, 95% CI = 0.84‒0.88; SER vs. NL: 0.89, 0.85‒0.93). Similar patterns were observed in B cells, CD4 + effector memory T cells, CD8 + naïve T cells, and CD8 + cytotoxic T cells. IHC staining of these immunological markers verified their roles in CRC progression. Our analysis revealed that CMS3 is a major subtype of AD. Consistently, higher immune activity was observed in premalignant lesions than in CRCs of the CMS3 subtype. This study provides additional insights into alterations in immune response and their important role in CRC premalignant lesion progression and subtypes.

Background and aims: Mutations in BRAF have been linked with colorectal cancers (CRC) showing high level microsatellite instability (MSI-H). However, the distribution of BRAF mutations in MSI-H cancers remains to be clarified with respect to precursor lesions and the CpG island methylator phenotype (CIMP). Methods: Forty three hyperplastic polyps (HP), nine mixed polyps (MP), five serrated adenomas (SA), 28 conventional adenomas (AD), 18 hereditary non-polyposis colorectal cancers (HNPCC), and 127 sporadic CRC (46 MSI-H and 81 non-MSI-H) were collected from patients undergoing colectomy for either CRC or hyperplastic polyposis. Twenty five of 57 serrated lesions were derived from four patients with hyperplastic polyposis. HP were further subdivided according to recently documented morphological criteria into 27 classical HP and 16 variant lesions described as “sessile serrated adenoma” (SSA). All tumours were screened for BRAF activating mutations. Results: The BRAF mutation was more frequent in SSA (75%) and MP (89%) than in classical HP (19%), SA (20%), and AD (0%) (p<0.0001), and also in sporadic MSI-H cancers (76%) compared with HNPCC (0%) and sporadic non-MSI-H cancers (9%) (p<0.0001). The BRAF mutation was identified more often in CIMP-high serrated polyps (72%) and CIMP-high CRC (77%) than in CIMP-low (30%) and CIMP-negative (13%) polyps (p = 0.002) as well as CIMP-low (18%) and CIMP-negative (0%) CRC (p<0.0001). Conclusions: The BRAF mutation was frequently seen in SSA and in sporadic MSI-H CRC, both of which were associated with DNA methylation. Sporadic MSI-H cancers may originate in SSA and not adenomas, and BRAF mutation and DNA methylation are early events in this “serrated” pathway.

Background and aimsPatients with hyperplastic polyposis syndrome (HPS) receive endoscopic surveillance to prevent malignant progression of polyps. However, the optimal treatment and surveillance protocol for these patients is unknown. The aim of this study was to describe the clinical and pathological features of a large HPS cohort during multiple years of endoscopic surveillance.MethodsDatabases were searched for patients with HPS, who were analysed retrospectively. Endoscopy reports and histopathology reports were collected to evaluate frequency of endoscopic surveillance and to obtain information regarding polyp and the presence of colorectal cancer (CRC).ResultsIn 77 patients with HPS, 1984 polyps were identified during a mean follow-up period of 5.6 years (range: 0.5–26.6). In 27 (35%) patients CRC was detected of which 22 (28.5%) at initial endoscopy. CRC was detected during surveillance in five patients (cumulative incidence: 6.5%) after a median follow-up time of 1.3 years and a median interval of 11 months. Of these interval CRCs, 4/5 were detected in diminutive serrated polyps (range: 4–16 mm). The cumulative risk of CRC under surveillance was 7% at 5 years. At multivariate logistic regression, an increasing number of hyperplastic polyps (OR 1.05, p=0.013) and serrated adenomas (OR 1.09, p=0.048) was significantly associated with CRC presence.ConclusionsHPS patients undergoing endoscopic surveillance have an increased CRC risk. The number of serrated polyps is positively correlated with the presence of CRC in HPS, thus supporting a ‘serrated pathway’ to CRC. To prevent malignant progression, adequate detection and removal of all polyps seems advisable. If this is not feasible, surgical resection should be considered.

BackgroundHigher body mass index (BMI) is associated with increased risk of colorectal cancer. How genetically predicted BMI may be associated with colorectal cancer precursors is unknown.AimsOur objective was to quantify the association of genetically predicted and measured BMI with risk of colorectal cancer precursors.MethodsWe evaluated the association of genetically predicted and measured BMI with risk of conventional adenomas, serrated polyps, and synchronous polyps among 27,426 participants who had undergone at least one lower gastrointestinal endoscopy in the Nurses’ Health Study, Nurses’ Health Study II, and Health Professionals Follow-up Study. Genetic risk score was derived from 97 BMI-related single nucleotide polymorphisms. Multivariable logistic regression evaluated each polyp subtype compared to non-polyps.ResultsFor conventional adenomas, the OR per 2-kg/m2 increase was 1.03 (95% CI, 1.01–1.04) for measured BMI and 0.98 (95% CI, 0.88–1.10) for genetically predicted BMI; for serrated polyps, the OR was 1.06 (95% CI, 1.04–1.08) and 1.04 (95% CI, 0.90–1.20), respectively; for synchronous polyps, the OR was 1.10 (95% CI, 1.07–1.13) and 1.09 (95% CI, 0.89–1.34), respectively. Genetically predicted BMI was associated with synchronous polyps in women (OR = 1.37, 95% CI: 1.05–1.79).ConclusionGenetically predicted BMI was not associated with colorectal cancer precursor lesions. The confidence intervals were wide and encompassed those for measured BMI, indicating that null findings may be due to insufficient power.

Colorectal cancer (CRC) development is a gradual process in which progressive histological alterations of the intestinal mucosa damage occur over years. This process can be influenced by modifiable external factors such as lifestyle and diet. Most CRC cases (>80%) originate from conventional adenomas through the adenomatous pathway and usually harbour dysplastic cells, whereas the serrated pathway is less frequent (<20% cases) and comprises hyperplastic polyps and other polyps containing dysplastic cells. The aim of the present work was to shed light on alterations of the faecal metabolome associated with hyperplastic polyps and conventional adenomas. Metabolites were analysed by Reversed-Phase High-Performance Liquid Chromatography-Quadrupole-Time of Flight Mass Spectrometry (RP/HPLC-Q/TOF-MS/MS) and Hydrophilic Interaction Liquid Chromatography–Quadrupole-Time of Flight Mass Spectrometry (HILIC-Q/TOF-MS/MS) and the results were integrated. Comparisons were performed between controls without mucosal lesions and the polyps’ group, hyperplastic polyps versus conventional adenomas, and hyperplastic polyps or conventional adenomas versus controls. Alterations of metabolites in specific biochemical modules differentiated hyperplastic polyps and conventional adenomas. The metabolome of the hyperplastic polyps was characterized by an enrichment in glycerophospholipids and an altered metabolism of the degradation pathways of xanthines/purines and pyrimidines, whereas the enrichment in some phenolic compounds and disaccharides, all of them from exogenous origin, was the main differential faecal signature of conventional adenomas. Further research could help to elucidate the contribution of diet and the intestinal microbiota to these metabolomics alterations.

Colonic crypts with normal epithelial lining displaying corrupted shapes (called non-dysplastic crypts with corrupted shapes, NDCs) were earlier recorded underneath the adenomatous glands of conventional colon adenomas in rats. To assess the frequency of NDCs in clinical sporadic conventional (tubular/villous) adenomas. NDCs found underneath the adenomatous epithelium in 255 sporadic conventional adenomas removed at endoscopy were classified into four groups: i) With fission distortions, ii) with length distortions, iii) with outline distortions, and iv) with axial polarity distortions. In 22 controls, the colonic mucosa proximal or distal to surgically removed colonic adenocarcinomas was scrutinized for NDCs. Nearly three-quarters of the sporadic conventional adenomas investigated here had three or more NDCs underneath the adenomatous tissue, those with ≥4 NDCs being more frequent (46.3%) than those having 1, 2 or 3 NDCs (p<0.05). Nineteen out of the 22 control colon segments had normal crypts and the remaining three had occasional NDCs (mean=3.7, range=2-5). NDCs were found underneath the adenomatous glands in all 255 sporadic conventional adenomas. Occasionally, NDCs were present in the mucosa of the stalk of pediculated conventional adenomas. The absence of adenomatous tissue in NDCs of the stalk should rule out the possibility that the adenomatous tissue on top had directly orchestrated the development of NDCs below. Moreover, NDCs rarely occurred in controls. Accordingly, NDCs emerge as a genuine phenomenon of crypt deformation in sporadic conventional adenomas. Considering that human colonic crypts typically divide at most once or twice during a lifetime, with an average crypt cycle length of 36 years, the accumulation of NDCs underneath sporadic conventional adenomas is remarkable. In light of these considerations, it is suggested that these putative mutated NDCs may represent the initial histological recordable event heralding the development of sporadic conventional adenomas in the human colon.

We recently noticed in nonpolypoid adenomas (NPA) and the adjacent normal mucosa, nondysplastic crypts in symmetric and asymmetric fission (NDCSAF). All NDCSAF found in 80 small NPA and in the adjacent mucosa were registered. A total of 178 NDCSAF (mean, 2.2) were found: 12 (6.7%) interspersed between adenomatous glands, 36 (20.2%) partially replaced by dysplastic epithelium, and 130 (73%) underneath the adenomatous tissue. Of the 61 cases with normal mucosa adjacent to NPA, 40 (65.6%) disclosed NDCSAF, and the remaining 21 (34.4%) normal crypts, exclusively. The accruing of NDCSAF within NPA and surrounding mucosa, are outstanding findings. Given that colonic crypts may undergo only one fission every 30-40 years, the accruing of NDCSAF in and about small NPA reveals mucosal hubs with pathological aberrations of cryptogenesis, probably conveyed by somatic mutations. The findings support the existence of field cancerization in the colonic mucosa.

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.

Progressive intestinal mucosal damage occurs over years prior to colorectal cancer (CRC) development. The endoscopic screening of polyps and histopathological examination are used clinically to determine the risk and progression of mucosal lesions. We analyzed fecal microbiota compositions using 16S rRNA gene-based metataxonomic analyses and the levels of short-chain fatty acids (SCFAs) using gas chromatography in volunteers undergoing colonoscopy and histopathological analyses to determine the microbiota shifts occurring at the early stages of intestinal mucosa alterations. The results were compared between diagnosis groups (nonpathological controls and polyps), between samples from individuals with hyperplastic polyps or conventional adenomas, and between grades of dysplasia in conventional adenomas. Some microbial taxa from the Bacillota and Euryarchaeota phyla were the most affected when comparing the diagnosis and histopathological groups. Deeper microbiota alterations were found in the conventional adenomas than in the hyperplastic polyps. The Ruminococcus torques group was enriched in both the hyperplastic polyps and conventional adenomas, whereas the family Eggerthellaceae was enriched only in the hyperplastic polyps. The abundance of Prevotellaceae, Oscillospiraceae, Methanobacteriaceae, Streptococcaceae, Christensenellaceae, Erysipelotrichaceae, and Clostridiaceae shifted in conventional adenomas depending on the grade of dysplasia, without affecting the major SCFAs. Our results suggest a reorganization of microbial consortia involved in gut fermentative processes.

Abstract Background Removal of colorectal polyps during screening could reduce the incidence of colorectal cancer (CRC). However, there is a lack of data on risk factors associated with recurrence of polyps, including conventional adenomas and serrated polyps (SPs). This study aimed to determine risk factors for recurrence of colorectal polyps and their subtypes based on the characteristics of the patients and polyps. Methods A total of 1,165 patients diagnosed with conventional adenoma or SP in the Sixth Affiliated Hospital of Sun Yat-sen University between January 2013 and December 2019 were enrolled in this study, including 668 cases with conventional adenomas, 385 with SPs, and 112 with coexistence of adenomas and SPs. Univariate analysis and multivariate logistic regression were used to identify potential risk factors for polyp recurrence. A nomogram was established according to risk factors and the performance was evaluated using calibration plots. Results During a median follow-up of 24 months, recurrent polyps were observed in 531 (45.6%) cases. Male, age ≥50 years, body mass index (BMI) ≥24 kg/m2, at least three polyps, smoking, alcohol consumption, family history of polyps, and family history of CRC were independent risk factors for polyp recurrence. The Harrell’s C-index of the nomogram developed with these parameters was 0.69 and the calibration plots showed good agreement between actual polyp recurrence and nomogram-predicted recurrence probability. In the subtype analyses, conventional adenomas had the same risk factors for recurrence as all polyps, while smoking, alcohol consumption, family history of polyps, and family history of CRC were not risk factors for SP recurrence. Conclusions We identified several risk factors for recurrence of colorectal polyps and found that some of them could increase the risk of adenoma recurrence but not SP recurrence, including smoking, alcohol consumption, and family history of polyps/CRC, which might help us to understand different etiology and biology between conventional adenomas and SPs.