Colorectal Precursor Lesions Research Articles

Age-Specific Differences in the Risk of Colorectal Precursor Lesions Among Patients with Type 2 Diabetes Undergoing Surveillance Colonoscopy.

The incidence rate of colorectal cancer (CRC) in young adults is rising in parallel with type 2 diabetes (T2D). The majority of CRC develop through two main subtypes of precursor lesions; adenomas and serrated lesions. The associations between age and T2D on development of precursor lesions remain uncertain. We studied the association of T2D with the development of adenomas and serrated lesions in individuals <50 versus ≥50 years of age, in a population undergoing long-term regular surveillance colonoscopy due to an elevated risk of CRC. A case-control study was conducted on patients who were enrolled in a surveillance colonoscopy program between 2010-2020. Findings at colonoscopy, clinical and demographic features were collected. Adjusted and unadjusted binary logistic regression assessed the association of age, T2D, sex, and other medical conditions and lifestyle-related factors with different subtypes of precursor lesions diagnosed at colonoscopy. Cox proportional hazards model analysis determined the association of T2D and other confounders with development time for precursor lesions. Cases included 412 patients <50y [mean age 38.7 (range, 24-49y)] and 824 sex-matched controls ≥50y [62.1 (50-75y)]. Individuals <50y were less likely to have been diagnosed with T2D than those ≥50y (7% vs 22%, P-value<0.001). During the follow-up period, there was no significant association between T2D and diagnosis of any precursor lesions, but when considering development time, individuals with T2D developed non-significant adenomas earlier than those without T2D (HR =1.46; 95% CI: 1.14-1.87; P-value=0.003). However, this was not independent of age or findings at index colonoscopy. T2D does not further increase the incidence of adenomas or serrated lesions in either a young or older cohort undergoing long-term surveillance colonoscopy.

Abstract IA025: Stem and metaplastic cell states and their influences on the tumor immune microenvironment in colonic pre-cancerous lesions

Abstract The immune microenvironment is critical to colorectal cancer (CRC) pathogenesis, regarding both prognosis and therapeutic responses. While much work has been done to characterize tumor microenvironments, less is known about those environments are established following transformation of epithelial cells. We hypothesize that mapping routes towards CRCs, from normal human colonic tissues and precursor polyps, will uncover additional mechanisms that define the CRC cellular landscape and identify targets with diagnostic or therapeutic utility. Here, we present a comparative atlas of the two most common colorectal precursor lesions, conventional adenomas and serrated polyps, and their resulting CRC counterparts using single-cell transcriptomics and multiplex imaging across two cohorts of human participants. Integrative analysis reveals adenomas arise from dysregulated WNT-driven expansion of stem cells, while serrated polyps are depleted of stem cell populations and are derived from differentiated cells transitioning through a pyloric metaplasia program. Mucosal damage associated with metaplasia is coupled to a cytotoxic immune microenvironment that precedes hypermutation. Mouse and organoid experiments validate the importance of the differentiation states of colonic tumor cells in driving cytotoxic immunity partly through increased expression of antigen-presentation machinery. These data provide constitute a rich resource into malignant progression of colorectal polyps and their microenvironments, serving as a framework for precision surveillance and prevention of CRC. Citation Format: Ken S. Lau. Stem and metaplastic cell states and their influences on the tumor immune microenvironment in colonic pre-cancerous lesions [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA025.

Somatic targeted mutation profiling of colorectal cancer precursor lesions

BackgroundMost colorectal cancers (CRC) arise from precursor lesions. This study aimed to characterize the mutation profile of colorectal cancer precursor lesions in a Brazilian population.MethodsIn total, 90 formalin-fixed paraffin-embedded colorectal precursor lesions, including 67 adenomas, 7 sessile serrated lesions, and 16 hyperplastic polyps, were analyzed by next-generation sequencing using a panel of 50 oncogenes and tumor suppressor genes. The genetic ancestry of the patients was estimated.ResultsSomatic driver mutations were identified in 66.7% of cases, including alterations in APC (32.2%), TP53 (20.0%), KRAS (18.9%), BRAF (13.3%) and EGFR (7.8%). Adenomas displayed a higher number of mutations, mainly in APC, compared to serrated polyps (73.1% vs. 47.8%, p = 0.026). Advanced adenomas had a significantly higher frequency of mutation in KRAS and a high overall mutation rate than early adenomas (92.9% vs. 59%, p = 0.006). A high degree of ancestry admixture was observed in the population studied, with a predominance of European components (mean of 73%) followed by African (mean of 11.3%). No association between genetic ancestry and type of lesions was found. The mutation profile of Brazilian colorectal precursor lesions exhibits alteration in APC, KRAS, TP53, and BRAF at different frequencies according to lesion type.ConclusionsThese results bestow the knowledge of CRC's biologic history and support the potential of these biomarkers for precursor lesions detection in CRC screening of the Brazilian population.

Methylation profile of colon cancer genes in colorectal precursor lesions and tumor tissue: perspectives for screening

Aims Epigenetic alterations of genes involved in colorectal carcinogenesis are likely to be informative biomarkers for early detection. We assessed the methylation profile of a panel of seven colon cancer-related genes comparing normal colon, colorectal cancer (CRC) precursor lesions and cancer tissues from a Brazilian cohort. Methods The cohort comprised 114 CRC patients, including 40 matched normal tissue, 47 patients with adenomas, 33 with serrated polyps and 8 with normal colonic biopsy. DNA methylation status of SEPT9, ALX4, NDRG4, BMP3, APC, p16 and MLH1 was determined by pyrosequencing and correlated with clinicopathological features. Sensitivity, specificity, positive predictive value and negative predictive value were calculated for all genes using cancer endpoint. Results The most frequently methylated genes in cancer and in precancer lesions were SEPT9, ALX4, NDRG4, and BMP3, ranging from 55.3 to 95% of the samples. Overall, the frequency of methylation of these four genes in normal colonic tissue was significantly lower as compared to cancer or precursor lesions both in adenoma–carcinoma (p < .001 and p < .050) and serrated (sessile-serrated lesion) (p < .001 and p < .050) pathways. Additionally, sensitivity for the cancer endpoint ranged from 65.6 to 91.8%, and specificity from 17.9 to 62.9% for SEPT9, ALX4, NDRG4, and BMP3 genes. Moreover, the comethylation of ≥4 genes was higher in sessile-serrated lesion (87.5%) and conventional adenomas (78.7%) than in hyperplastic polyps (43.7%) (p = .025) and was significantly associated with proximal cancers (p = .042). Conclusions Our study suggests the DNA methylation can constitute potential biomarkers in CRC screening of Brazilian population.

Different TERT Expression between Colorectal Adenoma and Serrated Polyp.

Background and Objectives: Telomere regulation have an association with colorectal cancer. Previous studies demonstrated its implication in colorectal carcinogenesis. This study aimed to identify the role of telomerase reverse transcriptase (TERT) in colorectal carcinogenesis and determine TERT expression and their associated genes in precancerous lesions. Materials and Methods: TERT expression in 93 colorectal precursor lesions was analyzed. This included 61 tubular adenomas (TAs) and 32 serrated polyps (SPs). Furthermore, KRAS and BRAF gene mutations and microsatellite instability were analyzed. Statistical tests were performed to analyze the relationship between variables. Results: TERT expression in TAs, when compared with those observed in paired adjacent nontumor tissues, was 0.92 ± 0.78. TERT expression levels were significantly lower in SPs (0.38 ± 0.14, p < 0.001). KRAS and BRAF mutations were mutually exclusive in TAs and SPs (p < 0.001). TERT expression tended to be associated with KRAS mutations (46.7% vs. 22.0%, p = 0.098) and low-grade tumors (35.0% vs. 16.0%, p = 0.096), but this difference was insignificant. Conclusions: TERT expression has a pivotal role in progression to TAs in colorectal tissue. Considering the association between TERT expression and KRAS mutation, therapeutic drugs targeting this pathway can be developed for cancer prevention.

Periodontal Disease, Tooth Loss, and Risk of Serrated Polyps and Conventional Adenomas.

Growing data indicate an association between periodontal disease and the development of cancer. However, the evidence for colorectal cancer has been inconsistent and longitudinal study examining its precursor lesions is lacking. We prospectively collected information on periodontal disease and number of tooth loss in the Nurses' Health Study (1992-2002) and the Health Professionals Follow-up Study (1992-2010). Polyp diagnosis was acquired via self-reported questionnaires and confirmed through review of medical records. We used logistic regression to calculate the multivariate-adjusted ORs and 95% confidence intervals (CI) with adjustment for smoking and other known risk factors for periodontal disease and colorectal cancer. In this study, we included 17,904 women and 24,582 men. We documented 2,336 cases of serrated polyps and 4,102 cases of conventional adenomas among 84,714 person-endoscopies throughout follow-up. The ORs of serrated polyps and conventional adenomas comparing individuals with and without periodontal disease were 1.17 (95% CI, 1.06-1.29) and 1.11 (95% CI, 1.02-1.19), respectively. Compared with participants without tooth loss, those who lost ≥4 teeth had 20% (OR, 1.20; 95% CI, 1.03-1.39) greater risk of serrated polyps (P trend 0.01). Among never smokers, similar associations with periodontal disease were observed for both serrated polyps (OR, 1.20; 95% CI, 1.02-1.41) and conventional adenomas (OR, 1.12; 95% CI, 1.00-1.26). History of periodontal disease and possibly higher number of tooth loss may modestly increase the risk of developing colorectal precursor lesions. Our findings advance our understanding of the interplay between oral health, microbiome, and early colorectal carcinogenesis.

1125 Body Fatness over the Life Course and the Risk of High-Risk Serrated Polyps and Advanced Conventional Adenomas

INTRODUCTION: Obesity is an established risk factor for colorectal cancer. Serrated polyp (SP) and conventional adenoma (CA) represent two distinct groups of colorectal premalignancy. In contrast to the well-documented effect of adulthood obesity, the influence of early-life body fatness on the risk of developing SPs and CAs remains unclear. METHODS: This prospective study within the Nurses’ Health Study (1990-2012), the Nurses’ Health Study 2 (1991-2013), and the Health Professional Follow-up Study (1990-2010) collected detailed information on body fatness at different ages and the diagnosis of SPs and CAs. We individually examined the risk of high-risk SPs (≥10 mm or proximal SPs) and advanced CAs (≥10 mm or advanced histology) in relation to body fatness in early childhood (age 5), late childhood (age 10), early adulthood (age 18 for women and 21 for men), middle adulthood (baseline) and weight change from early adulthood to middle adulthood. Multivariable-adjusted logistic regression for clustered data was used to calculate the odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Among 29221 men and 132546 women in the three cohorts who had undergone at least one lower bowel endoscopy during 18-20 years of follow-up, we documented 3119 cases of high-risk SP and 3299 cases of advanced CA. The ORs of high-risk SPs and advanced CAs ranged from 1.12 (95% CI, 1.02-1.23) to 1.25 (95% CI, 1.10-1.42) in women who were obese in early and late childhood. The associations were attenuated after adjusting for adulthood BMI. Body fatness in middle adulthood showed a strong positive relationship with the risk of both types of CRC precursor lesion in men and women. Weight change from early adulthood to middle adulthood was associated with greater risk of high-risk SPs in women (OR comparing weight gain ≥20.0 kg to gain or loss &lt; 2.0 kg, 1.39; 95% CI, 1.22-1.58) and men (OR, 1.40; 95% CI, 1.01-1.29), and advanced CAs in both women (OR, 1.14; 95% CI, 1.07-1.82) and men (OR, 1.21; 95% CI, 1.03-1.42). The associations were stronger for high-risk SPs than for advanced CAs in women (P heterogeneity = 0.01 for adulthood BMI, 0.004 for weight change). CONCLUSION: Weight gain during early adulthood and attained adiposity are associated with increased risk of high-risk SPs and advanced CAs in both men and women. There is heterogeneity in the associations among different types of colorectal precursor lesions in women but not in men. Body fatness in childhood is also associated with an increased risk in women.

Molecular profiling of longitudinally observed small colorectal polyps: A cohort study.

BackgroundKnowledge of the natural history of colorectal adenomas is limited because these lesions are removed upon detection. The few studies in which small adenomas have been left in situ for a limited period of time, have shown that most lesions remain stable or even completely regress. Specific DNA copy number changes (‘cancer associated events’ or CAEs) are associated with progression of adenomas to cancer. In this study we evaluated whether molecular features of progression correlated with growth of small polyps.MethodsSmall (6–9 mm) colorectal precursor lesions detected on CT-colonography (CTC) were left in situ and re-evaluated with CTC after three years. Based on volumetric change, polyps were classified as either grown, stable or regressed. Surveillance CTC was followed by colonoscopy, during which all lesions were resected. Using DNA isolated from FFPE polyp tissues, low-coverage whole genome sequencing was performed to determine DNA copy number profiles, as well as target enrichment mutation analysis and CpG island methylation phenotype (CIMP) analysis. Expression of DNA mismatch repair (MMR) proteins was determined by immunohistochemistry. Samples were marked as MMR proficient if all MMR proteins were expressed.FindingsOut of 68 polyps resected at colonoscopy, for 65 (96%) material was available. Of these, 31 (48%) had grown, 27 (41%) remained stable and 7 (11%) regressed. Polyps with at least one CAE had higher growth rates compared to polyps without CAEs (difference 91% growth (95% CI 13–169), p = .023). CAEs were absent in lesions that had partially regressed. Mutations occurred in 94% of the polyps, with higher growth rates being associated with polyps having ≥2 mutations compared to lesions with only 0–1 mutations (difference 99% growth (95% CI 9–189), p = .032). All samples were MMR proficient. No relation between growth and CIMP was observed.InterpretationMolecular alterations associated with colorectal cancer, correlated with growth of small polyps and were absent in polyps that regressed. Therefore, this longitudinal study provides in vivo support in the human setting for the functional role of these molecular alterations, that have mostly been identified by cross sectional observations in tissue samples of colorectal adenomas and cancers.FundAlpe d'Huzes- Dutch Cancer Society (project number NKI2013-6338).

Association of obesity with colonic findings in screening colonoscopy in a large population-based study.

Obesity is associated with an increased incidence of and mortality from colorectal cancer (CRC). Screening colonoscopy seems particularly important for individuals with obesity. The aim of this study is to analyse the characteristics of screening colonoscopy in individuals with obesity. We performed a cross-sectional analysis of records of 75,278 patients from a national colonoscopy screening programme in Poland. The database contained demographic data, colonoscopy results, self-reported data on weight and height, a standardized screenees' experience questionnaire and colorectal findings. Adenoma detection rate and advanced neoplasia detection rate increased significantly in groups of increasing body mass index (BMI). In subjects with morbid obesity, odds ratios for proximal adenoma and proximal advanced neoplasia were 1.69 (95% confidence interval (CI) 1.28-2.21) and 1.66 (95% CI 1.01-2.72), respectively, despite the fact that with BMI increasing over 30 the preparation for colonoscopy was worse. Moreover, caecal intubation increased with increasing BMI. Tolerance of colonoscopy was better and preparation for colonoscopy was less inconvenient in individuals with obesity. Obesity and morbid obesity are associated with increased detection of colorectal precursor lesions and better performance of screening colonoscopy. Participation in screening colonoscopy should be emphasized among individuals with obesity, taking into account the burden of CRC in this population.

Absence of TERT promoter mutations in colorectal precursor lesions and cancer.

Hotspot mutations (c.-124bp G > A and c.-146bp G > A) in the promoter region of the TERT gene have been recently described in several types of solid tumors, including glioma, bladder, thyroid, liver and skin neoplasms. However, knowledge with respect to colorectal precursor lesions and cancer is scarce. In the present study we aimed to determine the frequency of hotspot TERT promoter mutations in 145 Brazilian patients, including 103 subjects with precursor lesions and 42 with colorectal carcinomas, and we associated the presence of such mutations with the patients clinical-pathological features. The mutation analysis was conclusive in 123 cases, and none of the precursor and colorectal carcinoma cases showed TERT promoter mutations. We conclude that TERT mutations are not a driving factor in colorectal carcinogenesis.

Wnt disruption in colorectal polyps - the traditional serrated adenoma enters the fray.

The adenoma-carcinoma sequence describes the development of colorectal carcinoma (CRC) from benign colorectal precursor lesions. Molecular classification of established CRC has demonstrated considerable disease heterogeneity; however, as an emerging cancer frequently outgrows and destroys the initial precursor lesion, CRC molecular taxonomy can only be partially reconciled with histologically classified polyps. Thus, the molecular pathogenesis of some colorectal polyp types, including the traditional serrated adenoma (TSA), is still unclear. Now, candidate driver gene analysis of a cohort of different polyps reveals characteristic, but highly variable, mutations disrupting the Wnt signalling pathway across different histological polyp subtypes. How and when different precursor lesions acquire Wnt disruption reflects important distinctions in polyp biology, dependent on a combination of the dominant molecular pathway and the cell of origin of individual lesions. TSAs preferentially acquire ligand-dependent Wnt activating mutations, which means that the cancers that arise from these aggressive polyps may be sensitive to targeted Wnt inhibition. This paper demonstrates that applying next-generation sequencing technology to improve our understanding of colorectal precursor lesion molecular pathogenesis could also give important and translationally relevant insights into colorectal cancer biology. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Colorectal serrated pathway cancers and precursors.

The serrated pathway (SP) can be viewed as two parallel, but partially overlapping, arrays of colorectal precursor lesions, and their respective endpoint carcinomas, that are distinct from those of the conventional adenoma-carcinoma sequence (APC-pathway). In this review we focus at the outset on the clinical impact, pathological features, molecular genetics and biological behaviours of the various SP cancers. Then we summarize the clinicopathological features, classification and molecular profiles of the two main precursor lesions that anchor the respective pathways: (i) sessile serrated adenoma/polyp (SSA/P), also called sessile serrated lesion (SSL), and (ii) traditional serrated adenoma (TSA). Activating mutations of the RAS-RAF-MAPK pathway initiate and sustain the lesions of the SP, and CpG island methylation of the promoter regions of tumour suppressor and DNA repair genes play the major role in their neoplastic progression. The SP includes microsatellite stable (MSS) carcinomas that are among the most biologically aggressive colorectal carcinomas (CRC), and also accounts for the great preponderance of sporadic hypermutated, mismatch repair (MMR)-deficient or microsatellite instable (MSI) CRC. The identification, removal and appropriate classification of at-risk SP precursors and surveillance of individuals who harbour these lesions present a challenge and opportunity for CRC prevention and mortality reduction.

Fhit, Mlh1, P53 and phenotypic expression in the early stage of colorectal neoplasms

There are two different pathways for the development of colorectal carcinoma (CRC), adenoma-carcinoma sequence (ACS) and de novo (DN) carcinogenesis. To clarify the molecular and clinicopathological characteristics in colorectal carcinogenesis, we examined endoscopically resected specimens of 30 adenomas, 30 carcinoma in adenomas (CIAs), and 18 early pure colorectal carcinomas without any adenoma component (EPCs, so called DN carcinoma) and compared the expression of Fhit, Mlh1, Msh2, P53 and cellular phenotype (HGM, MUC2 and CD10). Markedly reduced or absent Fhit expression was noted in 8 (44%) of 18 EPCs, but none of the adenomas or CIAs (p<0.0001). Six (33%) of 18 EPCs showed loss of Mlh1 expression, but rarely in adenomas and CIAs (p=0.008). This altered Fhit expression was significantly higher in submucosal invasive cancers (p=0.001), lymphatic or venous invasive cancers (p=0.0018), and tumors with altered expression of Mlh1 (p=0.01). The incidence of P53 overexpression was significantly higher in EPCs (39%) and CIAs (27%) than in adenomas (3.3%) (p<0.05). There were significant differences in phenotypic expression between the adenomatous and carcinomatous areas. Moreover, in CIAs and EPCs, the rate of P53 overexpression was significantly higher in the CD10-positive cases (53%) than CD10-negative cases (19%) (p=0.04). The present findings suggested that aberrant Fhit and Mlh1 expression could be related to DN carcinogenesis and that P53 overexpression and changes in phenotypic expression could contribute to the malignant transformation of colorectal precursor lesions.