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Genetics in Medicine : Official Journal... Feb 2024The Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) was established by the International Society for Gastrointestinal Hereditary Tumours and...
Gene-specific ACMG/AMP classification criteria for germline APC variants: Recommendations from the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel.
PURPOSE
The Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) was established by the International Society for Gastrointestinal Hereditary Tumours and the Clinical Genome Resource, who set out to develop recommendations for the interpretation of germline APC variants underlying Familial Adenomatous Polyposis, the most frequent hereditary polyposis syndrome.
METHODS
Through a rigorous process of database analysis, literature review, and expert elicitation, the APC VCEP derived gene-specific modifications to the ACMG/AMP (American College of Medical Genetics and Genomics and Association for Molecular Pathology) variant classification guidelines and validated such criteria through the pilot classification of 58 variants.
RESULTS
The APC-specific criteria represented gene- and disease-informed specifications, including a quantitative approach to allele frequency thresholds, a stepwise decision tool for truncating variants, and semiquantitative evaluations of experimental and clinical data. Using the APC-specific criteria, 47% (27/58) of pilot variants were reclassified including 14 previous variants of uncertain significance (VUS).
CONCLUSION
The APC-specific ACMG/AMP criteria preserved the classification of well-characterized variants on ClinVar while substantially reducing the number of VUS by 56% (14/25). Moving forward, the APC VCEP will continue to interpret prioritized lists of VUS, the results of which will represent the most authoritative variant classification for widespread clinical use.
Topics: Humans; Genetic Testing; Genetic Variation; Adenomatous Polyposis Coli; Germ-Line Mutation; Germ Cells
PubMed: 37800450
DOI: 10.1016/j.gim.2023.100992 -
Current Opinion in Gastroenterology Nov 2023Adenomas are the most common benign lesions of the gastrointestinal tract. The current review aims to summarize recent literature regarding risk factors, natural... (Review)
Review
PURPOSE OF REVIEW
Adenomas are the most common benign lesions of the gastrointestinal tract. The current review aims to summarize recent literature regarding risk factors, natural history, diagnostic and staging technique, and management strategies for ampullary and nonampullary duodenal adenomas.
RECENT FINDINGS
Recent studies identified several possible risks factors for duodenal adenomas (e.g., cholecystectomy, proton pump inhibitor use), although these associations require corroboration. Chromoendoscopy and endocystoscopy may offer accuracy comparable to biopsies in expert hands. Recent publications underscore the reduction in morbidity with endoscopic resection for lesions without signs of malignancy with submucosal invasion. Submucosal injection did not improve safety of endoscopic ampullectomy.
SUMMARY
Surveillance may be a reasonable strategy for sub-centimeter ampullary adenomas occurring in familial adenomatous polyposis, as they carry a relatively low risk of malignancy. Endoscopic resection is the preferred strategy over surgery in patients without lesions suggestive of invasive malignancy. For nonampullary duodenal adenomas, several endoscopic resection techniques are available, each with their unique advantages and trade-offs. In patients who are not operative candidates but have intraductal extension, endoscopic ablation is an emerging option.
Topics: Humans; Adenoma; Endoscopy; Adenomatous Polyposis Coli; Risk Factors; Duodenal Neoplasms; Retrospective Studies
PubMed: 37807962
DOI: 10.1097/MOG.0000000000000976 -
BioRxiv : the Preprint Server For... May 2024Genetic factors and microbial imbalances play crucial roles in colorectal cancers (CRCs), yet the impact of infections on cancer initiation remains poorly understood....
BACKGROUND
Genetic factors and microbial imbalances play crucial roles in colorectal cancers (CRCs), yet the impact of infections on cancer initiation remains poorly understood. While bioinformatic approaches offer valuable insights, the rising incidence of CRCs creates a pressing need to precisely identify early CRC events. We constructed a network model to identify continuum states during CRC initiation spanning normal colonic tissue to pre-cancer lesions (adenomatous polyps) and examined the influence of microbes and host genetics.
METHODS
A Boolean network was built using a publicly available transcriptomic dataset from healthy and adenoma affected patients to identify an invariant Microbe-Associated Colorectal Cancer Signature (MACS). We focused on ( ), a CRC-associated microbe, as a model bacterium. MACS-associated genes and proteins were validated by RT-qPCR, RNA seq, ELISA, IF and IHCs in tissues and colon-derived organoids from genetically predisposed mice ( ) and patients (FAP, Lynch Syndrome, PJS, and JPS).
RESULTS
The MACS that is upregulated in adenomas consists of four core genes/proteins: CLDN2/Claudin-2 (leakiness), LGR5/leucine-rich repeat-containing receptor (stemness), CEMIP/cell migration-inducing and hyaluronan-binding protein (epithelial-mesenchymal transition) and IL8/Interleukin-8 (inflammation). MACS was induced upon infection, but not in response to infection with other enteric bacteria or probiotics. MACS induction upon infection was higher in organoids compared to WT controls. The degree of MACS expression in the patient-derived organoids (PDOs) generally corresponded with the known lifetime risk of CRCs.
CONCLUSIONS
Computational prediction followed by validation in the organoid-based disease model identified the early events in CRC initiation. MACS reveals that the CRC-associated microbes induce a greater risk in the genetically predisposed hosts, suggesting its potential use for risk prediction and targeted cancer prevention.
PubMed: 38853996
DOI: 10.1101/2024.05.26.595902 -
The American Journal of Gastroenterology Apr 2024Individuals with familial adenomatous polyposis (FAP) have an almost 20% lifetime risk of duodenal adenocarcinoma, currently the leading cause of death in FAP. The... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Individuals with familial adenomatous polyposis (FAP) have an almost 20% lifetime risk of duodenal adenocarcinoma, currently the leading cause of death in FAP. The Spigelman staging system provides guidance on the surveillance intervals and timing of prophylactic surgery. Still, its accuracy in predicting duodenal and papillary cancer development has not been systematically evaluated. We investigated the sensitivity and cancer risk of the Spigelman stages.
METHODS
We performed a systematic review on PubMed, MEDLINE, EMBASE, and Cochrane and used a random-effects model to pool effect sizes.
RESULTS
After removing duplicate entries, we screened 1,170 records and included 27 studies for quantitative analysis. Once duodenal polyposis reaches Spigelman stage IV, the risk of duodenal and papillary cancers increased to 25% (95% confidence interval [CI] 12%-45%). However, the sensitivity of Spigelman stage IV for these cancers was low (51%, 95% CI 42%-60%), especially for papillary adenocarcinoma (39%, 95% CI 16%-68%). We investigated the reasons behind these low values and observed that duodenal cancer risk factors included polyps >10 mm, polyp count >20, and polyps with high-grade dysplasia. Risk factors associated with papillary cancer included a papilla with high-grade dysplasia or >10 mm. The evidence on other risk factors was inconclusive.
DISCUSSION
The current Spigelman staging system had a low sensitivity for duodenal and papillary adenocarcinomas. Two Spigelman variables (duodenal villous histology and polyp count) and the lack of papilla-specific variables likely contributed to the low sensitivity values for duodenal and papillary cancers, respectively. While clinicians may be familiar with its current form, there is an urgent need to update it.
Topics: Humans; Adenomatous Polyposis Coli; Duodenum; Duodenal Neoplasms; Polyps; Risk Factors
PubMed: 38294150
DOI: 10.14309/ajg.0000000000002688 -
Cancer Letters Mar 2024The highly heterogenous nature of colorectal cancer can significantly hinder its early and accurate diagnosis, eventually contributing to high mortality rates. The... (Review)
Review
The highly heterogenous nature of colorectal cancer can significantly hinder its early and accurate diagnosis, eventually contributing to high mortality rates. The adenoma-carcinoma sequence and serrated polyp-carcinoma sequence are the two most common sequences in sporadic colorectal cancer. Genetic alterations in adenomatous polyposis coli (APC), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and tumour protein 53 (TP53) genes are critical in adenoma-carcinoma sequence, whereas v-Raf murine sarcoma viral oncogene homolog B (BRAF) and MutL Homolog1 (MLH1) are driving oncogenes in the serrated polyp-carcinoma sequence. Sporadic mutations in these genes contribute differently to colorectal cancer pathogenesis by introducing distinct alterations in several signalling pathways that rely on the endosome-lysosome system. Unsurprisingly, the endosome-lysosome system plays a pivotal role in the hallmarks of cancer and contributes to specialised colon function. Thus, the endosome-lysosome system might be distinctively influenced by different mutations and these alterations may contribute to the heterogenous nature of sporadic colorectal cancer. This review highlights potential connections between major sporadic colorectal cancer mutations and the diverse pathogenic mechanisms driven by the endosome-lysosome system in colorectal carcinogenesis.
Topics: Animals; Mice; Humans; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Colorectal Neoplasms; Mutation; Adenoma; Carcinoma
PubMed: 38290660
DOI: 10.1016/j.canlet.2024.216639 -
European Journal of Gastroenterology &... Dec 2023This study aimed to investigate the association between non-alcoholic fatty liver disease (NAFLD) and both colorectal adenomatous polyps and non-adenomatous polyps, in...
AIM
This study aimed to investigate the association between non-alcoholic fatty liver disease (NAFLD) and both colorectal adenomatous polyps and non-adenomatous polyps, in order to provide evidence for the prevention of colorectal cancer (CRC) in patients with NAFLD.
METHODS
A retrospective, cross-sectional study was conducted at the First People's Hospital of Kunshan, Jiangsu, China. The study included 3028 adults who underwent abdominal ultrasonography and colonoscopy over a 5 year period. We compared characteristics among patients with adenomatous polyps, non-adenomatous polyps, and without colorectal polyps using descriptive statistics. Logistic regression analyses were used to detect associations between NAFLD with the prevalence of adenomatous polyps and non-adenomatous polyps. NAFLD was determined by abdominal ultrasound. Colorectal polyps were assessed by data in the colonoscopy report and pathology report.
RESULTS
A total of 65% of patients with NAFLD had colorectal polys (52% adenomatous polyps and 13% non-adenomatous polyps), and 40% of patients without NAFLD had polyps (29% adenomatous polyps and 11% non-adenomatous polyps). After adjusting for confounding variables, NAFLD was significantly associated with the prevalence of adenomatous in males and females [odds ratio (OR) = 1.8, 95% confidence interval (CI): 1.6-2.2, P < 0.01], but was not associated with non-adenomatous polyps (OR = 1.2, 95% CI:0.9-1.5, P > 0.05).
CONCLUSION
NAFLD is associated with an increased risk of colorectal adenomatous polyps compared to the absence of polyps, but not associated with an increased risk of non-adenomatous polyps. These results provide important evidence for the prevention of CRC in patients with NAFLD.
Topics: Adult; Male; Female; Humans; Non-alcoholic Fatty Liver Disease; Colonic Polyps; Cross-Sectional Studies; Risk Factors; Retrospective Studies; Colorectal Neoplasms; Adenomatous Polyps; Colonoscopy; Rectal Neoplasms
PubMed: 37642651
DOI: 10.1097/MEG.0000000000002636 -
Gastroenterology Sep 2023Familial adenomatous polyposis (FAP) is a hereditary disorder that predisposes patients to colorectal cancer (CRC). Prophylactic colectomy has greatly reduced the risk...
BACKGROUND & AIMS
Familial adenomatous polyposis (FAP) is a hereditary disorder that predisposes patients to colorectal cancer (CRC). Prophylactic colectomy has greatly reduced the risk of CRC. However, new associations between FAP and the risk of other cancers have subsequently emerged. In this study, we assessed the risk of specific primary and secondary cancers among patients with FAP compared with matched controls.
METHODS
All known patients with FAP up until April 2021 were identified in the nationwide Danish Polyposis Register and paired with 4 unique controls matched by birth year, sex, and postal code. The risk of overall cancers, specific cancer types, and risk of a second primary cancer was assessed and compared with controls.
RESULTS
The analysis included 565 patients with FAP and 1890 controls. The overall risk of cancer was significantly higher for patients with FAP than for controls (hazard ratio [HR], 4.12; 95% confidence interval [CI], 3.28-5.17; P < .001). The increased risk was mainly due to CRC (HR, 4.61; 95% CI, 2.58-8.22; P < .001), pancreatic cancer (HR, 6.45; 95% CI, 2.02-20.64; P = .002), and duodenal/small-bowel cancer (HR, 14.49; 95% CI, 1.76-119.47; P = .013), whereas no significant difference was observed for gastric cancer (HR, 3.29; 95% CI, 0.53-20.23; P = .20). Furthermore, the risk of a second primary cancer was significantly higher for patients with FAP (HR, 1.89; 95% CI, 1.02-3.50; P = .042). Between 1980 and 2020, the risk of cancer among patients with FAP decreased by ∼50%.
CONCLUSIONS
Despite an absolute reduction in the risk of developing cancer among patients with FAP, the risk remained significantly higher than for the background population due to colorectal, pancreatic, and duodenal/small-bowel cancers.
Topics: Humans; Cohort Studies; Neoplasms, Second Primary; Adenomatous Polyposis Coli; Colorectal Neoplasms; Duodenal Neoplasms; Denmark
PubMed: 37201686
DOI: 10.1053/j.gastro.2023.05.010 -
Journal of Taibah University Medical... Aug 2023Colorectal cancer is a common cause of cancer-related mortality in KSA with a rising incidence. Although adenomatous polyps are well-recognized as precursors of...
OBJECTIVES
Colorectal cancer is a common cause of cancer-related mortality in KSA with a rising incidence. Although adenomatous polyps are well-recognized as precursors of colorectal cancer, local data are scarce. Therefore, in this study, we aimed to evaluate the characteristics of adenomatous colon polyps in the Saudi population.
METHODS
We retrospectively reviewed the electronic databases of all patients who underwent colonoscopy for any indication between January 2015 and December 2019 at a tertiary care hospital. This study included adult patients who were found to have colorectal polyps with identified histopathology reports. We collected clinical and pathological data, including patient age, sex, and histopathological polyp characteristics. A p-value <0.05 was considered significant for descriptive and analytical statistics.
RESULTS
A total of 184 patients with colorectal polyps with identified histopathology reports were included in the analysis. Of these, 130 (70.6%) patients were aged 50 years or older, and 135 (73.3%) were male. Among all polyps, 127 (69%) were adenomatous, 31 (16.8%) were hyperplastic, and 24 (13%) were inflammatory. For adenomatous polyps, 31 (24.4%) were observed in patients younger than 50 years, and high-grade dysplasia was observed in 23 (18%) polyps. Among patients with adenomatous polyps, the anatomical location was as follows: 27 (23%) in the cecum/ascending colon, 12 (9%) in the transverse colon, 45 (35%) in the descending/sigmoid colon, 25 (19%) in the rectum, and 18 (14%) at multiple sites. Age >50 years was significantly associated with adenomatous polyps (P = 0.03).
CONCLUSION
Approximately one-third of adenomatous polyps were detected proximal to the splenic flexure. Although adenomatous polyps were significantly associated with increasing age, 24% were observed in patients younger than 50 years of age. This finding supports the current recommendation to start screening at the age of 45.
PubMed: 36852232
DOI: 10.1016/j.jtumed.2022.12.018 -
Annals of Surgical Oncology Aug 2023In this study, we aimed to describe the clinical features, management, and outcomes of desmoid tumors (DTs) in familial adenomatous polyposis (FAP) patients at a...
OBJECTIVE
In this study, we aimed to describe the clinical features, management, and outcomes of desmoid tumors (DTs) in familial adenomatous polyposis (FAP) patients at a high-volume sarcoma center.
METHODS
Consecutive patients with FAP and DTs were identified from our institutional databases (1985-2021). Patient demographics, treatment, and outcomes were described. Categorical data were compared using Fisher's exact test, and Kaplan-Meier curves were used to estimate progression-free survival (PFS).
RESULTS
Forty-five patients with 67 DTs were identified: 39 mesenteric or retroperitoneal (58.2%), 17 abdominal wall (25.4%), 4 extremity (6%), 4 breast (6%) and 3 back (4.4%). Severe DT symptoms were present in 12 patients (26.7%). Initial treatments per tumor were observation in 30 (44.8%) DTs, chemotherapy in 15 (22.4%) DTs, surgery in 10 (14.9%) DTs, and other systemic therapies in 10 (14.9%) DTs. The majority of DTs remained stable with observation or a single intervention (77.8%). Median PFS was 23.4 years (95% confidence interval 7.6-39.2). In the 12 severely symptomatic patients, four patients required more than two interventions for DT control. At a median follow-up of 6.0 years (range 0.7-35.8 years), 33 (73.3%) patients were alive with disease, 7 (15.6%) were alive without disease, and 5 (11.1%) died of other causes. No patients died of DT-related complications.
CONCLUSIONS
The majority of DTs in FAP patients remained stable with observation or a single intervention. There were no DT-related deaths; however, 12 of 45 patients (26.7%) experienced significant tumor morbidity and required more interventions for disease control. Further studies on quality of life are required.
Topics: Humans; Fibromatosis, Aggressive; Quality of Life; Adenomatous Polyposis Coli; Mesentery
PubMed: 37237094
DOI: 10.1245/s10434-023-13675-1 -
JCI Insight Nov 2023Germline adenomatous polyposis coli (APC) mutation in patients with familial adenomatous polyposis (FAP) promotes gastrointestinal polyposis, including the formation of...
Germline adenomatous polyposis coli (APC) mutation in patients with familial adenomatous polyposis (FAP) promotes gastrointestinal polyposis, including the formation of frequent gastric fundic gland polyps (FGPs). In this study, we investigated how dysregulated Wnt signaling promotes FGPs and why they localize to the corpus region of the stomach. We developed a biobank of FGP and surrounding nonpolyp corpus biopsies and organoids from patients with FAP for comparative studies. Polyp biopsies and polyp-derived organoids exhibited enhanced Wnt target gene expression. Polyp-derived organoids with intrinsically upregulated Wnt signaling showed poor tolerance to further induction, suggesting that high Wnt restricts growth. Targeted genomic sequencing revealed that most gastric polyps did not arise via APC loss of heterozygosity. Studies in genetic mouse models demonstrated that heterozygous Apc loss increased epithelial cell proliferation in the corpus but not the antrum, while homozygous Apc loss was not maintained in the corpus yet induced hyperproliferation in the antrum. Our findings suggest that heterozygous APC mutation in patients with FAP may be sufficient to drive polyp formation in the corpus region while subsequent loss of heterozygosity to further enhance Wnt signaling is not tolerated. This finding contextualizes the abundant yet benign nature of gastric polyps in FAP patient corpus compared with the rare, yet adenomatous polyps in the antrum.
Topics: Humans; Animals; Mice; Wnt Signaling Pathway; Adenomatous Polyposis Coli; Adenomatous Polyps
PubMed: 37943618
DOI: 10.1172/jci.insight.174546