Search Results (113)

Familial adenomatous polyposis (FAP) is the most common hereditary colorectal adenomatous polyposis and cancer syndrome which has historically been associated with a near absolute risk of colorectal cancer. However, the morbidity and mortality from colorectal cancer has been greatly diminished by pre-symptomatic genetic testing which identifies affected individuals and by appropriately timed, risk-reducing surgery of the colorectum. Following colorectal surgery, cancer risk beyond the retained rectum or ileal pouch includes other gastrointestinal organs, especially those of the upper gastrointestinal tract. While genotype–phenotype correlations exist for the severity of colonic polyposis, they have not been demonstrated for upper gastrointestinal tract manifestations. We reviewed the impact of ethnicity on the upper gastrointestinal manifestations of FAP by a comparison of published data in patients with FAP from Asian and Western countries. Our main findings demonstrate that following risk-reducing surgery to mitigate colorectal cancer risk, patients with FAP remain at increased risk for upper gastrointestinal polyposis and cancer. The duodenal and gastric phenotype differs between patients with FAP from the West and the East, and all should be followed in a multidisciplinary surveillance program. Following risk-reducing surgery to mitigate colorectal cancer risk, patients with familial adenomatous polyposis remain at increased risk for upper gastrointestinal polyposis and cancer. The duodenal and gastric phenotype differs between patients with FAP from the West and the East, and all should be followed in a multidisciplinary surveillance program. Full article

Background and Objectives: Lynch syndrome (LS), an autosomal dominant condition arising from germline mutations in mismatch repair (MMR) genes, is a major cause of hereditary early-onset colorectal cancer (CRC). Although patients diagnosed before age 50 represent a critical subgroup where Lynch syndrome might be more prevalent, data on the precise frequency, clinical outcomes, and molecular correlates remain heterogeneous across studies. This systematic review was conducted to (1) estimate the prevalence of MMR deficiency (dMMR) and confirmed LS in patients diagnosed with CRC before the age of 50, and (2) examine immunohistochemistry (IHC) mismatch repair testing patterns and associated molecular findings (BRAF mutations, MLH1 promoter hypermethylation, somatic MMR gene alterations). Methods: Following a predefined search strategy in PubMed, Scopus, and Web of Science, five relevant studies were identified (n = 5). Each study comprised patients younger than 50 who underwent IHC-based tumor screening. Data extraction covered demographic details, number of patients tested, proportion with abnormal IHC, frequency of somatic or germline MMR gene mutations, and method of classification into sporadic dMMR vs. LS. Quality assessment was performed using recommended scales for observational studies. Results: Among 5 studies totaling 960 early-onset CRC patients, the frequency of dMMR CRC ranged from 8.4% to 19.1%. The confirmed prevalence of LS among all young-onset CRC was between 5.0% and 5.9% in three studies but reached 8.9% in another and 5.1% in yet another. Across all studies, the presence of right-sided tumors and histopathological features such as tumor-infiltrating lymphocytes were more common in dMMR cancers. Incorporation of MLH1-promoter hypermethylation and/or BRAF V600E mutation testing aided discrimination of sporadic dMMR CRC from germline LS cases. Conclusions: The prevalence of LS in CRC patients younger than 50 is clinically significant, at approximately 5–9%. Routine IHC-based MMR screening is both feasible and effective for detecting LS in early-onset CRC. Further research is needed to standardize universal testing protocols, delineate the role of additional molecular assays, and ensure comprehensive genetic counseling for at-risk individuals. Full article

Background: Pancreatic cancer (PC) is among the deadliest types of cancer globally. While early detection helps avert adverse outcomes, screening is only recommended for individuals at high risk, specifically those with familial and/or genetic predispositions. The objectives of this study are to systematically review primary studies on the cost-effectiveness of PC screening and to identify the critical factors that influence cost-effectiveness. Methods: This systematic review was performed using PRISMA guidelines. Economic evaluation studies on PC screening were identified from searches on the SCOPUS and PubMed databases. The quality of reporting of the selected articles was assessed according to CHEERS 2022. Using predefined inclusion and exclusion criteria, two reviewers conducted the title–abstract review, full-text review, and data extraction to select relevant articles. The authors’ consensus was used to settle disagreements. The primary outcome was the incremental cost-effectiveness ratio, measured by cost per quality-adjusted life year and cost per life year saved. Results: Nine studies were selected for the final review. Most studies demonstrated that one-time screening for PC among high-risk individuals was cost-effective compared with no screening, while others found annual screening to also be cost-effective. High-risk was generally defined as having a >5% lifetime risk of PC and included individuals with either familial pancreatic cancer (FPC) or genetic susceptibility syndromes such as Peutz–Jeghers Syndrome, hereditary pancreatitis, hereditary non-polypoid colorectal cancer syndrome, familial adenomatous polyposis, and BRCA2 mutations. Individuals with new-onset diabetes (NOD) were also considered high-risk. Screening using mainly endoscopic ultrasound was cost-effective among FPC individuals and those with genetic syndromes. Risk-based screening was also cost-effective among patients with NOD. Conclusion: Screening for PC is cost-effective among selected high-risk individuals. However, cost-effectiveness depends on epidemiological factors, cost, the diagnostic performance of screening tools, and the overall design of studies. Full article

Lynch syndrome (LS)—also known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC)—is caused by pathogenic germline mutations in DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, and PMS2. Although it accounts for only 1–5% of all colorectal cancers (CRCs), LS presents with a particularly high lifetime cancer risk and often occurs at younger ages. Identifying LS in patients under 60 years old is crucial for targeted surveillance and early interventions. Variations in clinical presentation and prognosis may exist based on the specific gene mutated, yet these patterns are not fully elucidated. This review aims to synthesize data on clinical outcomes among LS patients under 60, with an emphasis on how different MMR gene mutation patterns might influence prognosis, survival, and treatment decisions. Five population-based studies examining CRC patients younger than 60 years were included according to predefined eligibility criteria. Two independent reviewers screened and extracted data focusing on MMR deficiency detection methods (microsatellite instability [MSI] and/or immunohistochemistry [IHC]), rates of confirmed germline mutations, frequency of BRAF testing, and clinical endpoints such as stage distribution, survival outcomes, and recurrence. Risk of bias was assessed using standardized tools appropriate to each study design. The synthesis focused on comparing outcomes among individuals with MLH1, MSH2, MSH6, and PMS2 mutations, as well as delineating the proportion of patients with sporadic MSI under 60 years of age. Across the five studies, MSI positivity in CRC patients under 60 years ranged from 7.5% to 13%. The frequency of confirmed germline MMR mutations varied between 0.8% and 5.2% in specific cohorts, aligning with LS prevalence estimates of 1–5%. Different mutation patterns correlated with some variation in clinical presentation. Cases with MSH2 and MLH1 mutations more frequently exhibited synchronous or metachronous tumors, while MSH6 and PMS2 mutations displayed more heterogeneous IHC patterns. Where survival data were provided, LS patients under 60 years had better overall survival compared to MMR-proficient individuals, though some studies also noted a potential lack of benefit from standard 5-fluorouracil adjuvant therapy in MMR-deficient tumors. Screening by MSI or by IHC—supplemented with BRAF mutation testing to exclude sporadic MSI—facilitates early detection of LS in CRC patients under 60 and highlights notable differences between mutation types. Although overall outcomes for LS patients can be favorable, especially for stage II disease, the precise impact of each specific mutated gene on clinical course remains heterogeneous. Future large-scale prospective studies are needed to clarify optimal screening protocols and individualized treatment strategies for LS patients under 60. Full article

Background: Hereditary colorectal cancer syndromes, including familial adenomatous polyposis (FAP), Lynch syndrome (LS), and Peutz–Jeghers syndrome (PJS), are associated with an increased risk of small bowel cancer (SBC). Due to the low incidence and non-specific presentation of SBC, effective surveillance strategies are essential for early detection and management. This review aims to evaluate and compare current endoscopic techniques for small bowel surveillance in these patients. Methods: A comprehensive review was conducted using peer-reviewed studies sourced from PubMed. Various endoscopic modalities, including capsule endoscopy (CE), device-assisted enteroscopy (DAE), and intraoperative enteroscopy (IOE), were assessed for their diagnostic yield, safety, and clinical utility. Surveillance recommendations of the different syndromes were also examined. Results: CE offers high sensitivity but lacks histological sampling capability. DAE, including double-balloon enteroscopy (DBE) and single-balloon enteroscopy (SBE), enables direct visualization, biopsy, and therapeutic interventions, albeit with greater procedural complexity. In FAP, duodenal surveillance follows the Spigelman classification to stratify cancer risk, while jejunal and ileal polyps remain less studied. LS patients have an increased SBC risk, warranting tailored endoscopic approaches. In PJS, surveillance aims to mitigate intussusception risks and allow early malignancy detection. Conclusions: Optimized surveillance strategies in hereditary colorectal cancer syndromes require a multimodal approach, integrating advanced endoscopic techniques with genetic risk stratification. Centralized care in tertiary centers improves outcomes by ensuring standardized surveillance protocols and enhancing early cancer detection. Artificial intelligence (AI) applied to CE and DAE is shaping promising prospects for the future surveillance of small bowel polyps by enhancing diagnostic accuracy and reducing the duration of the diagnostic process. Further research should investigate AI-assisted imaging and molecular biomarkers to optimize screening strategies. Full article

Background: Prostate cancer (PC) is one of the most common oncological diseases among men. Up to 20% of PC cases are associated with hereditary risks or syndromes. The impact of common variants, particularly EHBP1 c.1185+30064G>A rs721048, on developing PC and other malignancies remains unclear. There are also no data on the frequency of this variant in the Kazakh population or its association with PC, nor its potential connection with other malignancies, particularly colorectal cancer (CRC). Methods: We utilized the TruSight Cancer Sequencing Panel to assess pathological genomic variants in 72 male patients with histologically verified aggressive PC and 119 patients of Kazakh nationality with histologically confirmed CRC compared to the control group. Results: A variant in the intron of the EHBP1 gene c.1185+30064G>A rs721048 was identified in 18 patients (25%) out of 72 with PC, while in the control group of 41 healthy males, the rs721048 variant was found in only 4 (9.8%) individuals. In the CRC group, rs721048 was detected in 17 cases (14.2%) and eight control individuals (10%). Conclusions: The frequency of the EHBP1 c.1185+30064G>A rs721048 variant in the PC group was significantly higher (p < 0.05) than in healthy males of Kazakh nationality. Identifying EHBP1 c.1185+30064G>A among the male population of Kazakhstan will help form the high-risk groups for PC to prevent the development of malignant neoplasms. The presence of rs721048 was not significantly associated with the risk of developing CRC in our study. Full article

Colorectal cancer (CRC) is one of the major reasons for cancer-related deaths around the world. Constitutive activation of WNT pathway, due to APC gene mutation, is the characteristic feature of most human colon tumors. Familial adenomatous polyposis (FAP) patients inherit APC mutations and pose an absolute risk of developing CRC in their lifetime. The genetically modified APC mouse models have paved the way to study various aspects of the hereditary human CRC, including biochemical, molecular, and histological aspects. Preclinical and clinical data suggest that certain dietary supplements, NSAIDs, natural products, and chemically synthesized compounds, can help in intercepting CRC incidence and progression by modulating various hallmarks of cancer. In this review, we have provided a summary of promising natural and synthetic agents that demonstrated chemopreventive efficacy against CRC in the FAP-mimicking APC^Min/+ mouse model. Full article

Of all new cases of colorectal cancer, Lynch syndrome (LS) accounts for approximately 3%. This syndrome is the most common hereditary cancer syndrome and is caused by pathogenic variants in the genes responsible for DNA mismatch repair. Although the relationship between colorectal cancer risk and diet is well established, little is known regarding the influence of diet and nutritional characteristics on LS’s clinical evolution. There is some evidence suggesting that individuals living with LS should follow general guidelines for diet and alcohol restriction/moderation, so as to achieve and maintain a favorable weight status and overall health and quality of life. However, more research is needed, preferentially from clinical studies of a prospective nature with robust designs, to better inform diet and behavioral patterns targeting cancer prevention in LS. Full article

Background: Hereditary polyposis syndromes are clinically and genetically heterogeneous conditions associated with increased colorectal cancer risk. They are classified based on polyp histology, inheritance mode, causal gene, and colonic and extracolonic manifestations. Their diagnosis is challenging due to overlapping and heterogeneous clinical presentations. Methods: A multigene next-generation sequencing panel was used to screen 75 index cases with colorectal polyps and a personal/family history of cancer for key hereditary polyposis-associated genes (APC, BMPR1A, MUTYH, PTEN, SMAD4, and STK11) in order to identify germline genetic variants. Results: In the screened index cases, we found 14 pathogenic variants involving APC, MUTYH, SMAD4, and STK11 and 6 variants of uncertain significance involving APC, BMPR1A, and SMAD4. In this cohort, four patients not fulfilling the recommended eligibility criteria of current National Comprehensive Cancer Network (NCCN) guidelines for genetic testing were molecularly diagnosed with a hereditary polyposis syndrome. Conclusions: Our findings indicate that stringent NCCN eligibility criteria for molecular screening may lead to missing some of the patients affected by hereditary polyposis syndromes. This highlights the need for a careful evaluation of patients’ clinical manifestations, polyp number, age of polyp onset, and family history to select appropriate candidates for molecular diagnosis of these conditions. Full article

A hereditary component of breast (BC) and colorectal cancer (CRC) has been described in approximately one-third of these tumor types. BC patients have an increased risk of developing CRC as a second primary tumor and vice versa. Germline genomic variants (NextSeq550, Illumina) were investigated in 24 unrelated BC and/or CRC patients and 7 relatives from 3 index patients. Fifty-six pathogenic or likely pathogenic variants were identified in 19 of 24 patients. We detected single-nucleotide variants (SNVs) in CRC predisposition genes (MLH1 and MUTYH) and other promising candidates (CDK5RAP3, MAD1L1, NOS3, and POLM). Eighteen patients presented SNVs or copy number variants (CNVs) in DNA damage repair genes. We also identified SNVs recently associated with BC or CRC predisposition (PABPC1, TYRO3, MAP3K1, SLC15A4, and LAMA1). The PABPC1c.1255C>T variant was detected in nine unrelated patients. Each patient presented at least one SNV/CNV in a candidate gene, and most had alterations in more than one gene, reinforcing a polygenic model for BC/CRC predisposition. A significant fraction of BC/CRC patients with a family history of these tumors harbored deleterious germline variants in DNA repair genes. Our findings can lead to strategies to improve the diagnosis, genetic counseling, and treatment of patients and their relatives. Full article

Background and aims: Hereditary colorectal cancer syndromes (HCCS), including familial adenomatous polyposis (FAP) and Lynch syndrome (LS), are the two most important high-risk conditions for colorectal cancer (CRC). Inflammatory bowel disease (IBD) increases the risk by two to six times compared with that in the general population. The intersection of these two conditions has rarely been documented in literature. We aimed to summarize the prevalence, pathogenesis, and current evidence-based management of IBD and HCCS and the underlying molecular mechanisms of accelerated carcinogenesis due to combined inflammation and genetic predisposition. Methods: PubMed and Scopus were searched until June 2024 to identify relevant studies investigating the epidemiology, pathogenesis, and management of IBD and coexisting hereditary CRC syndromes. Results: Co-occurrence of IBD and hereditary CRC syndromes is exceptionally uncommon. Individuals with LS and IBD tend to develop CRC at a younger age than those without IBD, with patients with ulcerative colitis facing particularly elevated risks. The interaction between mismatch deficiency and chronic inflammation requires further investigation. Full article

(1) Background: Familial adenomatous polyposis (FAP) is a hereditary condition characterized by the development of numerous adenomas in the large intestine, often necessitating colectomy due to an elevated risk of colorectal cancer. Despite surgical intervention, adenomas frequently recur, underscoring the importance of ongoing surveillance. This study evaluates the outcomes of a 12-year endoscopic follow-up after colectomy and gastrointestinal reconstruction for FAP. (2) Methods: A retrospective analysis was conducted on 41 FAP patients who underwent at least one postoperative endoscopic examination. Assessments of the pouch or rectum were performed every 12–18 months following ileorectal anastomosis and every 18–24 months after ileal pouch–anal anastomosis. Follow-up biopsies were assessed using the adopted Spigelman classification. (3) Results: Postoperative pathology revealed invasive colorectal cancer in three patients. Abdominoperineal resection was performed in two cases due to secondary invasive carcinoma, and one T1 tumor was radically removed with ESD. One patient underwent radical pouch excision following a nodal pelvic recurrence of rectal cancer. Over a 12-year observation period, the mean Spigelman score increased by 2 points, and the proportion of patients with low-grade polypoid lesions decreased. The quantity or size of polyps increased in 24 patients, decreased in 8 patients, and remained stable in 9 patients. In four patients, granular, laterally spreading tumors were discovered in the rectal stump. (4) Conclusions: Regular endoscopic surveillance in FAP patients facilitates early identification of neoplastic and inflammatory changes. The downstaging potential highlights the effectiveness of early interventions. While the Spigelman classification assessed polyps well, it did not predict cancer occurrence. A notable number of patients had invasive cancer at the time of surgery, underscoring the importance of early surgical qualification, which is particularly crucial for identifying upstaging or secondary cancer. Full article

Colorectal cancer (CRC) ranks third in terms of cancer incidence worldwide and is responsible for 8% of all deaths globally. Approximately 10% of CRC cases are caused by inherited pathogenic mutations in driver genes involved in pathways that are crucial for CRC tumorigenesis and progression. These hereditary mutations significantly increase the risk of initial benign polyps or adenomas developing into cancer. In recent years, the rapid and accurate sequencing of CRC-specific multigene panels by next-generation sequencing (NGS) technologies has enabled the identification of several recurrent pathogenic variants with established functional consequences. In parallel, rare genetic variants that are not characterized and are, therefore, called variants of uncertain significance (VUSs) have also been detected. The classification of VUSs is a challenging task because each amino acid has specific biochemical properties and uniquely contributes to the structural stability and functional activity of proteins. In this scenario, the ability to computationally predict the effect of a VUS is crucial. In particular, in silico prediction methods can provide useful insights to assess the potential impact of a VUS and support additional clinical evaluation. This approach can further benefit from recent advances in artificial intelligence-based technologies. In this review, we describe the main in silico prediction tools that can be used to evaluate the structural and functional impact of VUSs and provide examples of their application in the analysis of gene variants involved in hereditary CRC syndromes. Full article

Colorectal cancer (CRC) is one of the most frequent and mortality-causing neoplasia, with various distributions between populations. Strong hereditary predispositions are the causatives of a small percentage of CRC, and most cases have no transparent genetic background. This is a vast arena for exploring cancer low-susceptibility genetic variants. Nonetheless, the research that has been conducted to date has failed to deliver consistent conclusions and often features conflicting messages, causing chaos in this field. Therefore, we decided to organize the existing knowledge on this topic. We screened the PubMed and Google Scholar databases. We drew up markers by gene locus gathered by hallmark: oncogenes, tumor suppressor genes, genes involved in DNA damage repair, genes involved in metabolic pathways, genes involved in methylation, genes that modify the colonic microenvironment, and genes involved in the immune response. Low-penetration genetic variants increasing the risk of cancer are often population-specific, hence the urgent need for large-scale testing. Such endeavors can be successful only when financial decision-makers are united with social educators, medical specialists, genetic consultants, and the scientific community. Countries’ policies should prioritize research on this subject regardless of cost because it is the best investment. In this review, we listed potential low-penetrance CRC susceptibility alleles whose role remains to be established. Full article

Despite recent campaigns for screening and the latest advances in cancer therapy and molecular biology, gastrointestinal (GI) neoplasms remain among the most frequent and lethal human tumors. Most GI neoplasms are sporadic, but there are some well-known familial syndromes associated with a significant risk of developing both benign and malignant GI tumors. Although some of these entities were described more than a century ago based on clinical grounds, the increasing molecular information obtained with high-throughput techniques has shed light on the pathogenesis of several of them. The vast amount of information gained from next-generation sequencing has led to the identification of some high-risk genetic variants, although others remain to be discovered. The opportunity for genetic assessment and counseling in these families has dramatically changed the management of these syndromes, though it has also resulted in significant psychological distress for the affected patients, especially those with indeterminate variants. Herein, we aim to summarize the most relevant hereditary cancer syndromes involving the stomach and colon, with an emphasis on new molecular findings, novel entities, and recent changes in the management of these patients. Full article