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PubMed2026

Analysis of APC promoter 1B deletions in Russian families with familial adenomatous polyposis.

OBJECTIVE: Familial adenomatous polyposis (FAP) is a severe autosomal dominant hereditary cancer syndrome. Patients develop hundreds of adenomatous polyps throughout the colon with the risk of colorectal cancer, if untreated, approaching 100%. FAP is caused by pathogenic germline variants in the APC gene. Deletions in the APC 1B promoter cause FAP in a small subgroup of patients. Previous studies suggested that the APC promoter deletions in unrelated FAP patients from the US and Italy are identical and may thus have spread from a single founder. The aim of this study was to investigate whether a similar founder effect can be detected in the Russian population. PATIENTS AND METHODS: We performed whole-genome sequencing on five unrelated patients (three males and two females) with extensive (over 100) colon polyps, family history of FAP, and germline APC 1B promoter deletions previously detected by the multiplex ligation-dependent probe amplification (MLPA) and detected precise deletion boundaries. RESULTS: The patients carried deletions in the APC 1B promoter ranging from ~3 to ~122 kbp. We found no association between the deletion size and either the age of the onset or severity of the disease. All deletions were unique and no identical deletion boundaries were observed. However, in four patients, the right deletion breakpoints fell into a 1 kbp region downstream of the 1B promoter. The right breakpoints of several deletions detected in FAP patients from other countries also fell into this narrow region. CONCLUSION: The APC 1B promoter deletions analyzed in this study had arisen independently and there is thus no evidence of a founder effect. Therefore, at least for the cohort of FAP patients with APC 1B promoter deletions studied here, WGS did not provide an added diagnostic benefit to MLPA aside from precisely determining the deletion breakpoints.

APC promoter 1B deletion↗
PubMed2026

In vitro and in vivo studies on the impact of the familial adenomatous polyposis heterogeneous mutation MUC20-S671C on colorectal carcinogenesis and progression.

BACKGROUND: Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer (CRC). We performed genetic testing on nine FAP patients and identified a recurrent mutation at the 671st site of the MUC20 gene-MUC20-S671C. This mutation has a detection frequency of zero in the 1000 Genomes Project database. Previous studies have demonstrated that MUC20 can promote CRC progression through epithelial-mesenchymal transition (EMT). We conducted a series of experiments to analyze the impact of this mutation on CRC cells, aiming to infer its potential role and significance in CRC patients. METHODS: We introduced the MUC20-S671C mutation into the CRC SW480 cell line using the CRISPR-Cas9 technique and established a stable cell line carrying this mutation. We then conducted various experiments to assess the effects of this mutation. The Transwell assay was used to evaluate cell invasion and migration. We also examined cell proliferation, cell cycle progression, and apoptosis rate. Furthermore, we tested the tumorigenic ability of these cells in NOD-scid IL2Rγ[null] (NSG) mice. Additionally, transcriptome sequencing was performed on both cell lines and mouse tumor tissues to obtain molecular regulatory network data, and key molecules were further validated. RESULTS: The results of Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), and colony formation assays indicated that the proliferation ability of mutant cells was significantly reduced. The Transwell assay demonstrated a marked decline in the invasion and migration capabilities of mutant cells. Flow cytometry analysis revealed that the mutation increased the apoptosis rate of CRC cells and might have caused S-phase arrest. The tumor formation assay in nude mice showed that the tumorigenic ability of mutant cells was weakened. Transcriptome sequencing of both the cells and tumor tissues suggested that the mutation altered the expression of apoptosis- and cell cycle-related molecules and also affected EMT. Further experiments confirmed that key molecules involved in the EMT process, such as E-cadherin, were upregulated, while Vimentin, MMP9, and MMP14 were significantly downregulated, indicating that the mutation weakened the EMT capability of CRC cells. CONCLUSIONS: We have identified a novel mutation, MUC20-S671C, in patients with FAP. Our study demonstrates that this mutation exerts its tumor-suppressive effect by reversing the EMT process.

MUC20-S671C↗
PubMed2026

Risk of desmoid tumor based on APC pathogenic variant location and surgical history in familial adenomatous polyposis: a U.S. community cohort study.

Desmoid tumors (DT) are a leading cause of morbidity and mortality in patients with familial adenomatous polyposis (FAP), yet available data on DT risk remain limited and have been largely derived from large registries or tertiary referral centers. Risk in community-based U.S. populations is poorly defined, which hinders presurgical counseling. We conducted a retrospective cohort study of patients with pathogenic or likely pathogenic variants (PV/LPV) in APC identified through the Kaiser Permanente Northern California Electronic Database, a community-based system serving 4.6 million members. We evaluated the association of APC PV/LPV location and prior abdominal surgery with DT risk using multivariable logistic regression, adjusting for sex, race and ethnicity, and family history. Among 328 patients with FAP, 36 (11.0%) developed DT. DT risk was highest when the APC variant was centrally located (codon 600-1600). Family history was independently associated with increased risk (adjusted odds ratio [aOR] 4.34; 95% confidence interval [CI] 1.12-16.86). All colorectal surgeries were associated with a significantly elevated DT risk: ileostomy (aOR 12.07; 2.10-69.47), subtotal colectomy with ileorectal anastomosis (aOR 9.03; 1.63-49.96), and total proctocolectomy with ileal pouch-anal anastomosis (aOR 10.98; 2.12-56.81). In contrast, non-colorectal surgery was not associated with increased risk (aOR 0.73). In this large community-based U.S. cohort, central APC variant location, family history, and colorectal surgery were associated with increased DT risk. Our findings extend the current literature on DT risk in FAP and help refine presurgical risk-stratification and counseling for these patients.

Humans↗
PubMed2025

Single-cell spatial mapping reveals alteration of tissue microenvironment during early colorectal cancer.

Familial adenomatous polyposis (FAP) is a rare, hereditary syndrome that raises the risk of developing colorectal cancer (CRC). This disease model is well suited for studying the early stages of malignant transformation. Our spatial CODEX experiments reveal that, in contrast to normal mucosa, FAP mucosa, pre-cancer polyps and colorectal cancers exhibit substantial alterations in the cell type composition and tissue microenvironment. These early alterations include: an increase in the population of cancer-associated fibroblasts (CAFs), and the inhibition of tumor infiltrated lymphocytes and cell-adhesion protein by CAFs, the transformation of memory T cells into regulatory T cells, nuclear translocation of beta-catenin from the cell membrane, a decrease in the M1:M2 macrophage ratio, a notable increase in angiogenesis events. Our studies define the early stem cell, stromal, and immune steps of colorectal cancer and may benefit early detection, and therapeutic intervention.

Co-detection by Indexing (CODEX)↗
PubMed2025

A novel insertion/deletion in APC promotor 1B is associated with both gastric and colon polyposis.

Pathogenic variants in the APC gene are classically associated with autosomal dominant familial adenomatous polyposis (FAP), characterized by tens-to-thousands of colonic adenomatous polyps and a high-penetrance predisposition to colorectal cancer. More recently, specific PVs in the YY1 binding motif of APC promoter 1B have been associated with autosomal dominant gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), characterized by tens-to-thousands of fundic gland polyps and a predisposition to gastric cancer but which are only rarely associated with features consistent with FAP. Although management guidelines currently treat FAP and GAPPS as mutually exclusive conditions, the extent of phenotypic overlap is not well-characterized. Here, we present a multi-clinic and -laboratory collaboration reporting a previously undescribed APC promoter 1B insertion/deletion likely pathogenic variant in a family with mixed GAPPS and FAP phenotype. The family proband is a female of unspecified white ancestry. She was diagnosed with GAPPS at age 30 and, after developing gastric cancer at age 39, underwent curative gastrectomy. She is now 61 with a cumulative history of between 50 and 100 colon adenomas and recently completed subtotal colectomy. Her multi-gene panel testing in 2022 demonstrated a likely pathogenic insertion/deletion (indel) within the APC promoter 1B YY1 binding motif (APC c.-192_-191delATinsTAGCAAGGG). Review of a four-generation pedigree revealed the ages of gastric cancer presentation in the family ranged from 39-60's, with advanced gastric polyposis and prophylactic gastrectomy as early as ages 11 and 13 in the proband's daughter and nephew, respectively. Six of 10 (60%) family members known or presumed to carry the APC likely pathogenic variant underwent colectomy or hemicolectomy due to colon polyposis. The youngest known carrier in the family is a 12-year-old female, and the oldest living carrier is the proband's brother, age 66. A novel APC indel causes concomitant GAPPS and FAP presentations in this previously unreported large kindred. Mixed gastric and colon phenotypes have been rarely described in GAPPS families and the ages of presentation of gastric polyposis are strikingly young in the current family with prophylactic gastrectomies completed as early as age 11 and 13. These ages are significantly younger than the 15 years of age at which national guidelines currently recommend initiation of EGD for screening in GAPPS. Although the mechanism for this combined GAPPS-FAP phenotype is unclear, patients in this family and those with similar APC promoter 1B variants should be offered both gastric and colon cancer risk management.

Adult↗
PubMed2026

Parental Perspectives and Experiences with Genetic Testing and Surveillance for Cancer Predisposition in Healthy Young Children.

OBJECTIVES: To evaluate parental experiences following diagnosis of a cancer predisposition syndrome (CPS) in childhood and to assess parental perspectives on population-based genomic newborn screening (gNBS) for CPS. STUDY DESIGN: Participants were guardians of children diagnosed with a CPS by age 8, for whom cancer surveillance was recommended, and who had no history of cancer before the CPS diagnosis. Participants completed a demographic survey, genetic knowledge assessment, and a semistructured qualitative interview. Thematic analysis was performed on interview transcripts. Clinical data were abstracted from medical records. RESULTS: We enrolled 25 parents of children with 7 different CPS, including Li-Fraumeni syndrome (43%), familial adenomatous polyposis (14%), nevoid basal cell carcinoma syndrome (11%), and Beckwith-Wiedemann syndrome (11%). Parents characterized receiving a CPS diagnosis as emotionally challenging but also felt empowered by engagement in proactive cancer surveillance. They identified logistical, emotional, physical, and financial burdens of surveillance; however, most perceived that these burdens were outweighed by the medical and emotional advantages. The majority endorsed implementation of gNBS for pediatric cancer risk. CONCLUSIONS: Parents of presymptomatic children with a CPS experience both psychological distress and benefits following a genetic diagnosis. Despite the burdens of surveillance, parents express support for early genomic identification of cancer risk. These findings have implications for the care of children with CPS and inform implementation of population-based gNBS for CPS.

Humans↗
PubMed2026

Approaches to thyroid nodules in paediatric cancer predisposition syndromes.

OBJECTIVE: The objective of this work was to summarize current evidence and practical management considerations for thyroid nodules in children and adolescents with cancer predisposition syndromes (CPSs), focusing on follicular cell-derived nodules and non-medullary thyroid carcinoma (NMTC). METHODS: We synthesized current paediatric guideline recommendations and recent cohort, pathology, and molecular studies addressing CPS-associated nodular thyroid disease, including PTEN hamartoma tumour syndrome (PHTS), DICER1 syndrome, familial adenomatous polyposis, and related endocrine neoplasia syndromes. RESULTS: Evidence quantifying syndrome-stratified malignancy risk among paediatric CPS patients presenting with nodules remains limited and is largely derived from mixed-age or retrospectively ascertained cohorts with surveillance and verification bias. High-resolution ultrasound (US) is central to risk stratification. US-guided fine-needle aspiration (FNA) is a cornerstone of evaluation yet frequently yields indeterminate results, particularly in follicular-patterned and encapsulated lesions (e.g. PHTS and DICER1 syndrome), and sampling error is accentuated in polyclonal multinodular disease. Molecular testing may aid aetiologic clarification and, in selected settings, risk refinement. However, panels optimized for sporadic adult disease may have reduced 'rule-out' utility in CPSs. Biochemical assessment (TSH ± free thyroxine) complements imaging, while routine thyroglobulin is not recommended, and thyroid autoantibodies should be viewed as adjunctive rather than directive markers in CPSs. CONCLUSION: Management of thyroid nodules in paediatric CPSs is best approached through integrated, multidisciplinary risk assessment that combines expert ultrasound, context-aware cytology and molecular interpretation, and shared decision-making. This review proposes a CPS-adapted, multidisciplinary risk assessment framework and highlights the need for prospective multicentre registries and harmonized protocols to define syndrome-specific outcomes and evidence-based thresholds for surveillance and intervention.

Humans↗
PubMed2026

ACG Clinical Guideline: Diagnosis and Management of Adenomatous Colorectal Polyposis Syndromes.

The hereditary adenomatous colorectal polyposis syndromes are incurable, systemic, cancer risk predisposition syndromes with substantial morbidity and mortality. They differ in their mode of inheritance, age at disease onset, phenotypic expression, and cancer risk. The most common cancer risks involve the gastrointestinal tract including the colon, rectum, duodenum, ampulla, and stomach. Identifying these syndromes through personal and family history risk assessment and germline genetic testing, along with timely surgical and endoscopic management, can reduce cancer incidence and mortality. These guidelines use the Grading of Recommendations, Assessment, Development, and Evaluation methodology to provide clinical guidance on the selection of individuals who should undergo a risk assessment for a hereditary adenomatous colorectal polyposis syndrome, modality and timing of germline genetic testing, cancer risk mitigation through endoscopic and surgical interventions, and the role of chemoprevention. This document reviews the approach to genetic testing in patients with phenotypic colorectal polyposis and the impact of presymptomatic diagnosis in families with a known familial germline pathogenic variant or clinical features suggestive of a hereditary adenomatous polyposis syndrome. Management strategies for patients based on genetic test results or without genetic testing are provided. We also review colorectal and extracolonic phenotypic benign and malignant manifestations of the known hereditary syndromes with a focus on the 2 most common hereditary colorectal polyposis syndromes: familial adenomatous polyposis and MUTYH-associated polyposis. The document concludes with recommendations on polyposis and cancer risk mitigation strategies and highlights updates to management since the previous guideline was published.

Humans↗
PubMed2001

Interaction of Galpha 12 and Galpha 13 with the cytoplasmic domain of cadherin provides a mechanism for beta -catenin release.

The G12 subfamily of heterotrimeric G proteins, comprised of the alpha-subunits Galpha12 and Galpha13, has been implicated as a signaling component in cellular processes ranging from cytoskeletal changes to cell growth and oncogenesis. In an attempt to elucidate specific roles of this subfamily in cell regulation, we sought to identify molecular targets of Galpha12. Here we show a specific interaction between the G12 subfamily and the cytoplasmic tails of several members of the cadherin family of cell-surface adhesion proteins. Galpha12 or Galpha13 binding causes dissociation of the transcriptional activator beta-catenin from cadherins. Furthermore, in cells lacking the adenomatous polyposis coli protein required for beta-catenin degradation, expression of mutationally activated Galpha12 or Galpha13 causes an increase in beta-catenin-mediated transcriptional activation. These findings provide a potential molecular mechanism for the previously reported cellular transforming ability of the G12 subfamily and reveal a link between heterotrimeric G proteins and cellular processes controlling growth and differentiation.

Adenocarcinoma↗