Familial adenomatous polyposis (FAP) is a disorder of autosomal dominant inheritance that is responsible for around 1% of colorectal cancer (CRC) cases. To determine the mutation profile of FAP-specific to the Hungarian population. This prospective single-center study enrolled patients with clinically suspected FAP or attenuated FAP (aFAP). Whole-exome next-generation sequencing was performed to detect variants of 50 FAP priority genes and 173 CRC predisposing genes or other CRC disease-associated genes. To identify larger deletions and insertions, a multiplex amplifiable probe hybridization technique was used. The identified genes were then classified according to the American College of Medical Genetics and Genomics guidelines. A total of 26 index patients with clinically suspected FAP (n = 21) and aFAP (n = 5) were enrolled. APC gene alterations were confirmed in 92.31% of the cases (region 1B deletion, n = 2; whole-gene deletion, n = 4; frameshift mutation, n = 2; nonsense mutation, n = 5, and splice mutation, n = 1), with the remaining two cases having CHEK2 and MSH3 gene alterations. According to pathogenicity, 21 cases had pathogenic mutations, 6 cases had likely pathogenic mutations, and 16 cases had variants of unknown significance (VUS). The most frequent of the latter were the POLE (n = 5) and PIEZO1 (n = 4) gene variants. Germline mutations in the APC gene were confirmed in more than 90% of Hungarian patients with clinically suspected FAP. Although the role of VUS genes is unclear, they are highly likely to play a role in the development of CRC.

Background/Objectives: Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by pathogenic variants in the adenomatous polyposis coli (APC) gene. Its attenuated form (AFAP) is characterized by fewer colorectal polyps and later onset of colorectal cancer. We aimed to characterize the molecular effects of a novel APC gene variant (NM_000038.6: c.1620_1624delinsT) identified in a patient with AFAP. Methods: A 56-year-old man with the AFAP phenotype underwent germline testing via a multigene NGS panel, which identified a novel APC gene variant (NM_000038.6: c.1620_1624delinsT). In silico analyses predicted disruption of the canonical donor splice site and a frameshift followed by the introduction of a premature stop codon. The transcriptional impact of the identified APC gene variant was investigated by mRNA analysis. Results: mRNA analysis revealed two distinct APC transcripts: the first transcript led to a truncated protein (p.Leu540PhefsTer8), and the second transcript lacked exon 12, resulting in an in-frame 26 amino acid deletion of APC protein (p.Ala517_Gly542del). The transcript lacking exon 12 was more abundant than the transcript with a premature stop codon, likely due to degradation through nonsense-mediated decay. Conclusions: The APC gene variant (NM_000038.6: c.1620_1624delinsT) exhibits a dual transcriptional effect, revealing its pathogenic role in AFAP. This study highlights the diagnostic value of combined DNA-RNA germline testing for improving the clinical classification of novel APC gene variants and their genotype-phenotype correlations in FAP.

Attenuated familial adenomatous polyposis (AFAP) is a disorder caused by germline pathogenic variants in APC and is characterized by the presence of <100 colonic polyps and a high lifetime risk of developing colorectal cancer. Salivary gland basal cell tumours are uncommon and have not previously been reported in AFAP. We present a family with AFAP and multiple salivary gland tumours, including basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC). The colon and salivary gland tumours showed abnormal nuclear β-catenin staining. Genomic analysis of both parotid BCACs showed copy-number-neutral loss of heterozygosity (CNN-LOH) at the APC locus, implicating loss of full-length APC in the aetiology of parotid BCACs. In contrast, the submandibular BCAC showed a p.(Ile35Thr) CTNNB1 mutation. Spatial transcriptomic analysis revealed a stepwise increase in the expression of WNT pathway genes across the proband's salivary lesions, from benign (intercalated duct hyperplasia and BCAs) to malignant (BCACs). Our results showcase BCA and BCAC as potential new phenotypes of AFAP. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Oligopolyposis is defined as between 10 and 100 polyps in the large intestine. If the polyps are adenomas, at least 15% of affected patients will have a syndrome of hereditary colorectal cancer predisposition. Management is aimed at preventing the development of cancer, and options include chemoprevention, colectomy, and colonoscopy, with colectomy generally favored. The role of colonoscopy is relatively unexplored. To present the results of colonoscopic control of patients with oligopolyposis. Retrospective study of a cohort of patients with oligopolyposis separated by genotype and histology. Hereditary colorectal cancer center. Those with oligopolyposis preferring management with sequential colonoscopy to colectomy and who underwent at least 3 years of follow-up were included. Colonoscopy, polypectomy, and surgical resection. Number of colonoscopies, complications of colonoscopies, length of follow-up, number of polyps at first and last colonoscopy, size of the largest polyp at first and last colonoscopy, incidence and stage of cancer, and timing of the cancer diagnosis. There were 59 patients: 29 with sessile serrated polyposis, 13 with MUTYH -associated polyposis, 8 with attenuated familial adenomatous polyposis, and 9 with oligopolyposis not otherwise specified. Patients with familial adenomatous polyposis were 20 years younger than those in the other groups. Patients averaged 1 colonoscopy per year for a mean follow-up between 5 and 11 years. One patient had a post-polypectomy hemorrhage, but there was no perforation and no admission. No patient needed surgery to control benign polyposis. Nine patients had cancer, 6 diagnosed and resected before the start of the colonoscopic surveillance. Three patients with sessile serrated polyposis developed interval cancers while on surveillance, all stage 1. These 3 patients were the only ones who needed colectomy. Relatively low numbers of familial adenomatous polyposis and oligopolyposis patients. Lack of specific data on variants. In compliant patients and experienced hands, endoscopic control of oligopolyposis can be safe and effective. See Video Abstract . ANTECEDENTES:La oligopoliposis se define como la presencia de entre 10 y 100 pólipos en el intestino grueso. En el caso que se trataran de adenomas, al menos el 15% de los pacientes afectados presentará una predisposición al síndrome hereditario de cáncer colorrectal. El tratamiento se centra en prevenir el desarrollo del cáncer y las opciones incluyen quimioprevención, colectomía y colonoscopia, siendo la colectomía la que generalmente se prefiere. El papel de la colonoscopia es relativamente inexplorado.OBJETIVO:Presentar los resultados del control colonoscópico de pacientes con oligopoliposis.DISEÑO:Estudio retrospectivo de una cohorte de pacientes con oligopoliposis, separados por genotipo e histología.ESCENARIO:Centro de cáncer colorrectal hereditario.PACIENTES:Pacientes con oligopoliposis que prefirieron el tratamiento con colonoscopia secuencial a la colectomía, y que se sometieron a al menos tres años de seguimiento.INTERVENCIONES:Colonoscopia y polipectomía, resección quirúrgica.PRINCIPALES MEDIDAS DE RESULTADOS:Número de colonoscopias, complicaciones de las colonoscopias, duración del seguimiento, número de pólipos en la primera y última colonoscopia, tamaño del pólipo más grande en la primera y última colonoscopia, incidencia y estadio del cáncer, y momento del diagnóstico.RESULTADOS:Se incluyeron 59 pacientes: 29 con poliposis serrada sésil, 13 con poliposis asociada a MUTYH, 8 con poliposis adenomatosa familiar (PAF) atenuada y 9 con oligopoliposis no especificada. Los pacientes con PAF eran 20 años más jóvenes que los demás grupos. Los pacientes promediaron una colonoscopia al año durante una media de seguimiento de entre 5 y 11 años. Un paciente sufrió una hemorragia pospolipectomía, pero no se produjo ninguna perforación ni ingreso hospitalario. Ningún paciente requirió cirugía para controlar la poliposis benigna. Nueve pacientes presentaron cáncer, 6 de ellos diagnosticados y resecados antes del inicio de la vigilancia colonoscópica. Tres pacientes con poliposis serrada sésil desarrollaron cánceres de intervalo durante la vigilancia, todos en estadio 1. Estos fueron los únicos pacientes que necesitaron colectomía.LIMITACIONES:Número relativamente bajo de pacientes con PAF y oligopoliposis. Falta de datos específicos sobre variantes.CONCLUSIONES:En pacientes cumplidores y con experiencia, el control endoscópico de la oligopoliposis puede ser seguro y eficaz. (Traducción-Dr Osvaldo Gauto ).

Risk-reducing colectomy in familial adenomatous polyposis syndrome is the standard of care. This has increased the importance of surveillance for extracolonic malignancies in postcolectomy individuals. We sought to define the present-day incidence of all cancers and mortality in familial adenomatous polyposis. Retrospective longitudinal cohort study. Two large academic hospitals. Eligible patients carried an APC pathogenic variant or met clinical criteria for familial adenomatous polyposis. Cancer diagnosis, mortality, and associated risk factors. A total of 358 patients were identified. The percentage who exhibited a classic familial adenomatous polyposis phenotype was 63.7%; 21.2% were de novo, and 82.7% had a colectomy. Colorectal cancer was the most common cancer (n = 59; 16.5%). Colorectal cancer diagnoses were associated with de novo familial adenomatous polyposis (OR 7.8 [95% CI, 3.51-17.35]; p < 0.001). Thyroid, duodenal/small bowel, gastric, and neuroendocrine tumors were reported in 7.5%, 3.1%, 2.8%, and 2.5% of patients, respectively. Rates of cancer were similar in classic and attenuated familial adenomatous polyposis. Thirty-nine patients (10.9%) died at a mean age of 49.6 ± 17.1 years. Twenty-six deaths were malignancy-related, and colorectal cancer was the leading cause (n = 10). All colorectal cancer-related deaths occurred in individuals with classic familial adenomatous polyposis, and 9 of 10 individuals were not previously diagnosed with the syndrome. Gastric and duodenal/small bowel cancers were the second leading causes (4 deaths each), and all occurred after colectomy. Fifty-nine percent of all deaths were attributable to a familial adenomatous polyposis-related malignancy or morbidity. Retrospective clinical data. Colorectal cancer remains the most common malignancy and cause of death in familial adenomatous polyposis. However, nearly all colorectal cancer-related deaths occurred in individuals unaware of their familial adenomatous polyposis diagnosis, and none occurred in the attenuated syndrome. In patients who had a colectomy, gastric and duodenal/small bowel cancers are now the leading causes of death. See Video Abstract . ANTECEDENTES:La colectomía para reducir el riesgo en el síndrome de poliposis adenomatosa familiar es el estándar de atención. Esto ha aumentado la importancia de la vigilancia de las neoplasias malignas extracolónicas en individuos post-colectomía.OBJETIVO:Buscamos definir la incidencia actual de todos los cánceres y la mortalidad en la poliposis adenomatosa familiar.DISEÑO:Estudio de cohorte longitudinal retrospectivo.ESCENARIO:Dos grandes hospitales académicos.PACIENTES:Los pacientes elegibles portaban una variante patogénica de APC o cumplían los criterios clínicos para la poliposis adenomatosa familiar.PRINCIPALES MEDIDAS DE RESULTADOS:Diagnóstico de cáncer, mortalidad,y factores de riesgo asociados.RESULTADOS:Se identificaron 358 pacientes. El 63,7% presentaban un fenotipo clásico de poliposis adenomatosa familiar, el 21,2% eran de novo y el 82,7% se había sometido a una colectomía. El cáncer colorrectal fue el cáncer más común (n = 59, 16,5%). Los diagnósticos de cáncer colorrectal se asociaron con poliposis adenomatosa familiar de novo (odds ratio 7,8 (IC del 95 % 3,51-17,35; p < 0,001)). Se informaron tumores de tiroides, duodenales/intestino delgado, gástricos y neuroendocrinos en el 7,5 %, 3,1 %, 2,8 % y 2,5 % de los pacientes, respectivamente. Las tasas de cáncer fueron similares en la poliposis adenomatosa familiar clásica y atenuada. 39 pacientes (10,9 %) murieron a una edad media de 49,6 ± 17,1 años. 26 muertes estuvieron relacionadas con neoplasias malignas y el cáncer colorrectal fue la causa principal (n = 10). Todas las muertes relacionadas con cáncer colorrectal ocurrieron en individuos con poliposis adenomatosa familiar clásica y 9/10 no habían sido diagnosticados previamente con el síndrome. El cáncer gástrico y de duodeno/intestino delgado fueron las segundas causas principales (4 muertes cada uno), y todas ocurrieron después de una colectomía. El 59% de todas las muertes fueron atribuibles a una neoplasia maligna o morbilidad relacionada con la poliposis adenomatosa familiar.LIMITACIONES:Datos clínicos retrospectivos.CONCLUSIONES:El cáncer colorrectal sigue siendo la neoplasia maligna y la causa de muerte más común en la poliposis adenomatosa familiar. Sin embargo, casi todas las muertes relacionadas con el cáncer colorrectal ocurrieron en personas que desconocían su diagnóstico de poliposis adenomatosa familiar, y ninguna ocurrió en el síndrome atenuado. En los pacientes que se sometieron a una colectomía, los cánceres gástrico y de duodeno/intestino delgado son ahora las principales causas de muerte. (Traducción-Dr Yolanda Colorado ).