Familial Adenomatous Poliposys Italian Network (Rete Italiana Poliposi Adenomatosa Familiare) (RIPAF)

Rete Italiana Poliposi Adenomatosa Familiare (RIPAF)

RIPAF (Rete Italiana Poliposi Adenomatosa Familiare) is a national, multicenter observational registry designed to establish a coordinated Italian network for the management of Familial Adenomatous Polyposis (FAP) and related adenomatous polyposis syndromes. The registry includes patients with APC-related FAP (classic and attenuated forms), MUTYH-associated polyposis (MAP), and adenomatous polyposis not associated with APC or MUTYH mutations (NAMP), including cases linked to other susceptibility genes or without identified pathogenic variants.

The study combines retrospective and prospective data collection across 28 Italian centers. Its primary purpose is to generate standardized, large-scale clinical data to better characterize disease presentation and evolution, evaluate current surveillance and surgical strategies, and assess oncological outcomes and quality-of-care indicators in real-world practice.

The registry will collect detailed information on genotype-phenotype correlations, colorectal and upper gastrointestinal cancer incidence, desmoid tumor development, timing and type of prophylactic surgery, postoperative outcomes, and long-term survival. Additional objectives include evaluating adherence to surveillance guidelines, timing of genetic diagnosis, and preventive surgical uptake among at-risk relatives.

By harmonizing data collection and promoting collaboration among referral centers, RIPAF aims to reduce variability in clinical management across Italy, improve risk stratification and decision-making, and create a national platform to support future multicenter research initiatives and international collaborations in hereditary colorectal cancer syndromes.

Study Overview

• Status: Active, not recruiting
• Conditions: Colorectal Cancer; Turcot Syndrome; Desmoid Tumor; Duodenal Adenoma; Familial Adenomatous Polyposis (FAP); Desmoid-Type Fibromatosis; Hereditary Colorectal Cancer Syndrome; Gardner Syndrome; Attenuated Familial Adenomatous Polyposis (AFAP); MUTYH-Associated Polyposis (MAP); Non-APC/MUTYH Associated Polyposis (NAMP); Upper Gastrointestinal Polyposis; Hereditary Polyposis Syndrome

Detailed Description

RIPAF is a nationwide, multicenter, observational registry developed to address the current heterogeneity in the management of Familial Adenomatous Polyposis and related hereditary adenomatous polyposis syndromes in Italy. Although several specialized centers provide care for these patients, clinical practice varies in terms of genetic workup, surveillance protocols, timing and type of prophylactic surgery, and management of extracolonic manifestations. This fragmentation limits the possibility of conducting large-scale analyses and generating robust multicenter evidence.

The registry is designed to create a structured collaborative framework that integrates expertise from 28 participating institutions, enabling standardized data collection and long-term follow-up.

Study Population:

Eligible participants include pediatric and adult patients diagnosed with adenomatous colorectal polyposis, defined as more than 10 synchronous adenomas or at least 20 cumulative adenomas across colonoscopies. The registry encompasses:

APC-associated familial adenomatous polyposis (classic phenotype with >100 adenomas and attenuated phenotype with 10-99 adenomas); MUTYH-associated polyposis (biallelic pathogenic variants); Adenomatous polyposis associated with other susceptibility genes (e.g., POLE, POLD1, NTHL1, MSH3, GREM1); Polyposis cases without identified pathogenic variants (NAMP), provided adenomas represent the predominant histological type.

Patients with non-adenomatous polyposis syndromes (e.g., hamartomatous or serrated polyposis) are excluded.

Study Design and Data Collection:

This is an observational registry with both retrospective and prospective components. Each participating center defines its retrospective observation period according to local data availability, while prospective enrollment continues throughout the study duration.

Data are entered into a centralized, pseudonymized REDCap database hosted by the coordinating center. The infrastructure incorporates encrypted data storage, two-factor authentication, role-based access control, audit trails, and compliance with GDPR and Good Clinical Practice requirements. Direct identifiers remain stored locally at each participating institution and are not shared within the network.

Collected variables include:

Demographic characteristics (age class, sex, geographic region); Genetic data (genes tested, specific pathogenic variants, mutation location, testing date, family history); Clinical presentation at diagnosis (age, symptoms, polyp burden and distribution, histology, presence of colorectal cancer); Extracolonic manifestations (duodenal polyps with Spigelman stage, desmoid tumors, thyroid abnormalities, CNS tumors, other associated conditions); Surveillance data (colonoscopy and upper endoscopy intervals and findings); Surgical data (type of procedure-IRA versus IPAA-surgical approach, timing, indications, complications, functional outcomes); Oncological outcomes (colorectal and upper gastrointestinal cancers, staging, treatments, recurrence); Desmoid tumor management and outcomes; Follow-up information including vital status and cause of death; Quality-of-life measures when available.

Dates are recorded as time intervals from a reference date to ensure anonymization during data export.

Study Objectives:

The registry pursues three principal domains of investigation:

Natural History and Genotype-Phenotype Correlations:

Comprehensive evaluation of disease evolution across genetic subtypes, including age at onset, cancer incidence, extracolonic manifestations, and variability in clinical severity.

Prognostic and Therapeutic Determinants:

Analysis of overall and cancer-specific survival, impact of different surgical strategies (total colectomy with ileorectal anastomosis versus restorative proctocolectomy with ileal pouch-anal anastomosis), laparoscopic versus open approaches, incidence of rectal stump cancer, and outcomes of desmoid tumors following prophylactic surgery.

Quality-of-Care Assessment:

Measurement of time from symptoms to genetic diagnosis, adherence to surveillance protocols, timing of prophylactic surgery, and concordance between surgical management of probands and preventive interventions in relatives.

Governance and Quality Assurance:

The network is supervised by a Steering Committee, supported by multidisciplinary scientific and data management committees. Built-in validation rules, automated consistency checks, and periodic data cleaning procedures ensure data reliability. Each center accesses only its own patient data, while the coordinating center can analyze the full pseudonymized dataset without access to direct identifiers.

Sample Size and Timeline:

The estimated target population is approximately 1,500-2,000 patients based on the census of participating centers. The initial project duration is 36 months, encompassing ethics approvals, database development, retrospective data entry, prospective enrollment, interim analysis, and dissemination of results. The registry infrastructure is intended to remain operational beyond the initial funding period to enable extended follow-up.

Clinical and Scientific Impact:

By integrating clinical, genetic, surgical, and outcome data within a single national platform, RIPAF aims to:

Reduce variability in clinical management; Improve risk stratification and personalization of care; Benchmark surgical and oncological outcomes; Facilitate case discussion and knowledge exchange among centers;

Provide a foundation for national and international collaborative research, including engagement with European reference networks.

The registry ultimately seeks to enhance survival, optimize preventive strategies, and improve quality of life for individuals affected by hereditary adenomatous polyposis syndromes.

• Study Type: Observational
• Enrollment (Estimated): 1500

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20133
    • Fondazione IRCCS Istituto Nazionale dei Tumori

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients will be categorized into cohorts based on genetic and phenotypic characteristics. The FAP Classic Phenotype cohort includes patients with pathogenic APC variants presenting with more than 100 colorectal adenomas and classic extracolonic manifestations. The AFAP Attenuated Phenotype cohort comprises patients with pathogenic APC variants presenting with 10-99 colorectal adenomas and later age of onset. The MAP cohort consists of patients with biallelic MUTYH pathogenic variants presenting with 10 to a few hundred polyps of adenomatous, hyperplastic, or serrated histology. The NAMP cohort includes patients without identified APC or MUTYH variants, which may include variants in POLE, POLD1, NTHL1, MSH3, GREM1, or cases with no identified genetic defect. Additional clinical variants include Gardner Syndrome (FAP with desmoid tumors, fibromas, cysts, osteomas) and Turcot Syndrome (FAP with CNS neoplasms, particularly medulloblastoma).

Description

Inclusion Criteria:

• patients with documented colorectal polyposis (>10 synchronous adenomas or ≥20 adenomas across multiple colonoscopies);
• patients who have undergone genetic testing with the following results: a pathogenic variant (PV) in APC (FAP); biallelic pathogenic variants in MUTYH (MAP); other pathogenic variants identified in genes such as POLE, POLD1, NTHL1, MSH3, and GREM1;
• patients in whom no pathogenic variants have been identified in known genes (NAMP);
• histologically, the majority of polyps must be adenomas.

Exclusion Criteria:

• Patients with polyposis syndromes of different etiology not meeting the above inclusion criteria, such as Peutz-Jeghers syndrome, Juvenile polyposis syndrome, Serrated polyposis syndrome, or Cowden syndrome.
• Patients whose polyp burden does not meet the specified thresholds or whose polyps are predominantly non-adenomatous (hyperplastic, serrated, hamartomatous).
• Patients who refuse to provide informed consent.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Natural History Characterization	This includes comprehensive analysis of genotype-phenotype correlations, age at diagnosis, polyp burden at diagnosis and over time, colorectal cancer incidence, and prevalence and timing of extracolonic manifestations across all polyposis subtypes.	Throughout study period, up to 36 months and extended follow-up
Quality of Care Indicators	This encompasses measurement of time intervals from symptom onset to genetic diagnosis, adherence to surveillance colonoscopy and upper endoscopy protocols, time from diagnosis to prophylactic surgery in appropriate candidates, and rate of prophylactic surgery uptake in at-risk family members.	Throughout study period, up to 36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Assessed across all cohorts	Up to 36 months and extended long-term follow-up
Cancer-Specific Survival	Including colorectal cancer-specific survival and upper gastrointestinal cancer-specific survival.	Up to 36 months and extended long-term follow-up
Desmoid Tumor Outcomes	Incidence of desmoid tumors overall and post-prophylactic surgery	Up to 36 months and extended long-term follow-up
Surgical Outcomes	Overall survival after preventive surgery.	Up to 36 months and extended long-term follow-up
Surgical approach Outcomes	Surgical approach, open versus laparoscopic.	Up to 36 months and extended long-term follow-up
Surgical oncological outcomes	Incidence of rectal stump cancer in patients who underwent IRA	Up to 36 months and extended long-term follow-up
APC Genotype-Phenotype Correlation Analysis	Examining relationships between APC mutation location and phenotype severity	Up to 36 months and extended long-term follow-up
MUTYH Genotype-Phenotype Correlation Analysis	MUTYH variants and clinical presentation	Up to 36 months and extended long-term follow-up

Collaborators and Investigators

• Sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
• Collaborators: Istituto Nazionale Tumori IRCCS - Fondazione G. Pascale; IRCCS Ospedale San Raffaele
• Investigators: Principal Investigator: Marco Vitellaro, MD, IRCCS Istituto Nazionale dei Tumori

Study record dates

Study Major Dates

• Study Start (Actual): May 13, 2024
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: February 26, 2026
• First Submitted That Met QC Criteria: March 4, 2026
• First Posted (Actual): March 10, 2026

Study Record Updates

• Last Update Posted (Actual): March 10, 2026
• Last Update Submitted That Met QC Criteria: March 4, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Natural History Study; Familial Adenomatous Polyposis; National Registry; APC gene; Hereditary Cancer Syndrome; Desmoid Fibromatosis; Ileal Pouch-Anal Anastomosis; Colorectal Cancer Prevention; Multicenter Registry; MUTYH gene; POLE gene; POLD1 gene; NTHL1 gene; MSH3 gene; GREM1 gene; Polyposis Registry; Prophylactic Colectomy; Ileorectal Anastomosis; Genotype-Phenotype correlation; Cancer Surveillance Strategy; Quality of Care Indicators; REDCap Database; European Reference Network; ERN GENTURIS
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Genetic Diseases, Inborn; Intestinal Diseases; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplasms, Glandular and Epithelial; Colonic Diseases; Adenoma; Congenital Abnormalities; Abnormalities, Multiple; Neoplasms, Connective and Soft Tissue; Neoplasms, Connective Tissue; Adenomatous Polyps; Intestinal Polyposis; Neoplasms, Fibrous Tissue; Fibroma; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Colorectal Neoplasms; Adenomatous Polyposis Coli; Neoplastic Syndromes, Hereditary; Desmoid Tumors; Turcot syndrome; Attenuated familial adenomatous polyposis; Polyposis Syndrome, Hereditary Mixed, 1; Gardner Syndrome
• Other Study ID Numbers: INT 35/24

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No