ONCOGBA: Malignant Neoplasms Incidence in GBA-PD (NCT06814431)

ONCOGBA: Malignant Neoplasms Incidence in GBA-PD (NCT06814431)

Overview

The ONCOGBA study (NCT06814431) is an observational retrospective cohort study designed to investigate whether heterozygous [GBA1](/genes/gba) mutations increase the incidence of malignant neoplasms in [Parkinson's disease](/diseases/parkinsons-disease) patients compared to both idiopathic PD patients and the general population. Sponsored by Azienda USL IRCCS di Reggio Emilia in Italy, this study leverages the Italian movement disorder registry to construct a large cohort of approximately 3,000 PD patients for rigorous epidemiological analysis.

This study addresses a critical knowledge gap at the intersection of lysosomal dysfunction, neurodegeneration, and oncogenesis — a triad that has attracted increasing research attention since the discovery that GBA1 mutations confer both PD risk and may modify cancer susceptibility.

Trial Details

ONCOGBA: Malignant Neoplasms Incidence in GBA-PD (NCT06814431)

Overview

The ONCOGBA study (NCT06814431) is an observational retrospective cohort study designed to investigate whether heterozygous [GBA1](/genes/gba) mutations increase the incidence of malignant neoplasms in [Parkinson's disease](/diseases/parkinsons-disease) patients compared to both idiopathic PD patients and the general population. Sponsored by Azienda USL IRCCS di Reggio Emilia in Italy, this study leverages the Italian movement disorder registry to construct a large cohort of approximately 3,000 PD patients for rigorous epidemiological analysis.

This study addresses a critical knowledge gap at the intersection of lysosomal dysfunction, neurodegeneration, and oncogenesis — a triad that has attracted increasing research attention since the discovery that GBA1 mutations confer both PD risk and may modify cancer susceptibility.

Trial Details

| Attribute | Value |
|-----------|-------|
| NCT Number | NCT06814431 |
| Official Title | Study on the Incidence of Malignant Neoplasms in Patients with Parkinson's Disease and Heterozygous Mutation of the GBA Gene |
| Acronym | ONCOGBA |
| Status | Recruiting |
| Study Type | Observational |
| Design | Retrospective Cohort |
| Enrollment | 3,000 participants (estimated) |
| Sponsor | Azienda USL IRCCS di Reggio Emilia |
| Conditions | Idiopathic Parkinson's Disease, GBA1-associated Parkinson's Disease |
| Start Date | November 23, 2023 (actual) |
| Primary Completion | December 2025 (estimated) |
| Completion | September 2026 (estimated) |
| Last Verified | February 2025 |
| Central Contact | Franco Valzania, MD — +39 0522 296494 |

Scientific Rationale

The GBA1-Cancer Connection

The link between GBA1 mutations and cancer risk emerges from the fundamental role of glucocerebrosidase (GCase) in lysosomal function and cellular homeostasis[@gba2024a][@gba2025e]:

Lysosomal dysfunction is a shared feature of both Gaucher disease pathogenesis and PD neurodegeneration. When GCase activity is impaired, glucosylceramide and related sphingolipids accumulate within cells. This accumulation affects multiple cellular processes:

Epidemiological Evidence

Prior studies have suggested a bidirectional relationship between PD and cancer, with GBA1 mutations potentially modulating this relationship[@blook2024]:

• Increased cancer risk in GBA carriers: Multiple studies report elevated rates of hematological malignancies (particularly lymphoma and leukemia) and certain solid tumors in GBA mutation carriers
• PD-cancer paradox: While PD patients generally have lower overall cancer rates than age-matched controls (possibly due to inverse epidemiological associations), GBA-PD patients may deviate from this pattern
• Mechanistic overlap: Both neurodegeneration and carcinogenesis involve impaired autophagy, mitochondrial dysfunction, and inflammation

Mechanistic Links Between GBA1 and Cancer

Understanding why GBA1 mutations might increase malignancy risk involves several interconnected pathways[@pavan2023][@chen2022]:

Key Mechanisms

Study Design

Retrospective Cohort Structure

The ONCOGBA study employs a retrospective cohort design using the Italian movement disorder registry:

┌─────────────────────────────────────────────────────────────────┐
│ Italian Movement Disorder Centers (4 Sites) │
│ Consecutive PD Patients (2020–2025) │
│ │
│ ┌──────────────────────────┐ ┌──────────────────────────┐ │
│ │ GBA-PD Cohort │ │ Idiopathic PD Cohort │ │
│ │ Heterozygous GBA1 │ │ No GBA1/LRRK2 │ │
│ │ pathogenic variant │ │ mutations │ │
│ │ ~500 patients │ │ ~2,500 patients │ │
│ └──────────┬───────────────┘ └──────────┬───────────────┘ │
│ │ │ │
│ └───────────────┬───────────────┘ │
│ ▼ │
│ Comparison against General Population │
│ Cancer Incidence Data (Italian Cancer Registries) │
└─────────────────────────────────────────────────────────────────┘

Diagnostic Criteria

All patients are diagnosed using the UK Parkinson's Disease Society Brain Bank Diagnostic Criteria, ensuring diagnostic accuracy and consistency across all four recruiting sites.

Study Arms

| Arm | Description | Expected Size |
|-----|-------------|---------------|
| GBA-PD | PD patients with documented heterozygous pathogenic GBA1 variant | ~500 |
| Idiopathic PD | PD patients without GBA1 or LRRK2 pathogenic mutations | ~2,500 |

Outcomes

Primary Outcome

"Evaluation of Increased Incidence of Malignant Neoplasms in Parkinson's Disease Patients with GBA1 Mutation Compared to the General Population"

This endpoint requires:

• Systematic cancer incidence ascertainment in both cohorts
• Standardized incidence rate calculation using age/sex-adjusted population data from Italian cancer registries
• Comparison of observed vs. expected cancer cases in GBA-PD vs. general population

Secondary Outcomes

• Sex (male vs. female)
• Age at PD onset
• Center of recruitment
• Tumor type (hematologic vs. solid malignancies)

Exploratory Analyses

• Duration of PD before cancer diagnosis
• Correlation between specific GBA1 mutations and cancer types
• Interaction with other genetic modifiers
• Effect of PD medications on cancer incidence

Eligibility Criteria

Inclusion Requirements

Exclusion Criteria

Study Sites

Recruiting Locations

| Site | City | Role |
|------|------|------|
| Ospedale A. Perrino | Brindisi, Italy | Clinical assessment, genetic sampling |
| IRCCS Istituto Neurologico Carlo Besta | Milan, Italy | Clinical assessment, genetic sampling, data coordination |
| Azienda USL IRCCS di Reggio Emilia | Reggio Emilia, Italy | Lead site, sponsor, data management |
| Ospedale Santa Chiara di Trento | Trento, Italy | Clinical assessment, genetic sampling |

Central Contact

Franco Valzania, MD

• Phone: +39 0522 296494
• Email: franco.valzania@ausl.re.it
• Institution: Azienda USL IRCCS di Reggio Emilia

Methodology

Genetic Screening

All patients undergo comprehensive genetic screening for GBA1 mutations using:

• Sequencing: Full GBA1 coding region sequencing (exons 1-11)
• Copy number analysis: MLPA to detect large deletions/duplications
• Pseudogene exclusion: Specific methods to distinguish GBA from GBAP1 (glucocerebrosidase pseudogene 1)

Cancer Ascertainment

• Cross-linking with Italian cancer registries for validated cancer diagnoses
• Medical record review for cancer diagnosis confirmation
• Pathological classification of tumor types (ICD-O-3 coding)
• Temporal relationship to PD onset documented

Statistical Analysis

Expected Impact

Clinical Significance

The ONCOGBA study will provide the first large-scale, systematic evaluation of cancer risk in GBA-PD patients:

Research Implications

Positive findings would:

• Support the GBA1-cancer mechanistically shared pathway hypothesis
• Identify GBA-PD as a high-risk group requiring enhanced cancer surveillance
• Open therapeutic avenues targeting the lysosomal-autophagy axis for both neurodegeneration and cancer prevention

Relationship to Other GBA-PD Research

Within the GBA-PD Therapeutic Landscape

The ONCOGBA study complements interventional GBA-PD trials by addressing an important epidemiological question:

| Trial Focus | Example | Study Type |
|-------------|---------|------------|
| GCase enhancement | NCT05778617 (Ambroxol UCL) | Interventional |
| Substrate reduction | NCT04154077 (Venglustat) | Interventional |
| Gene therapy | NCT05424306 (PR001) | Interventional |
| Cancer epidemiology | NCT06814431 (ONCOGBA) | Observational |

Mechanistic Cross-Links

The ONCOGBA study findings will inform other GBA-PD research by:

• Establishing whether GBA1 dysfunction confers broad cancer susceptibility
• Identifying whether specific GBA1 mutations correlate with particular cancer types
• Providing epidemiological data on the GBA1-lysosome-cancer axis that can guide therapeutic targeting

Related Pages

• [GBA Gene](/genes/gba)
• [GBA1 Gene](/genes/gba1)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Gaucher Disease](/diseases/gaucher-disease)
• [Glucocerebrosidase Pathway in PD](/mechanisms/gba-glucocerebrosidase-parkinsons)
• [GBA Therapy in Parkinson's Disease](/mechanisms/gba-therapy-parkinsons)
• [Ambroxol to Slow Progression in PD (NCT05778617)](/clinical-trials/ambroxol-parkinson-progression-nct05778617)
• [Ambroxol ASPro-PD Trial (NCT05827068)](/clinical-trials/ambroxol-aspro-pd)

External Links

• [ClinicalTrials.gov NCT06814431](https://clinicaltrials.gov/study/NCT06814431)
• [Azienda USL IRCCS di Reggio Emilia](https://www.ausl.re.it/)
• [IRCCS Istituto Neurologico Carlo Besta](https://www.besta.fondazione.it/)
• [Italian Movement Disorder Society](https://www.simspd.it/)

References