New Strategies to Detect Cancers in Carriers of Mutations in RB1

New Strategies to Detect Cancers in Carriers of Mutations in RB1: Blood Tests Based on Tumor-educated Platelets, or Extracellular Vesicles.

Rationale: Individuals with a cancer predisposition due to a mutation in the paradigm tumor suppressor gene RB1, have a high risk to develop the childhood cancer retinoblastoma (Rb). Biopsies are not possible in Rb, before treatment selection. Heritable Rb patients have also a high risk to develop other types of second primary, either childhood or adult, malignancies (SPMs), notably sarcomas and melanomas. Remarkably, SPMs are now the leading cause of death in heritable-Rb-survivors. Unfortunately, there are no well-developed regular surveillance protocols for SPMs in Rb survivors available right now. Recently, new non-invasive cancer test have been developed, based on either RNA-sequencing data from platelets (ThromboSeq), or on extracellular membrane vesicles (EVs) derived from tumor cells present in blood.

Objective:

• Determine the non-cancerous baseline in adult RB1-mutation carriers (heritable-Rb-survivors).
• Contribute to the biobanking of blood and cancerous tissues from RB1-mutation carriers with SPMs.
• The development of blood-based tests, either platelet or EV-based, for the detection of (the type of) tumors in RB1-mutation carriers.

Study design: Cross-sectional multicenter trial.

Study population:

• 40 Rb patients (children),
• 40 controls (children),
• 153 Rb survivors (adults),
• 153 controls (adults),
• 10 Rb survivors with SPM (children/adults).

Main study parameters/endpoints:

• Determine the non-cancerous baseline in adult RB1-mutation carriers (heritable-Rb-survivors).
• Contribute to the biobanking of blood and cancerous tissues from RB1-mutation carriers with SPMs.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

Two blood samples totalling 10ml blood will be collected for every participant. Additionally, a short questionnaire has to be filled in concerning their and their family's cancer history. Blood draws will be done, when participants are already present in the hospital for other appointments, and thus no extra visits are required. For all children, blood will be collected through an already present IV, and so no extra venepuncture is required. Children have to be included because Rb is a tumor only present in this patient group.

Inclusion Criteria:

Adult (16 years and older):

• Group 1: germline mutation RB1.
• Group 2 (control): no germline mutation RB1.

Pediatric (until 6 years of age):

• Group 1: somatic or germline mutation RB1 and retinoblastoma.
• Group 2 (control): no mutation RB1.

Exclusion Criteria:

Adult (16 years and older):

• Group 1: concomitant heritable (inherited) disorder other than caused by monoallelic mutation of RB1.
• Group 2 (control): cancer or already known cancer predisposition syndrome.

Pediatric (until 6 years of age):

• Group 1: concomitant heritable (inherited) disorder other than caused by monoallelic mutation of RB1.
• Group 2: cancer or already known cancer predisposition syndrome.