Family awareness of genetic risk in affected Caucasian ancestry members with bladder cancer (BC) associated with germline variants in DNA‐repair genes (gDRGs).

Abstract

868 Background: The aim of this study is to evaluate the awareness of Bladder Cancer (BC) in families with at least one affected Caucasian ancestry member harbouring germline variants in DNA‐repair genes (gDRGs). Methods: Data were collected from a prospective, monocentric cohort study founded by AIRC - Fondazione AIRC per la Ricerca sul Cancro (registered and emended with the number ID-IG-25027-V1.3). The study was conducted from June 2024 to August 2025 in a university tertiary hospital by a multidisciplinary approach to the patient (collaboration of the Departments of Oncology, Urology, Pathology, Radiology, and Medical Genetics Laboratory). We recruited patients with pathological diagnosis of muscle invasive BC (MIBC) who underwent radical cystectomy (RC). All the patients were offered to be tested for pathogenic variants (PVs), likely pathogenic variants (LPVs) and variants of unknown significance (VUS) in gDRGs. We includes Germline Homologous Recombination Repair (gHRR) plus Mismatch Repair (gMMR) variants. All of them who were positive for at least one variant were contacted to offer a family genetic counselling and testing for un-affected first-degree members. Un-affected gDRG positive members were offered a structured screening for early diagnosis of BC. The primary endpoint was to evaluate the willingness of un-affected subjects to be tested. The secondary endpoint was the acceptance to participate and attend, if resulted positive, to the screening programme. Results: Among 75 eligible patients, 72 underwent successful germline sequencing and 23 patients (30.6%) harboured at least one gDRG variant (mainly in ATM, ATR, BARD1, BRCA1-2, CHEK2, PALP2 and PMS2). Over those 23 patients, 22 (95.6%) accepted to share the genetic outcome with their un-affected family members. We identified 55 un-affected subjects aged between 35 and 75 years old (probands). Only 3 (5.4%) probands refused to be tested for gDRG variants. One (1.8%), with a family history of BRCA2, declared to have been previously tested as positive, and 51 (92.8%) were interested to be tested. All of them, if resulted positive, were agreed to participate in the subsequent screening programs by annual urine cytology, urine molecular test (Epicheck/Xpert Bladder Detection test), abdominal ultrasounds assessment and cystoscopy when indicated. Conclusions: These preliminary findings seem supporting a high awareness of genetic risk of affected Caucasian ancestry patients with BC when associated to gDRGs. We strongly support the urgent need to implement and expand awareness and BC screening programs in genetic high-risk populations.