Bladder cancer (BC) screening in un-affected Caucasian ancestry family members of patients who tested positive for germline homologous recombination repair (gHRR) and mismatch repair (gMMR) variants.

Abstract

TPS879 Background: According to GLOBOCAN, in 2020 there were 573 000 new BC cases and predictions show a significant increase in BC cases from 2020 to 2040 especially in developing countries. This epidemiological trend combined with the highest lifetime costs of any other cancer, requires urgent actions and investment in early detection and screening of individuals at higher risk. The International Agency for Research on Cancer (IARC) reports cigarette smoking as the leading cause of BC and occupational and environmental exposure to carcinogens as the second greatest risk factor behind smoking. However, up to 4.3% of BC patients have a first-degree relative with BC, and up to 50% of urothelial cancer patients have a family history of cancer. BC is rarely attributed to hereditary causes, but recent studies suggest inherited factors may play a larger role respect to the past. Swedish Family-Cancer Database identified a likely genetic predisposition to urinary BC in 7% of cases and an Italian prospective case-control study, found about 30% BC patients harbouring germline at least pathogenic (PV), likely pathogenic (LPV), or variants of unknown significance (VUS). The knowledge of such data prompted us to test the feasibility and performance of a dedicated screening in un-affected Caucasian ancestry family members of BC patients tested positive for gHRR and/or gMMR. Methods: This is an observational, single centre, prospective cohort study of un-affected Caucasian ancestry relatives older than 35 yrs of BC patients tested positive for gHRR and/or gMMR. The study was founded by AIRC - Fondazione AIRC per la Ricerca sul Cancro; registered and emended with the number ID-IG-25027-V1.3. First degree consanguineous (brother-sistes-son-doughter-1stG nephew) relatives of patients with BC positive for gHRR and gMMR, who underwent radical cystectomy, and consanguineous relatives of patients with known BRCA1/2+ cancer or heredo-family cancers are defined as probands. Probands will be offered a genetic counselling and testing for the variants they are likely to have. We will offer a screening program to positive for germline variants un-affected population, consisting of annual urine cytology, urine molecular test, abdominal ultrasounds assessment and cystoscopy when indicated. Positive or suspected cases will undergo trans urethral resection (TUR) for pathological sampling. The main objectives of this exploratory study will be: to report the rate of un-affected subjects who accepted counseling and testing; to identify the frequency of gHRR and gMMT, to describe the genes tested and the distribution of PV, PL and VUS, reporting the cases of BC occurred in screened population. Considering about 80 RC Hospital/year and a yield of 30% of gDRS variants with 2.5 un-affected family members, we foresee to enroll about 50 subject/year. Clinical trial information: r ID-IG-25027-V1.3.