Variants of unknown significance (VUS) in DNA repair genes in Caucasian men with muscle invasive bladder cancer (MIBC): A case of “serendipity” pushing for a BC screening program.
Authors: Lazzeri Massimo , Lughezzani Giovanni , Contieri Roberto , Avolio Pier Paolo , Fasulo Vittorio , Paciotti Marco , Chiarelli Giuseppe , Garofano Giuseppe , Soldà Giulia , Asselta Rosanna , Capalbo Anita , Colombo Piergiuseppe , Cavalli Pietro , Buffi NicolòMaria , Saita Alberto , Casale Paolo , Rodolfo Hurle 
Published: February 2025

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Background:
In 2021 we started an enhanced PCa screening in healthy Caucasian men with germline DNA repair pathogenic variants. Over 109 enrolled men, we found two naïve patients with bladder cancer (BC), but none with PCa. This observation prompted us to investigate the prevalence of germline pathogenic variants in patients with BC and suggest genetic counselling, testing and screening for healthy relatives of subject with BC.
Methods:
This is a prospective ongoing study aiming to detect, by exome analysis, the prevalence of germline pathogenic (PV), likely pathogenic (LPV) variants and variant of unknown significance (VUS) in patients with BC attending the urological department from January 2024. The following DNA repair genes were considered:
ATM
,
ATR
,
MRE11A
,
BAP1
,
BARD1
,
BRCA1
,
NBN
,
BRCA2
,
PALB2
,
BRIP1
,
CHEK2
,
RAD51C
,
FAM175A
,
RAD51D
,
GEN1
, and
XRCC1
, plus mismatch repair genes
MLH1
,
PMS2
,
MSH2
, and
MSH6
. Healthy relatives (>35 years) of patients tested positive, are being offered genetic counselling, testing and finally screening for early detection of BC. Screening consists of urine analysis, urine cytology, ultrasound abdominal assessment and cystoscopy, when indicated, every year. The study is financed/supported by Associazione Italiana per la Ricerca sul Cancro (AIRC): Protocol ICH-2812, code IG 2020-ID-25027.
Results:
From January to March 2024, 41 patients with BC (25 non-muscle invasive, NMIBC and 16 muscle invasive, MIBC) were tested. Overall, we found 919 variants in the 20 DNA repair genes analysed, of which 385 rare (minor allele frequency <1%). No PV and LPV were identified, while 18 VUS were found in 12 patients (29.3%; mean age 66.75 SD 11.75 vs. 69.82 SD 13.71 in negative).The reported variants affected the following genes:
ATM
(4);
ATR
(3);
BARD1
(3);
PMS2
(2), and
BRCA2
,
CHEK2
,
MSH6
,
NBN
,
PALB2
,
GEN1
(1 variant each). Interestingly, all variants were found in MIBC patients or HG-NMIBC, whereas no variant was observed in low-grade NMIBC (p< 0.00001, Fisher exact test). Patients with multiple variants had a significant lower age: mean age 58.16 SD 9.02 p<0.01.
Conclusions:
According to Merriam-Webster dictionary “serendipity” is the phenomenon of finding valuable or agreeable things not sought for. Starting from a PCa screening in healthy men, although no clearly pathogenic variants were identified in our BC cohort, we found the presence of about 30% of VUS linked to aggressive cancers and patient low age. Those findings challenge the current (no)recommendation on genetic counselling and testing in this setting and strongly support the urgent need to raise awareness of genetic risk for BC and to design effective public health promotion policies.