Prognostic impact of germline deleterious variants and variants of uncertain significance in advanced prostate cancer: A call for functional elucidation.
Authors: Alonso Monasterio Maitane , Tellaetxe Elorriaga Iñigo , Fernández Ricardo , Carrera Sergio , Jiménez Labaig Pablo , Mosteiro Lorena , Vázquez Manuela , García-Olaverri Jorge , Iturregui Ane Miren , Büchser David , Gómez-Iturriaga Alfonso , Urresola Aranzazu , Fernández Iratxe , Iza Estibaliz , Iruarrizaga Eluska , Mañe Joan Manel , Elcoroaristizabal Xabier , Ruiz-Ontañón Patricia , Erramuzpe Asier , Novo Eneko 
Published: February 2025

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Background:
Prostate cancer remains the most prevalent solid tumor in men and the third leading cause of cancer-related mortality globally. Tumor aggressiveness and poorer clinical outcomes are associated with certain germline variants. Current technological developments in genetic testing have improved the identification of variants of uncertain significance (VUS), adding complexity to the challenging process of clinical decision-making. The aim of this project was to explore the potential correlation between the identified germline variants and the clinical outcomes in patients with metastatic prostate cancer (mPC).
Methods:
This retrospective study was conducted at a tertiary care center and included a cohort of 57 patients with mPC who underwent germline genetic testing from January 2021 to December 2022. DNA sequencing was performed by next-generation sequencing (Miniseq, Illumina) using a custom gene panel of 72 genes, and two commercial software packages were employed for variant identification. Variant reanalysis was performed in April 2024. A descriptive and exploratory statistical analysis together with a survival analysis was conducted. Hazard ratios (HRs) with 95% confidence intervals (CIs) estimated with the Cox Proportional Hazards model and p-values for the survival curves obtained by the Kaplan-Meier estimator are presented.
Results:
A total of 57 patients were included in the analysis, of whom 27/57 (47.5%) had synchronous metastatic disease, while 18/57 (39.1%) had a high-volume tumor (CHAARTED criteria) and 22/57 (47.8%) had high-risk disease (LATITUDE criteria). Of all patients, 19 (33,3%) carried reportable germline variants. Of these, 5 (15.8%) were classified as pathogenic or likely pathogenic, 14 (73.68%) were classified as VUS and in two cases (10.53%) both co-occurred. The impact of the reported variants (including VUS) in homologous recombination repair (HRR) genes (
BRCA1, BRCA2, BARD1, RAD50, RAD51C, RAD51D, PALB2, ATM, CHEK2, NBN
) is summarized in the accompanying table.
Conclusions:
These results seem to indicate that carrying a VUS in an HRR gene could be associated with worse overall survival. This finding further emphasizes the need to report and elucidate the clinical significance of VUS through precise functional studies. A comprehensive somatic and clinical outcome analysis is ongoing.

Survival analysis summary.

Germline HRRreportable variants
mOS* (months)
mOS* (months)
N(patients with reportable variants)
HR 95% CI
p- value

Pathogenic/Likely Pathogenic vs. None (including VUS)
53.4
56.3
3
1.27[0.38 – 4.20]
0.86

Only VUS vs. None
40.4
72.0
11**
1.76[0.73 – 4.21]
0.0478

All vs. None
50.3
72.0
14
2.05[0.99 – 4.24]
0.0263

*The diagnosis of metastatic prostate cancer serves as the baseline for OS.

**One patient was excluded from analysis for having both pathogenic and VUS HRR variants.