Aug 2026· Galen medical journal· 0 citations· 20 references
TL;DR
High-risk and early-onset PCa is associated with rare germline DDR alterations, and expanded germline testing in younger patients is supported and potential relevance for precision oncology approaches is suggested.
Abstract
Background: Prostate cancer (PCa) is a biologically heterogeneous disease, with a subset of cases driven by hereditary germline alterations. Methods: Targeted germline sequencing using the Twist Fixed Panel was performed in nine high-risk PCa patients (median age 47; range 30–61). Variants were classified based on ClinVar, gnomAD, and in silico prediction tools.
Results: Pathogenic and likely pathogenic variants in DNA damage repair (DDR) genes were identified, including BRCA2, BRIP1, PALB2, and BRCA1. A homozygous ATM variant was observed in one patient. Several ultra-rare variants in MLH3 and BARD1 were also detected. Most variants had allele frequencies <10-6. Conclusions: High-risk and early-onset PCa is associated with rare germline DDR alterations. These findings support expanded germline testing in younger patients and suggest potential relevance for precision oncology approaches, although functional validation is required..
Simple Summary Breast cancer is one of the most common cancers among women, but its genetic causes remain poorly characterized in North African populations. In this study, we investigated germline genetic variants in 165 Tunisian breast cancer patients using targeted next-generation sequencing of a multigene cancer panel. We identified pathogenic or likely pathogenic variants (P/LPVs) in BRCA1 and BRCA2 genes in 19 patients (11.5%), with several recurrent variants and additional variants not previously reported in our Tunisian cohort. P/LPV carriers were more frequently younger at diagnosis and showed significant associations with family history and several clinical features. We also identified P/LPVs in other genes. In addition, 56 variants of uncertain significance (VUS) were detected, of which 7 were prioritized through computational analyses. Additional functional or segregation evidence should be collected to establish pathogenicity. Our findings expand the available genetic data on breast cancer in Tunisia and highlight the importance of population-specific genomic studies for improving variant interpretation and genetic counseling.
N. Ammous-Boukhris, Rania Abdelmaksoud-Dammak, W. Ben Kridis et al.· Cancers· 0 citations
Germline PVs in NCCN-recommended DDR genes and the KLK3 I179T variant identify a subset of men at elevated risk of PCSM, including those with apparently localized disease.
Lucy Lu, Julian Xu, Zhu-Qing Shi et al.· Prostate Cancer and Prostati...· 1 citation
Rare variants in MSH6 and BRCA2 are significantly associated with increased HCC risk, revealing a previously unconfirmed role for DNA repair genes in HCC susceptibility across ancestrally diverse populations and may inform genetic risk stratification and surveillance strategies.
A. Garófalo, Perapa Chotiprasidhi, Josephine P. Johnson et al.· JHEP Reports· 0 citations
Suggestive evidence supporting associations between rare germline variants in eight hereditary cancer genes and lung cancer were obtained from two large independent datasets.
Sierra R. Broad, Jun Wei, Keri L. Denson et al.· Annals of Thoracic Surgery· 0 citations
PURPOSE
Germline ATM pathogenic or likely pathogenic (P/LP) variants are increasingly recognized as clinically relevant in hereditary cancer predisposition, their integration into routine testing remains heterogeneous across countries. We describe the prevalence, tumor spectrum and relative risk associated with germline ATM P/LP variants in individuals with breast and pancreatic cancer.
METHODS
We conducted a five-year retrospective (2019-2025) reanalysis of the ATM gene in 1,707 probands tested with hereditary breast and ovarian cancer (HBOC) or pancreatic cancer panels in our center. For all probands that underwent targeted ATM reanalysis, relative risks (RR) and odds ratios (OR) were calculated. Family-based segregation was performed when possible.
RESULTS
Targeted ATM re-analysis identified 33 additional probands with P/LP variants, increasing diagnostic yield from 7.3% to 9.1% in HBOC and from 4.3% to 9.7% in pancreatic cancer. Among 22 breast-cancer probands, mean age at diagnosis was 47 years. Case-control comparison yielded OR 3.85 (95% CI 2.43-6.08; P=8.5×10-9) for breast cancer and OR 15.81 (95% CI 6.31-39.66; P=4.0×10-9) for pancreatic cancer.
CONCLUSION
This work strengthens the role of ATM in cancer predisposition panels and supports its inclusion in French national hereditary cancer panel recommendations, together with implementation of appropriate surveillance and counseling for individuals harboring ATM P/LP variants.
Iulian O. Ban, L. Mansour-Hendili, Ana María Navarro et al.· Genetics in Medicine· 0 citations
Background/Objectives: Triple-negative breast cancer (TNBC) is enriched for germline pathogenic variants in BRCA1/2 and other DNA repair genes, but the additional value of extended germline profiling beyond BRCA1/2 remains insufficiently characterized in Russian patients. We aimed to characterize germline pathogenic/likely pathogenic variants (GPV/LPVs) and variants of uncertain significance (VUSes) in cancer predisposition and homologous recombination repair (HRR)-related genes in Russian TNBC patients and to assess the additional yield of extended germline profiling beyond BRCA1/2. Methods: We retrospectively analyzed germline DNA from 275 patients with histologically confirmed TNBC. Exome sequencing was performed for 204 patients and focused HRR-panel testing for 71 patients on the MGISEQ-G400 platform. Results: Overall, 114 patients (41.5%) harbored at least one germline GPV/LPV. BRCA1/2 GPV/LPVs were detected in 53 patients (19.3%), with BRCA1 predominating over BRCA2 (48 vs. 5 carriers) and the recurrent BRCA1 c.5329dup variant accounting for 23 cases. In the exome subset, 79 of 204 patients (38.7%) carried a GPV/LPV in Groups 1–3, including 48 (23.5%) with BC-related GPV/LPVs; non-BRCA Group 1 genes contributed seven additional carriers beyond BRCA1/2-only analysis. The expanded HRR set identified 52 GPV/LPV carriers (25.5%) versus 45 (22.1%) in the reference HRR panel, while the common HRR gene set identified 68 carriers (24.7%) in the full cohort. In addition, 183 unique VUSes were found in Groups 1–3 in the exome subset, affecting 128 patients (62.7%). Conclusions: Russian TNBC patients show a substantial germline GPV/LPV burden dominated by BRCA1/2 alterations and the recurrent BRCA1 c.5329dup founder variant. Extended germline profiling identified additional non-BRCA and HRR-related findings beyond BRCA1/2, but the incremental yield was moderate and accompanied by a considerable VUS burden. Broader germline testing may therefore support hereditary risk assessment and exploratory HRR-focused stratification, but non-BRCA HRR findings should not be considered sufficient for therapy selection without additional tumor-level or clinical evidence.
P. Shatalov, A. Bukaeva, E. Veselovsky et al.· Biomedicines· 0 citations
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