Potential advantage of clinical exome sequencing in BRCA1/2-negative families: a retrospective study of a cohort of 500 patients at a high-risk for hereditary cancers.

Comprehensive Genomic Profiling Reveals the Mutational Spectrum and Clinical Significance of BRCA1/2 and Other Cancer-Susceptibility Genes in Breast Cancer Patients from Southern Tunisia

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.

Exome-based cancer driver gene comprehensive testing can provide a genetic diagnosis for individuals with triple-negative breast cancer

Triple-negative breast cancer (TNBC) is characterized by aggressive behaviour, high tumor heterogeneity, and an increased likelihood of recurrence and early metastasis. These factors hinder successful treatment. Genetic diagnosis enables personalized clinical recommendations and treatment options. The objective of this study was to validate whole-exome sequencing (WES) and variant prioritization in cancer susceptibility genes (CSG) associated with hereditary cancer (HC) predisposition in TNBC patients (n = 24). We present the development of a reproducible bioinformatic pipeline and its technical validation in a validation cohort (n = 25). This cohort comprised individuals with diverse primary tumors who had a previously confirmed molecular diagnosis of a hereditary cancer syndrome, serving as gold-standard cases to assess the pipeline’s analytical accuracy. We consolidated a comprehensive panel of cancer genes and determined all variants in the TNBC discovery cohort (12.5% of patients), identifying three pathogenic germline variants (gPV) in ATM, RAD51D, and BRCA1. These genes are involved in the molecular pathway of DNA repair by homologous recombination (HRD). Our results demonstrate that the developed bioinformatic pipeline provides reliable genetic diagnosis of cancer predisposition syndromes from exome data, applicable not only to TNBC patients but also to individuals with any cancer suspected of having a hereditary component.

Targeted Germline Sequencing Identifies Ultra-Rare DDR Variants in High-Risk Prostate Cancer

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.

Multi-ancestry sequencing analysis in 293,141 participants identifies predisposition DNA repair genes associated with HCC risk.

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.

Prevalence and clinical impact of PIK3CA and PTEN alterations from reflex genomic testing of newly diagnosed colorectal cancer: a population-based series

Background Results from the Adjuvant Low dose Aspirin in Colorectal Cancer (ALASCCA) clinical trial demonstrate a survival benefit associated with aspirin use in patients with non-metastatic colorectal cancer (CRC) harbouring phosphoinositide 3-kinase (PI3K) pathway alterations. Identification of patients in routine clinical care is required for implementation of this therapeutic approach. A real-world analysis of reflex diagnostic testing was performed to assess prevalence of PI3KCA and PTEN gene alterations and potential clinical impact. Methods Next generation sequencing panel testing of all newly diagnosed CRC as part of a Lynch screening service began in the Northern Ireland Cancer Network in 2022. Profiling, using a capture hybridisation assay and custom Small Cancer Panel covers all coding regions of PTEN and PIK3CA with a limit of detection of 4% variant allele frequency (VAF). Results 1516 CRC patients underwent genomic profiling at the point of diagnosis from January 2024-March 2025. Across all CRC stages, 170 patients (11.2%) had tumours harbouring PIK3CA mutations with the majority occurring in exon 9 and 20. A further 51 of 1516 tumours (3.4%) demonstrated PTEN mutations. Of 221 patients with PIK3CA/PTEN alterations, 174 (79%) had non-metastatic CRC, of whom 6 (3.4%) had an absolute contraindication to aspirin use. Overall, 168 (11.1%) of 1516 patients in this cohort were therefore identified by this reflex testing pathway as potentially eligible for treatment. Conclusions Prevalence of PIK3CA and PTEN alterations in this series (14.6%) was lower than in the ALASCCA trial (37%) but these results represent a real-world rather than a highly selected trial population. Regardless, our findings support implementing testing for use of a safe, inexpensive repurposed drug and underscore the importance of upfront testing for timely treatment decision-making and implementation of trial findings into routine practice.

Prevalence of BRCA1/2 variants in an Ovarian Cancer Cohort: outcomes from a Nationwide Testing Program.