HRD

Pattern-driven genomic features, including mutational signatures2, homologous recombination deficiency3, tumour mutational burden and tumour heterogeneity scores4, were associated with clinical outcomes, highlighting their potential utility as predictive biomarkers for clinical evaluation of treatments such as CDK4/6 and HER2 inhibitors, as well as adjuvant and neoadjuvant chemotherapy. These findings highlight the power of large-scale, clinically annotated whole-genome sequencing in advancing our understanding of how genomic alterations shape patient outcomes.

Our findings highlight the effectiveness of LP-WGS ctDNA CNA analysis as a promising approach for diagnosis and risk stratification of pediatric neuroblastic tumors, and for monitoring chemotherapy response. Particularly, ctDNA analysis is minimally invasive, rapid and cost-effective, which could bring additional benefits in pediatric practices.

Immune profiling shows P2 as immunosuppressive, characterized by LGALS9 and M2 macrophages. Our proteogenomic analyses provide a molecular landscape of LMS, revealing biological insights, patient outcome stratification, and therapeutic targets.

ERpHER2n-Basal breast cancer represents a clinically high-risk subgroup whose molecular resemblance to TNBC highlights potential therapeutic opportunities, particularly for immunotherapy and DNA repair-targeting treatments.

Functional assays in both T47D and MCF7 cells demonstrated that co-expression of N4BP2L2 restored HR activity and reduced olaparib sensitivity in EXO1-overexpressing cells. These findings suggest EXO1 overexpression serves as a marker of functional HR deficiency and a potential predictor of PARP inhibitor response, highlighting the EXO1-N4BP2L2 axis as a promising biomarker and therapeutic target, especially for guiding PARP inhibitor use beyond BRCA-mutated tumors.

PARPi selection differed by HRD status, with niraparib favored in HR-proficient and olaparib in HRD-positive tumors. No additional profiling was required for PARPi therapy recommendation, and no incidental findings beyond the scope of HRD testing were detected. Molecular profiling with F1CDx proved to be a technically feasible, clinically impactful, and time-efficient assay, demonstrating its value in supporting molecular-guided PARPi therapy recommendations in the routine care of HGSOC patients.

Its combined format and accessibility render it well-suited for real-world use in personalized ovarian cancer care. Its additional capacity to reveal more extensive tumor genomic alterations improves clinical decision-making and underscores the importance of integrating HRD scoring with comprehensive molecular profiling in personalized oncology.

Fluzoparib, the domestically developed PARPi in China, has demonstrated significant efficacy in BRCA-mutated ovarian cancer. In the field of supportive care, megestrol acetate (MA) is recommended as the first-line preferred therapeutic agent for cancer-related anorexia by major guidelines, though its role in first-line ovarian cancer therapy remains unexplored, and evidence for its combination with PARPi is lacking...Imaging assessments revealed significant tumor reduction without disease progression or grade ≥3 adverse events observed throughout follow-up. This case highlights the potential of combining PARPi and hormone therapy as a 'chemotherapy-free' precision treatment model for elderly and HRD-positive ovarian cancer patients, offering a promising strategy to balance efficacy and tolerability in a population traditionally underserved by conventional regimens.

Additionally, potential biomarkers derived from broad genomic data, including tumor mutation burden, mutation signatures, scar-based homologous recombination deficiency signatures, and RNA subtypes, were validated for their clinical utility. This large-scale, unbiased genomic dataset addresses the limitations of previous genomic studies in PDAC, facilitating comprehensive clinico-genomic analyses with significant clinical utility.

We develop FFPErase, a machine learning framework that filters SNV/indel artifacts and delivers clinical grade variant reporting allowing accurate quantification of clinically relevant biomarkers. Comparison of FFPErase WGS calls to clinical reporting by FDA-approved panel tests demonstrates 99% sensitivity and enables reporting of 24% more clinically relevant findings.

PARPi efficacy depends strongly on BRCA and HRD status. Olaparib-based regimens provide the greatest clinical benefit with acceptable safety in BRCA+ and HRD+ disease, whereas PARPi appear to be of limited value in HRD-negative ovarian cancer.

Furthermore, we found that HELLS is co-expressed with PARP1 in cancer cells, and its loss is synthetic lethal with homologous recombination deficiency (HRD). This work unveils new functions of HELLS in modulating SSB repair and responses to clinically relevant DNA alkylation damage, thus offering new insights into the potential therapeutic value of targeting HELLS in cancer.