Utility of Homologous Recombination Deficiency Biomarkers Across Cancer Types.

Area of Science:

• Genomics
• Cancer Biology
• Precision Oncology

Background:

• Homologous recombination DNA repair deficiency (HRD) predicts sensitivity to platinum-based chemotherapy and PARP inhibitors in specific cancers like breast, ovarian, pancreatic, and prostate.
• BRCA1/2 alterations and genomic scars are established biomarkers for HRD in these cancers.
• The clinical significance of alterations in other homologous recombination repair (HRR)-related genes across diverse cancer types remains underexplored.

Purpose of the Study:

• To systematically investigate HRR gene alterations and their association with genomic scar signatures (HRD scores) across all solid tumor types.
• To explore the influence of sex and TP53 mutations on the relationship between HRR alterations and genomic scar scores.
• To evaluate the utility of comprehensive HRD analysis in predicting response to DNA-damaging chemotherapy and patient survival.

Main Methods:

• Utilized The Cancer Genome Atlas (TCGA) data for comprehensive analysis of HRR pathway gene alterations, loss-of-heterozygosity, genomic scar scores (HRD score, mutational signature 3 ratio), DNA methylation, gene expression, TP53 mutations, sex, and clinical data.
• Performed integrated analysis of genomic, epigenomic, transcriptomic, and clinical data to assess HRD comprehensively.
• Correlated HRR gene alterations and HRD scores with clinical outcomes, including response to chemotherapy.

Main Results:

• Biallelic alterations in HRR genes beyond BRCA1/2 were linked to increased genomic scar scores.
• The interplay between HRR gene alterations and genomic scar scores was significantly modulated by patient sex and the presence of somatic TP53 mutations.
• HRD-defined cases exhibited distinct gene expression profiles and demonstrated improved survival when treated with DNA-damaging agents.

Conclusions:

• This study validates the broad applicability of HRD analysis across all cancer types.
• Comprehensive HRD assessment can refine chemotherapy decision-making, enhancing treatment efficacy.
• The findings represent a significant step forward in the field of precision oncology, enabling more personalized treatment strategies.