Microhomology-Driven Genomic Alterations in Cancer Genomes: Patterns, Prevalence, and Clinical Implications.
Homologous recombination deficiency (HRD) can force cancer cells to rely on alternative DNA repair pathways, including microhomology-mediated end joining (MMEJ), an error-prone mechanism that can generate deletions with microhomology at repair junctions. Because such patterns may reflect DNA repair defects with clinical relevance, this study aimed to assess the biological and prognostic…
Microhomology-mediated end joining (MMEJ) is an error-prone DNA repair pathway utilized by cancer cells when they cannot rely on homologous recombination deficiency (HRD). This study aimed to evaluate the biological and prognostic significance of microhomology-associated deletions (MADs), as well as optimize detection parameters.
The research focused on assessing the utility of whole-exome sequencing (WES) versus whole-genome sequencing (WGS) in identifying MADs. Applying an Mlt = 2 threshold maximized the precision and statistical reliability of MAD identification. The study found that inactivation of tumor suppressor genes, such as RB1 and CCDC122, was associated with increased MAD burden, which correlated with extended overall survival in ovarian cancer.
The analysis also identified candidate gene-level alterations, including FDX1 and PDE8B, whose Loss of Function (LoF) increased MAD burden across tumors. Quantifying these genetic vulnerabilities and the resulting MAD burden may offer a prognostic biomarker and a foundation for personalized therapies.
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