Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas

TLDR

DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. We employed protein‑structure analyses and a machine‑learning classifier on gene‑expression data to predict functional consequences of rare DDR mutations and identify phenocopying alterations. Mutations with loss of heterozygosity were found in over one‑third of DDR genes, including TP53 and BRCA1/2, with additional epigenetic silencing of EXO5, MGMT, and ALKBH3 in ~20% of samples, and homologous recombination deficiency varied across cancers, being common in ovarian cancer but linked to worse outcomes in others, and these alterations have functional consequences that may influence progression and guide therapy.

Abstract

<h2>Summary</h2> DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including <i>TP53</i> and <i>BRCA1/2</i>. Other prevalent alterations included epigenetic silencing of the direct repair genes <i>EXO5</i>, <i>MGMT</i>, and <i>ALKBH3</i> in ∼20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations. A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious <i>TP53</i> mutations. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy.