Data from Pan-cancer Analysis of Homologous Recombination Repair–associated Gene Alterations and Genome-wide Loss-of-Heterozygosity Score

Abstract

<div>AbstractPurpose:<p>To study associations across tumor types between genome-wide loss of heterozygosity (gLOH) and alterations in homologous recombination repair (HRR)-associated genes beyond <i>BRCA1</i> and <i>BRCA2</i>.</p>Experimental Design:<p>Genomic profiling using a targeted next-generation sequencing assay examining 324–465 genes (FoundationOne, FoundationOne Heme, and FoundationOne CDx; Foundation Medicine, Inc.) was performed in a cohort of 160,790 samples across different tumor types. Zygosity predictions and gLOH status were calculated and linked with alterations in 18 HRR-associated genes (<i>BRCA1</i>, <i>BRCA2</i>, <i>PALB2</i>, <i>BARD1</i>, <i>ATR</i>, <i>ATRX</i>, <i>ATM</i>, <i>BAP1</i>, <i>RAD51B</i>, <i>RAD51C</i>, <i>RAD51D</i>, <i>BRIP1</i>, <i>NBN</i>, <i>CHEK1</i>, <i>CHEK2</i>, <i>FANCA</i>, <i>FANCC</i>, <i>MRE11</i>) and other genomic features, using Fisher's exact test and Mann–Whitney <i>U</i> tests.</p>Results:<p>We identified a strong correlation between elevated gLOH and biallelic alterations in a core set of HRR-associated genes beyond <i>BRCA1</i> and <i>BRCA2</i>, such as <i>BARD1</i>, <i>PALB2</i>, <i>FANCC</i>, <i>RAD51C</i>, and <i>RAD51D</i> (particularly in breast, ovarian, pancreatic, and prostate cancer). Monoallelic/heterozygous alterations in HRR-associated genes were not associated with elevated gLOH. gLOH was also independently associated with <i>TP53</i> loss. Co-occurrence of <i>TP53</i> loss and alterations in HRR-associated genes, and combined loss of <i>TP53-PTEN</i> or <i>TP53-RB1</i>, was associated with a higher gLOH than each of the events separately.</p>Conclusions:<p>Biallelic alterations in core HRR-associated genes are frequent, strongly associated with elevated gLOH, and enriched in breast, ovarian, pancreatic, and prostate cancer. This analysis could inform the design of the next generation of clinical trials examining DNA repair–targeting agents, including PARP inhibitors.</p></div>