Understanding CHEK2’s role in breast cancer by analyzing breast cancers with and without CHEK2-specific genomic profiles

We previously revealed CHEK2 -specific genomic features, suggesting a different underlying biology. Here, we analyzed CHEK2 -specific structural variant size distributions in 926 primary and metastatic breast cancers. We devised a method to identify ER+ samples without CHEK2 mutation but displaying the CHEK2 -specific profiles and studied the associated phenotypes. Duplications in CHEK2 and ER+ CHEK2-like tumors were mainly localized on chromosomes 11 and 17. However, we did not observe regions or genes specific for CHEK2 or ER+ CHEK2-like tumors. Genes with increased mutation frequency in ER+ CHEK2-like were observed but these were not significant after multiple testing correction. The number of structural variants was significantly higher in ER+ CHEK2-like samples, while it was lower in number of mutations. We here show the feasibility to identify ER+ CHEK2-like cases using structural variant size profiles. This did not lead to convincing CHEK2 -specific driver genes, suggesting CHEK2- mutant cancers select the same drivers as CHEK2-unlike cancers. The specific structural variant sizes hint at CHEK2 -mutant cancers affect or maintain their genome stability differently. This furthers understanding of CHEK2 mechanisms and its untangling of ER+ breast cancer biology.