Abstract 3627: The genomic landscape of breast cancers from CHEK2 c.1100delC mutation carriers
Authors: Smid Marcel , Schmidt Marjanka K. , Prager - van der Smissen Wendy J. , Ruigrok - Ritstier Kirsten , Cornelissen Sten , Schreurs Maartje A. , Collee J. Margriet , Adank Muriel A. , Hooning Maartje J. , Martens John W. , Hollestelle Antoinette 
Published: June 2022

Abstract
Women who carry the germline CHEK2 c.1100delC mutation have a 2.3-fold increased life-time risk to develop breast cancer (BC). Their BCs are mostly of the luminal/ER+ subtype and diagnosed at a younger age than BCs in sporadic patients. BC patients carrying a CHEK2 c.1100delC mutation are at an increased risk of developing a contralateral BC and have a worse survival compared to sporadic BC patients although resistance to either endocrine or chemotherapy does not appear to play a role herein. To unravel the biological mechanism by which CHEK2 c.1100delC exerts its tumorigenic potential, whole genome sequencing was performed of matching normal and primary BC (pBC) DNA from twenty female CHEK2 c.1100delC mutation carriers at Hartwig Medical Foundation (HMF). We compared the somatic pBC genomes of these twenty patients to 560 pBC genomes from the International Cancer Genome Consortium including 30 BRCA1 and 25 BRCA2 mutation carriers and 329 sporadic ER+ pBC patients. The validation cohort consisted of 517 metastatic BC (mBC) genomes from the Center for Personalized Cancer Treatment that were sequenced at HMF and included 24 mBC genomes from CHEK2 c.1100delC mutation carriers. We found that CHEK2 pBC and mBC genomes were dissimilar to pBC and mBC genomes of BRCA1 and BRCA2 mutation carriers and did not show evidence of a homologous recombination deficiency (HRD) phenotype. Instead, CHEK2 pBC and mBC genomes were very similar to genomes of sporadic ER+ pBC and mBC patients in terms of tumor mutational burden, single and double base substitution signatures as well as small insertion/deletion signatures. The size distribution of structural variants (SVs), however, was different for CHEK2 pBCs and mBCs compared with ER+ as well as BRCA1 and BRCA2 pBCs and mBCs. Importantly, the CHEK2 c.1100delC mutation was associated with an increased frequency of larger (&gt; 1Mb) deletions, inversions and tandem duplications (TDs) with peaks at specific sizes. Although CHEK2 mBC genomes more frequently harbored chromothripsis compared with other mBC subtypes, this did not explain the CHEK2-specific SV size distribution pattern. Moreover, increased chromothripsis in CHEK2 mBC genomes was not associated with a higher frequency of somatic TP53 mutations. In fact, we did not observe any somatic TP53 mutations among CHEK2 pBC and mBC genomes. This mutual exclusiveness suggests CHEK2-driven tumorigenesis could act through the TP53 signaling pathway. To conclude, CHEK2 BC genomes do not harbor somatic TP53 mutations and display a unique SV size distribution profile. Moreover, the absence of an HRD phenotype among CHEK2 BC genomes suggests PARP inhibitors will not be effective for treatment of BC in CHEK2 c.1100delC mutation carriers. Increasing knowledge of the mechanisms of CHEK2-driven tumorigenesis may ultimately lead to the development of tailored strategies for treatment and prevention of BC for CHEK2 mutation carriers.
Citation Format: Marcel Smid, Marjanka K. Schmidt, Wendy J. Prager - van der Smissen, Kirsten Ruigrok - Ritstier, Sten Cornelissen, Maartje A. Schreurs, J. Margriet Collee, Muriel A. Adank, Maartje J. Hooning, John W. Martens, Antoinette Hollestelle. The genomic landscape of breast cancers from CHEK2 c.1100delC mutation carriers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3627.