Abstract P4-04-01: The landscape of somatic genetic alterations in breast cancers from CHEK2 germline mutation carriers
Authors: Kumar R , Pei X , Selenica P , Wen HY , Powell S , Robson M , Riaz N , Reis-Filho JS , Weigelt B , Mandelker D 
Published: May 2019

Abstract
Introduction: Checkpoint kinase 2 (CHEK2) is a tumor suppressor gene, which regulates cell cycle in response to DNA damage response. Selected CHEK2 germline mutations have been shown to confer an increased risk of breast cancer development. Multiple founder mutations in CHEK2 have been identified, and meta analyses have shown that CHEK2 truncating variants confer a higher breast cancer risk than missense variants. Here, we assessed the phenotype and repertoire of genetic alterations of breast cancers from 33 patients with CHEK2 pathogenic germline variants.
Materials and methods: We performed targeted capture massively parallel sequencing (≥410 genes) of tumor and normal samples from 13 patients with CHEK2 pathogenic germline variants, and retrieved whole exome sequencing (WES) data (BAM files) of tumor and normal samples from 20 patients with CHEK2 germline pathogenic variants included in the TCGA breast cancer study. In addition, we retrieved WES data of BRCA1, BRCA2 and ATM associated breast cancers from TCGA and Weigelt et al. (JNCI 2018). Somatic mutations, copy number alterations, mutational signatures and large-scale transitions (LSTs) were defined using state-of-the-art bioinformatics algorithms.
Results: Of the 33 CHEK2-associated breast cancers included in this study, 21 had missense and 12 had loss-of-function (LoF) germline mutations, and 81% were ER-positive and 12% HER2-positive. CHEK2-associated breast cancers statistically significantly less frequently displayed an ER-negative/HER2-negative phenotype (0%) than BRCA1- (80%) or BRCA2-associated (33%) breast cancers (BRCA1, p&lt;0.0001 for both comparisons), but were similar to ATM-associated breast cancers. Biallelic inactivation of CHEK2 through loss of heterozygosity (LOH) of the wild-type allele was present in 17 of 33 samples (52%). LOH of the CHEK2 wild-type allele was significantly more frequent in tumors with LOF mutations than in those with missense mutations (78% vs 36%, respectively; p=0.0394). PIK3CA (36%) and GATA3 (33%) were the two most recurrently mutated genes in these samples. TP53 somatic mutations were detected in five cases, four of which harbored missense CHEK2 germline mutations. Unlike BRCA1- and BRCA2-associated breast cancers, but akin to ATM-associated breast cancers, CHEK2-associated breast cancers lacked the mutational signature associated with homologous recombination (HR) DNA repair defects (i.e. signature 3) and only five cases displayed high LST scores.
Conclusion:CHEK2-associated breast cancers are phenotypically and genetically distinct from BRCA1- and BRCA2-associated breast cancers, but similar to ATM-associated breast cancers. Akin to ATM-associated breast cancers, CHEK2-associated breast cancers are preferentially ER-positive, lack genomics features consistent with defective HR, and have a repertoire of somatic genetic alterations similar to those of non-BRCA1/2 ER-positive breast cancers. Our results suggest that either CHEK2 germline mutations contribute to an increased risk of breast cancer independently of the HR DNA repair defects or that the mutational signatures caused by CHEK2 pathogenic germline mutations differ from those caused by pathogenic germline mutations affecting bona fide HR-related genes (e.g. BRCA1, BRCA2 and PALB2).
Citation Format: Kumar R, Pei X, Selenica P, Wen HY, Powell S, Robson M, Riaz N, Reis-Filho JS, Weigelt B, Mandelker D. The landscape of somatic genetic alterations in breast cancers from CHEK2 germline mutation carriers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-04-01.