Abstract 1816P
Background
CHEK2-associated neoplasms account for a significant proportion of hereditary breast cancer (BC). The contribution of loss of heterozygosity (LOH) phenomenon to the pathogenesis of CHEK2-dependent tumors remains poorly understood, and almost all available data concern only one mutation type - CHEK2 1100delC.
Methods
We determined the prevalence of LOH in 50 breast tumors from treatment-naïve patients carrying CHEK2 1000delC, CHEK2 IVS2+1G>A, or CHEK2 del5395 germline alterations. Testing of CHEK2 LOH was performed by assessing the mutation locus itself (allele-specific PCR, Sanger sequencing) and by genotyping of surrounding single nucleotide polymorphisms (digital droplet PCR). Paired tumor and normal DNA samples from 20 cases were subjected to either whole exome (n = 9) or targeted (n = 11) sequencing analysis.
Results
CHEK2 LOH was detected in 27/50 (54%) cases. It was observed in 10/19 (53%) CHEK2 1000delC-associated, 6/12 (50%) CHEK2 IVS2+1G>A-associated, and 11/19 (58%) CHEK2 del5395-associated tumors. In one carcinoma from a carrier of the CHEK2 IVS2+1G>A alteration, the loss of mutated allele was confirmed. CHEK2-dependent BC demonstrated a pattern of mutations characteristic for luminal breast neoplasms: PIK3CA alterations were present in 9/20 (45%) tumors, while TP53 lesions – in 3/20 (15%) cases. Three types of genomic features typical for BRCAness/homologous DNA repair deficiency (HRD) phenotype, namely the total level of chromosomal instability (CIN), the presence of BRCA-related mutational signature 3, and the number of indels longer than 5 nucleotides, were evaluated in 9 cases, including 4 BC with CHEK2 LOH. High-level CIN and signature 3 were observed in 3 cases each, and the share of long (≥5 bp) indels varied from 5% to 67%. Only one tumor had all three features of HRD simultaneously, it also demonstrated the highest fraction of signature 3 (42%) and the highest number of long indels. This neoplasm contained somatic TP53 mutation and CHEK2 LOH.
Conclusions
Somatic loss of wild-type CHEK2 gene copy is observed in about half of breast tumors arising in carriers of truncating CHEK2 mutations. Unlike BRCA1/2-associated BC, most of CHEK2-related neoplasms do not show the genomic signs of homologous DNA repair deficiency.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Russian Science Foundation, grant number 21-75-30015.
Disclosure
All authors have declared no conflicts of interest.