Abstract 2005P
Background
ATM, BRCA1, BRCA2 and RAD51C genes are tumour suppressor genes (TSGs) that play an important role in DNA repair pathways. Structural variations (SVs) of TSGs are more likely to influence their normal biological functions. Our study aims to explore the genomic SVs of ATM, BRCA1, BRCA2 and RAD51C genes in the Chinese population.
Methods
Formalin-fixed paraffin-embedded (FFPE) samples and matched peripheral blood of 10194 Chinese solid tumor patients were collected for next-generation sequencing (NGS) based 450 genes panel assay (Cancer Sequencing YS panel, CSYP). Genomic alterations including single base substitution, short and long insertions/deletions, copy number variations, gene fusions and rearrangement were assessed. SVs are sequence variants >50bp in size, including long Indels (deletions, duplications and insertions), inversions, and rearrangements. SVs calling was conducted by the CSYP algorithm.
Results
Genomic alterations of ATM, BRCA1, BRCA2 or RAD51C were detected in 10% (993/10194) of Chinese patients with frequencies 4%, 3%, 4% and 0.4%, respectively. Among those patients, 235 (24%) patients harbored germline mutations, 714 (72%) patients harbored somatic mutations, and 44 (4%) patients harbored both somatic and germline mutations. In all classes of somatic alterations, frequencies of SVs in ATM, BRCA1, BRCA2 and RAD51C were 6%, 31%, 21% and 16%, respectively. Rearrangements constituted 72%, 89%, 80%, 67% of SVs in ATM, BRCA1, BRCA2 and RAD51C. Rearrangements disrupting protein structures would induce dysfunction of these genes. Among the rearrangements in BRCA1/2, intron 11/12 (18/64) of BRCA1 and intron 24 (14/59) of BRCA2 were more likely to be hot breakpoints. BRCA1 rearrangements in intron11/12 are expected to interrupt serine containing domain, which is phosphorylated by ATM. Moreover, most of the BRCA2 rearrangements in the intron 24 would cause the loss of BRCA-2_OB3 domain.
Conclusions
NGS targeted sequencing shows that 15% of ATM/BRCA1/BRCA2/RAD51C mutated patients were harboring SVs, which could benefit from PARP inhibitors. It indicated that certain domains of BRCA1/2 were more likely to be involved in rearrangement, which could be studied more in the future.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Sun Yat-sen University Cancer Center.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.