Abstract 177P
Background
Breast cancer (BC) is the most common female malignancy worldwide. Alterations in homologous recombination repair gene (HRR) are responsible for early-onset BC or ovarian cancer incidence among different ethnic group. Individuals with inherited mutations in HRR gene should be offered the risk-reduction strategies, surveillance and chemoprevention. This study aimed to reclassify the variants of unknown significance by using the comprehensive human proteo-genomics database that annotates disease mutations and population variants through the lens of sites of post-translational modifications.
Methods
Thirty seven BC Buryat patients (indigenous population of the Russian Federation) with young-onset and/or bilateral and/or familial BC were included into the study. The median age of the patients at the time of BC diagnosis was 41 years (range 25–51 years). Genomic DNA isolated from blood samples was used to prepare libraries using a capture-based target enrichment kit (Hereditary Cancer Solution™, SOPHiA GENETICS, Switzerland) covering 27 genes (ATM, APC, BARD1, BRCA1, BRCA2 and others). NGS sequencing (150 bp paired-end) was performed on a NextSeq 500 System (Illumina, USA). The data were reclassified by using the Active Driver DB tool.
Results
We re-examined 135 rare variants with MAF less 0,005 (41 VUS, 25 conflicting, 64 benign/likely benign and 5 new variants). We identified 10 out of 135 (8%) mutations that affecting the sites of post-translational modification in proteins (PTM mutations). Of 135 rare mutations, 1 benign was reclassified as network-rewiring - motif loss mutation, 3 VUS and 1 new variant were reclassified as distal PTM-associated mutations, 2 new and 1 benign variants were classified as proximal PTM-associated mutations and 1 benign and 1 conflicting variants were classified as direct PTM-associated mutations.
Conclusions
For the first time, 8% (10 out of 135) mutations that affecting the sites of post-translational modification in proteins (PTM mutations) were identified among early-onset breast cancer women of mongoloid origin.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
The reported study was funded by RFBR according to research project 18-29-09046.
Disclosure
All authors have declared no conflicts of interest.