Breast cancer (BC) shows a high incidence both in Kazakhstan and worldwide. Presence of BRCA1 and BRCA2 genes defects, as well as non-BRCA genes can increase the risk of BC and they are still under study. There is evidence of the effect of germline mutations on the survival outcomes of breast cancer patients, according to the molecular characteristics of the tumor in different subgroups.
The study enrolled 235 unrelated patients from the Kazakh population (the average age 34.25 ± 4.56) with BC. Genomic DNA was obtained from peripheral blood and sequencing was performed using TruSight Cancer Kit on the MiSeq platform.
Bioinformatics analysis of NGS data identified 64 pathogenic variants, the heterozygous state were found in 62 (26.4%) patients, 8 (12.5%) variants were not previously described in databases.The most frequent pathogenic mutations were in the genes BRCA1 (24 variants (37.5%) and BRCA2 (18 (28.1%)). Additional pathogenic variants were identified in the non-BRCA genes (APC, ATM, BLM, CHEK2, PALB2, TP53, ERCC2, FANCA, FANCM, NBN, PMS1, PMS2, SDHB and XPA). 84 of the patients (43.3%) had early stage BC, 101 (52.0%) locally advanced, 9 (4,6%) with advanced forms of BC. 45 (23.2%) had disease progression after complex treatment: bone mets in 10 cases, 6 patients had liver mets, 11 lung and 6 patients had brain mets, 12 had combination of different metastases- visceral crisis. 6 cases showed cancer-related death, 5 of them had metastasis in CNS. Luminal A and B was in 27 (13.9%) and 81 (41.7%) cases, 20 (10.3%) patients had Her2-enriched, and 64 (32.9%) had triple-negative subtype of tumor according IHC. The triple-negative molecular subtype of the tumor was found most in the BRCA1-associated group, almost two times higher than in the group of patients without pathogenic mutations (58.3% versus 29.5%, χ2 = 9.45, p = 0.002), the difference is statistically significant. Her2-enriched and triple-negative subgroups had worse OS than Luminal subtypes (hazard ratio, HR 1.20 95% CI: 1.12-1.51) and worse OS, showing 3 patients with a combination of pathogenic BRCA1/2, CHEK2, PALB2, TP53 mutations.
The presence of germline mutations in combination with aggressive subtypes significantly decreases overall survival in young women with breast cancer in the Kazakh population.
Kazakh Institute of Oncology and Radiology.
Ministry of Healthcare of Kazakhstan.
All authors have declared no conflicts of interest.