Association of rs28714259 polymorphism with a risk of early-onset chronic anthracycline-mediated cardiotoxicity in patients with breast cancer.

Abstract

e13504 Background: Numerous pharmacogenetic studies have led to the identification of genetic polymorphisms associated not only with the development of cardiovascular disease, but also increase the risk of complications due to the use of anthracycline drugs, widely used in the treatment of cancer. The purpose of this study was to assess the prevalence of rs28714259 polymorphism and to study possible correlation with anthracycline-mediated cardiotoxicity (AMC). Methods: The study included 173 Caucasian patients (median age 55 years) with a diagnosis of breast cancer without diagnosed cardiovascular pathology who underwent treatment in the RRIO, Rostov-on-Don in 2019. For genotyping of SNP rs28714259, DNA was extracted from blood using DNA-sorb-B (AmpliSens, Russia) and HRM-PCR was performed on a CFX96 amplifier (Bio-Rad, USA). The presence of polymorphism was confirmed by Sanger sequencing with a Genetic Analyzer 3500 (ABI, USA). The obtained results were compared with European population (1000 Genome). Results: 13 patients (7.5%) with an early-onset of chronic AMC were founded after three courses of chemotherapy. The allelic frequency rs28714259 was 0.079, the frequency of AG genotypes was 0.135, and AA was 0.012. It was shown that the presence of this SNP leads to an increase risk of cardiovascular pathology at an early stage by more than 4 times (OR = 4.186, p = 0.006). In addition, when comparing with the European population, the highest probability of developing early-onset chronic AMC was determined for patients with the AA genotype (more than 22 times, p = 0.001). Conclusions: In this study, a statistically significant association of rs28714259 presence with developing early-onset chronic AMC was revealed, which seems promising for the early determination of the risk group in the management of cancer patients.

A non-coding GWAS variant impacts anthracycline-induced cardiotoxic phenotypes in human iPSC-derived cardiomyocytes

“…Very few of the identified genetic variants, however, have been functionally validated using a disease relevant model. Our group identified and validated the association of a common germline SNP, rs28714259 (G/A), with risk of anthracyclineinduced HF through a GWAS in a large phase III adjuvant breast cancer trial with validation in two independent, phase III trials; findings also replicated by other investigators 22,23 . Here, using hiPSC-CM models with either intrinsic rs28714259 polymorphisms or with deletion of the rs28714259 locus, we provide evidence of rs28714259's functional impact on cardiomyocyte survival and contractility.…”

“…The variant, rs28714259 , was then validated in two independent phase III adjuvant breast cancer trials: E1199 and BEATRICE (OR = 1.9; p = 0.04, and OR = 4.2; p = 0.018, respectively). Recently, the association of rs287142559 with the risk of AIC was validated in an independent dataset (OR = 4.2; p = 0.006) by other investigators 23 . Herein, we explored the role of rs28714259 polymorphism in AIC utilizing a clinically relevant model of hiPSC-derived cardiomyocytes (hiPSC-CMs).…”

Pharmacogenetics of anticancer antibiotics

“…Ассоциация полиморфизма rs28714259 с АИК подтверждена другими исследованиями. В частности, в работе отечественных авторов было показано, что у женщин с раком молочной железы при носительстве аллеля А риск быстрого развития сердечнососудистой патологии увеличен в 4 раза (р=0,006), а у женщин с генотипом АА -увеличен в 22 раза (р=0,001) [36].…”