- Meta-analysis identified SNPs associated with adverse responses to anti-angiogenesis cancer drug bevacizumab
- SNPs were associated with increased risk of hypertension or proteinuria
- Genetic markers indicating risk of drug toxicity can guide treatment decisions and patient monitoring protocols
Researchers at The University of North Carolina at Chapel Hill (UNC) have discovered biomarkers that indicate individual patients’ propensities to serious drug side effects. Tumors induce angiogenesis as they grow and spread. Targeting the VEGF (vascular endothelial growth factor) signaling pathway with anti-angiogenesis drugs such as bevacizumab is an effective way to hinder metastasis. However, these drugs induce hypertension and/or kidney toxicity (proteinuria)—potentially life threatening conditions—in as many as 40% of patients, and physicians currently lack procedures for determining which patients will react adversely.
UNC researchers performed a genome-wide association study (GWAS) on data collected from 4 randomized clinical trials for breast, prostate, and pancreatic cancers, in which a total of 1039 patients were treated with bevacizumab. The GWAS meta-analysis identified single nucleotide polymorphism (SNP) gene variants that were associated with hypertension or proteinuria across the 4 studies. The group found that an AàG SNP in an intronic region of a gene highly expressed in the arteries and important for regulating vasoconstriction, KCNAB1, increases the risk of hypertension, and a CàA SNP between two genes expressed in kidney and endothelial cells, DNAH5 and TRIO, increases the risk of proteinuria. The hypertension results were replicated in yet another sample set of 582 patients. The group also found that the prevalence of hypertension, proteinuria, or both was higher in females than in males. Although the meta-analysis was performed on patients of genetically European ancestry, the global frequency of each SNP variant is known, as well as the frequencies across various ethnicities, so these findings could improve outcomes for patients of all ancestries. Additionally, these findings are expected to hold for other anti-angiogenesis cancer drugs that lead to hypertension and proteinuria. We are looking for partners to further develop and commercialize these findings into a clinical genetic test that guides physician decisions around cancer treatment plans or patient monitoring.
Name: Ruthie Arieti