Abstract
Doxorubicin and the ERBB2 targeted therapy, trastuzumab, are routinely used in the treatment of HER2+ breast cancer. In mouse models, doxorubicin is known to cause cardiomyopathy and conditional cardiac knock out of Erbb2 results in dilated cardiomyopathy and increased sensitivity to doxorubicin-induced cell death. In humans, these drugs also result in cardiac phenotypes, but severity and reversibility is highly variable. We examined the association of decline in left ventricular ejection fraction (LVEF) at 15,204 single nucleotide polymorphisms (SNPs) spanning 72 cardiomyopathy genes, in 800 breast cancer patients who received doxorubicin and trastuzumab. For 7033 common SNPs (minor allele frequency (MAF) > 0.01) we performed single marker linear regression. For all SNPs, we performed gene-based testing with SNP-set (Sequence) Kernel Association Tests: SKAT, SKAT-O and SKAT-common/rare under rare variant non-burden; rare variant optimized burden and non-burden tests; and a combination of rare and common variants respectively. Single marker analyses identified seven missense variants in OBSCN (p = 0.0045–0.0009, MAF = 0.18–0.50) and two in TTN (both p = 0.04, MAF = 0.22). Gene-based rare variant analyses, SKAT and SKAT-O, performed very similarly (ILK, TCAP, DSC2, VCL, FXN, DSP and KCNQ1, p = 0.042–0.006). Gene-based tests of rare/common variants were significant at the nominal 5% level for OBSCN as well as TCAP, DSC2, VCL, NEXN, KCNJ2 and DMD (p = 0.044–0.008). Our results suggest that rare and common variants in OBSCN, as well as in other genes, could have modifying effects in cardiomyopathy.
Highlights
Dilated cardiomyopathy (DCM) is the underlying cause of >50% of heart transplants
13/72 genes: VCL, DMD, OBSCN, RYR2, TPM1, KCNQ1, JAG1, SGCD, SCN5A, RBM20, SCN4B, TTN and CACNA1C showed at least one single nucleotide polymorphisms (SNPs) (MAF > 0.01) with evidence of association with chemotherapy- and trastuzumab-induced decline in left ventricular ejection fraction (LVEF), p < 0.05: (Table 2)
As an exploratory effort to identify putative modifying variants, we conducted a genetic association study of decline in LVEF following treatment with combination doxorubicin and trastuzumab in 800 patients from a breast cancer clinical trial across 72 genes that are causative of cardiomyopathies
Summary
The high morbidity and mortality associated with this disease underscore the need for a better understanding of the underlying molecular defects Efforts to identify these defects have made great progress and acknowledge the complexity of the genetic architecture of DCM. ~40% of individuals test positive at known DCM loci [2,3] and even within families who fulfil these criteria, age at onset, response to treatment and disease progression is variable [4]. Despite this fact, the search for the ‘missing’ genetic cause and definition of pathogenicity relies predominantly on a familial-based strategy and criteria, making it difficult to demonstrate pathogenicity in sporadic cases, even when all possible causes other than genetic, (coronary artery disease, chemotherapy-induced cardiotoxicity, valvular disease or repair) are ruled out
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