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J. Cardiovasc. Dev. Dis. 2017, 4(2), 6; doi:10.3390/jcdd4020006

Breast Cancer Clinical Trial of Chemotherapy and Trastuzumab: Potential Tool to Identify Cardiac Modifying Variants of Dilated Cardiomyopathy

1
Health Sciences Research, Mayo Clinic, Jacksonville, FL 32224, USA
2
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA
3
Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
4
Hematology/Oncology, Mayo Clinic, Jacksonville, FL 32224, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Andy Wessels
Received: 27 March 2017 / Revised: 26 April 2017 / Accepted: 3 May 2017 / Published: 4 May 2017
(This article belongs to the Special Issue Genetics and Treatment of Dilated Cardiomyopathy)
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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. View Full-Text
Keywords: dilated cardiomyopathy; modifying variants; GWAS; LVEF; OBSCN; breast cancer; trastuzumab; doxorubicin dilated cardiomyopathy; modifying variants; GWAS; LVEF; OBSCN; breast cancer; trastuzumab; doxorubicin
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Serie, D.J.; Crook, J.E.; Necela, B.M.; Axenfeld, B.C.; Dockter, T.J.; Colon-Otero, G.; Perez, E.A.; Thompson, E.A.; Norton, N. Breast Cancer Clinical Trial of Chemotherapy and Trastuzumab: Potential Tool to Identify Cardiac Modifying Variants of Dilated Cardiomyopathy. J. Cardiovasc. Dev. Dis. 2017, 4, 6.

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