. 2019 Jul 2;140(1):31-41.

doi: 10.1161/CIRCULATIONAHA.118.037934. Epub 2019 Apr 16.

Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy

Pablo Garcia-Pavia^{1

2

3}, Yuri Kim^{4

5}, Maria Alejandra Restrepo-Cordoba^{1

2}, Ida G Lunde^{4

6}, Hiroko Wakimoto⁴, Amanda M Smith⁷, Christopher N Toepfer^{4

8}, Kelly Getz⁷, Joshua Gorham⁴, Parth Patel^{4

9}, Kaoru Ito⁴, Jonathan A Willcox⁴, Zoltan Arany⁷, Jian Li⁷, Anjali T Owens⁷, Risha Govind^{10

11}, Beatriz Nuñez¹², Erica Mazaika^{10

11}, Antoni Bayes-Genis^{2

13}, Roddy Walsh^{10

11}, Brian Finkelman⁷, Josep Lupon^{2

13}, Nicola Whiffin^{10

11

14}, Isabel Serrano¹⁵, William Midwinter^{10

11}, Alicja Wilk^{10

11}, Alfredo Bardaji¹⁵, Nathan Ingold^{10

11}, Rachel Buchan^{10

11}, Upasana Tayal^{10

11}, Domingo A Pascual-Figal^{2

16}, Antonio de Marvao^{10

11

14}, Mian Ahmad^{10

11}, Jose Manuel Garcia-Pinilla^{2

17}, Antonis Pantazis^{10

11}, Fernando Dominguez^{1

2}, A John Baksi^{10

11}, Declan P O'Regan¹⁴, Stuart D Rosen^{10

11}, Sanjay K Prasad^{10

11}, Enrique Lara-Pezzi^{2

10

18}, Mariano Provencio¹², Alexander R Lyon^{10

11}, Luis Alonso-Pulpon^{1

2}, Stuart A Cook^{10

14

19}, Steven R DePalma^{4

20}, Paul J R Barton^{10

11}, Richard Aplenc⁷, Jonathan G Seidman⁴, Bonnie Ky⁷, James S Ware^{10

11

14}, Christine E Seidman^{4

14

20

9}

Affiliations

¹ Hospital Universitario Puerta de Hierro, Madrid, Spain (P.G.-P., M.A.R.-C., F.D., L.A.-P.).
² Centro de Investigación Biomédica en Red Enfermedades in Cardiovascular Diseases (CIBERCV), Madrid, Spain (P.G.-P., M.A.R.-C., A.B.-G., J. Lupon, D.A.P.-F., J.M.G.-P., F.D., E.L.-P., L.A.-P.).
³ University Francisco de Vitoria, Pozuelo de Alarcón, Madrid, Spain (P.G.-P.).
⁴ Harvard Medical School, Boston, MA (Y.K., I.G.L., H.W., C.N.T., J.G., P.P., K.I., J.A.W., S.R.D., J.G.S., C.E.S.).
⁵ Massachusetts General Hospital, Boston (Y.K.).
⁶ Oslo University Hospital and University of Oslo, Norway (I.G.L.).
⁷ Perelman School of Medicine and University of Pennsylvania Health System, Philadelphia (A.M.S., K.G., Z.A., J. Li, A.T.O., B.F., R.A., B.K.).
⁸ University of Oxford (C.N.T.).
⁹ Brigham and Women's Hospital, Boston MA (P.P., C.E.S.).
¹⁰ National Heart & Lung Institute, Imperial College London, UK (R.G., E.M., R.W., N.W., W.M., A.W., N.I., R.B., U.T., A.d.M., M.A., A.P., A.J.B., S.D.R., S.K.P., E.L.-P., A.R.L., S.A.C., P.J.R.B., J.S.W.).
¹¹ Royal Brompton & Harefield NHS Foundation Trust, London, UK (R.G., E.M., R.W., N.W., W.M., A.W., N.I., R.B., U.T., A.d.M., M.A., A.P., A.J.B., S.D.R., S.K.P., A.R.L., P.J.R.B., J.S.W.).
¹² Hospital Universitario Puerta de Hierro, Universidad Autónoma de Madrid, Spain (B.N., M.P.).
¹³ Hospital Universitario Germans Trias i Pujol, Badalona, Spain (A.B.-G., J. Lupon).
¹⁴ MRC London Institute of Medical Sciences, Imperial College UK (N.W., D.P.O., S.A.C., J.S.W., C.E.S., A.d.M.).
¹⁵ Hospital Universitario de Tarragona Joan XXIII. IISPV, Rovira Virgili University, Spain (I.S., A.B.).
¹⁶ Hospital Universitario Virgen de la Arrixaca, University of Murcia. Spain (D.A.P.-F.).
¹⁷ Hospital Universitario Virgen de la Victoria, IBIMA, Malaga, Spain (J.M.G.-P.).
¹⁸ Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (E.L.-P.).
¹⁹ National Heart Centre Singapore and Duke-National University of Singapore (S.A.C.).
²⁰ Howard Hughes Medical Institute, Chevy Chase, MD (S.R.D., C.E.S.).

PMID: 30987448
PMCID: PMC6613726
DOI: 10.1161/CIRCULATIONAHA.118.037934

Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy

Pablo Garcia-Pavia et al. Circulation. 2019.

. 2019 Jul 2;140(1):31-41.

doi: 10.1161/CIRCULATIONAHA.118.037934. Epub 2019 Apr 16.

Authors

Affiliations

¹ Hospital Universitario Puerta de Hierro, Madrid, Spain (P.G.-P., M.A.R.-C., F.D., L.A.-P.).
² Centro de Investigación Biomédica en Red Enfermedades in Cardiovascular Diseases (CIBERCV), Madrid, Spain (P.G.-P., M.A.R.-C., A.B.-G., J. Lupon, D.A.P.-F., J.M.G.-P., F.D., E.L.-P., L.A.-P.).
³ University Francisco de Vitoria, Pozuelo de Alarcón, Madrid, Spain (P.G.-P.).
⁴ Harvard Medical School, Boston, MA (Y.K., I.G.L., H.W., C.N.T., J.G., P.P., K.I., J.A.W., S.R.D., J.G.S., C.E.S.).
⁵ Massachusetts General Hospital, Boston (Y.K.).
⁶ Oslo University Hospital and University of Oslo, Norway (I.G.L.).
⁷ Perelman School of Medicine and University of Pennsylvania Health System, Philadelphia (A.M.S., K.G., Z.A., J. Li, A.T.O., B.F., R.A., B.K.).
⁸ University of Oxford (C.N.T.).
⁹ Brigham and Women's Hospital, Boston MA (P.P., C.E.S.).
¹⁰ National Heart & Lung Institute, Imperial College London, UK (R.G., E.M., R.W., N.W., W.M., A.W., N.I., R.B., U.T., A.d.M., M.A., A.P., A.J.B., S.D.R., S.K.P., E.L.-P., A.R.L., S.A.C., P.J.R.B., J.S.W.).
¹¹ Royal Brompton & Harefield NHS Foundation Trust, London, UK (R.G., E.M., R.W., N.W., W.M., A.W., N.I., R.B., U.T., A.d.M., M.A., A.P., A.J.B., S.D.R., S.K.P., A.R.L., P.J.R.B., J.S.W.).
¹² Hospital Universitario Puerta de Hierro, Universidad Autónoma de Madrid, Spain (B.N., M.P.).
¹³ Hospital Universitario Germans Trias i Pujol, Badalona, Spain (A.B.-G., J. Lupon).
¹⁴ MRC London Institute of Medical Sciences, Imperial College UK (N.W., D.P.O., S.A.C., J.S.W., C.E.S., A.d.M.).
¹⁵ Hospital Universitario de Tarragona Joan XXIII. IISPV, Rovira Virgili University, Spain (I.S., A.B.).
¹⁶ Hospital Universitario Virgen de la Arrixaca, University of Murcia. Spain (D.A.P.-F.).
¹⁷ Hospital Universitario Virgen de la Victoria, IBIMA, Malaga, Spain (J.M.G.-P.).
¹⁸ Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (E.L.-P.).
¹⁹ National Heart Centre Singapore and Duke-National University of Singapore (S.A.C.).
²⁰ Howard Hughes Medical Institute, Chevy Chase, MD (S.R.D., C.E.S.).

PMID: 30987448
PMCID: PMC6613726
DOI: 10.1161/CIRCULATIONAHA.118.037934

Abstract

Background: Cancer therapy-induced cardiomyopathy (CCM) is associated with cumulative drug exposures and preexisting cardiovascular disorders. These parameters incompletely account for substantial interindividual susceptibility to CCM. We hypothesized that rare variants in cardiomyopathy genes contribute to CCM.

Methods: We studied 213 patients with CCM from 3 cohorts: retrospectively recruited adults with diverse cancers (n=99), prospectively phenotyped adults with breast cancer (n=73), and prospectively phenotyped children with acute myeloid leukemia (n=41). Cardiomyopathy genes, including 9 prespecified genes, were sequenced. The prevalence of rare variants was compared between CCM cohorts and The Cancer Genome Atlas participants (n=2053), healthy volunteers (n=445), and an ancestry-matched reference population. Clinical characteristics and outcomes were assessed and stratified by genotypes. A prevalent CCM genotype was modeled in anthracycline-treated mice.

Results: CCM was diagnosed 0.4 to 9 years after chemotherapy; 90% of these patients received anthracyclines. Adult patients with CCM had cardiovascular risk factors similar to the US population. Among 9 prioritized genes, patients with CCM had more rare protein-altering variants than comparative cohorts ( P≤1.98e-04). Titin-truncating variants (TTNtvs) predominated, occurring in 7.5% of patients with CCM versus 1.1% of The Cancer Genome Atlas participants ( P=7.36e-08), 0.7% of healthy volunteers ( P=3.42e-06), and 0.6% of the reference population ( P=5.87e-14). Adult patients who had CCM with TTNtvs experienced more heart failure and atrial fibrillation ( P=0.003) and impaired myocardial recovery ( P=0.03) than those without. Consistent with human data, anthracycline-treated TTNtv mice and isolated TTNtv cardiomyocytes showed sustained contractile dysfunction unlike wild-type ( P=0.0004 and P<0.002, respectively).

Conclusions: Unrecognized rare variants in cardiomyopathy-associated genes, particularly TTNtvs, increased the risk for CCM in children and adults, and adverse cardiac events in adults. Genotype, along with cumulative chemotherapy dosage and traditional cardiovascular risk factors, improves the identification of patients who have cancer at highest risk for CCM.

Clinical trial registration: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01173341; AAML1031; NCT01371981.

Keywords: cardiomyopathies; drug therapy; genetics; medical oncology; titin.

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Comment in

Genetics of cancer therapy-induced cardiomyopathy.
Huynh K. Huynh K. Nat Rev Cardiol. 2019 Jul;16(7):384-385. doi: 10.1038/s41569-019-0204-3. Nat Rev Cardiol. 2019. PMID: 31040400 No abstract available.

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Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy

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Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy

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