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Genetic Predisposing Variants Associated with Cancer Therapy-Induced Cardiomyopathy

37 Pages Posted: 26 Sep 2018

See all articles by Pablo Garcia-Pavia

Pablo Garcia-Pavia

Hospital Universitario Puerta de Hierro-Majadahonda, Department of Cardiology, Heart Failure and Inherited Cardiac Diseases Unit; CIBER in Cardiovascular Diseases (CIBERCV); Francisco de Vitoria University

Yuri Kim

Harvard University - Medical School

Alejandra Restrepo-Cordoba

Universidad Autónoma de Madrid - Hospital Universitario Puerta de Hierro-Majadahonda

Ida G. Lunde

Harvard University - Medical School

Hiroko Wakimoto

Harvard University - Medical School

Amanda M. Smith

University of Pennsylvania - Perelman School of Medicine

Christopher N. Toepfer

Harvard University - Medical School

Kelly Getz

Taipei Medical University

Joshua Gorham

Harvard University - Medical School

Parth Patel

Harvard University - Medical School

Kaoru Ito

Harvard University - Medical School

Jonathan A. Wilcox

Harvard University - Medical School

Zoltan Arany

University of Pennsylvania - Perelman School of Medicine

Jian Li

University of Pennsylvania - Perelman School of Medicine

Anjali Owens

University of Pennsylvania - Perelman School of Medicine

Risha Govind

Imperial College London - National Heart and Lung Institute

Beatriz Nuñez

Universidad Autónoma de Madrid - Hospital Universitario Puerta de Hierro-Majadahonda

Erica Mazaika

Imperial College London - National Heart and Lung Institute

Antoni Bayes-Genis

CIBER in Cardiovascular Diseases (CIBERCV)

Roddy Walsh

Imperial College London - National Heart and Lung Institute

Brian Finkelman

University of Pennsylvania - Perelman School of Medicine

Josep Lupon

CIBER in Cardiovascular Diseases (CIBERCV)

Nicky Whiffin

Imperial College London - National Heart and Lung Institute

Isabel Serrano

Hospital Universitario de Tarragona Joan XXIII

William Midwinter

Imperial College London - National Heart and Lung Institute

Alicja Wilk

Imperial College London - National Heart and Lung Institute

Alfredo Bardaji

Hospital Universitario de Tarragona Joan XXIII

Nathan Ingold

Government of the United Kingdom - National Health Service (NHS)

Upasana Tayal

Imperial College London - National Heart and Lung Institute

Domingo A. Pascual-Figal

CIBER in Cardiovascular Diseases (CIBERCV)

Mian Ahmad

Imperial College London - National Heart and Lung Institute

Jose Manuel Garcia-Pinilla

CIBER in Cardiovascular Diseases (CIBERCV)

Antonis Pantazis

Government of the United Kingdom - National Health Service (NHS)

Fernando Dominguez

Universidad Autónoma de Madrid - Hospital Universitario Puerta de Hierro-Majadahonda

John Baksi

Imperial College London - National Heart and Lung Institute

Declan O'Regan

Imperial College London

Sanjay Prasad

Imperial College London - National Heart and Lung Institute

Enrique Lara-Pezzi

CIBER in Cardiovascular Diseases (CIBERCV)

Mariano Provencio

Universidad Autónoma de Madrid - Hospital Universitario Puerta de Hierro-Majadahonda

Alex Lyon

Imperial College London - National Heart and Lung Institute

Luis Alonso-Pulpon

Universidad Autónoma de Madrid - Hospital Universitario Puerta de Hierro-Majadahonda

Stuart A. Cook

Imperial College London - National Heart and Lung Institute

Steven DePalma

Harvard University - Medical School

Paul Barton

Imperial College London - National Heart and Lung Institute

Richard Aplenc

University of Pennsylvania - Perelman School of Medicine

Jonathan G. Seidman

Harvard University - Medical School

Bonnie Ky

University of Pennsylvania - Perelman School of Medicine

James Ware

Imperial College London - National Heart and Lung Institute

Christine Seidman

Harvard University - Medical School

More...

Abstract

Background: Cancer therapy-induced cardiomyopathy (CCM) is associated with cumulative drug exposures and pre-existing cardiovascular disorders. These parameters incompletely account for substantial inter-individual susceptibility to CCM. We therefore hypothesised that rare variants in cardiomyopathy genes might contribute to CCM.

Methods:  Using a case-control study, we analysed 213 CCM patients from three cohorts: retrospectively recruited adults with diverse cancers (N=99), prospectively phenotyped breast cancer adults (N=73) and prospectively phenotyped children with acute myeloid leukemia (N=41). Control cohorts included 2053 cancer patients participating in The Cancer Genome Project (TCGA), 445 healthy volunteers, and the Genome Aggregation Database (gnomAD). We compared the frequency of rare variants in cardiomyopathy genes, including nine pre-specified genes between groups. Clinical characteristics and outcomes were assessed, stratified by genotypes. A prevalent CCM genotype was modeled in anthracycline-treated mice.

Findings: CCM was diagnosed 0.4-9 years after chemotherapy; 90% of patients received anthracyclines. 12.2% of CCM patients exhibited rare protein-altering variants among the nine prioritized genes versus 3.4% of healthy volunteers (p=5.16e-05). Titin-truncating variants (TTNtv) predominated, occurring in 7.5% CCM patients versus 1.1% TCGA participants (p=7.36e-08), 0.7% healthy volunteers (p=4.04e-06), and gnomAD population (p=6.09e-09). Adult CCM patients with TTNtv versus those without experienced more heart failure and atrial fibrillation (p=0.003). Consistent with human data, anthracycline-treated TTNtv mice and isolated TTNtv cardiomyocytes showed sustained contractile dysfunction unlike wildtype (p=0.0004 and p<0.002, respectively).

Interpretation: Rare variants in cardiomyopathy-associated genes, particularly TTNtv, increase the risk for CCM in children and adults, and adverse cardiac events in adults. Genotype improves identification of cancer patients at highest risk for CCM.

Funding Statement: Instituto de Salud Carlos III, John S LaDue Memorial Fellowship at Harvard Medical School, Wellcome Trust, UK Medical Research Council, NIHR Biomedical Research Unit, Foundation Leducq, British Heart Foundation, National Institutes of Health and the Howard Hughes Medical Institute.

Declaration of Interests: CES and JGS are founders and own shares in Myokardia Inc., a startup company that is developing therapeutics that target the sarcomere. Myokardia had no involvement in this study.

Ethics Approval Statement: Research protocols were reviewed and approved by institutional ethics board at each participating site [for Cohorts A,B, and C (human patients)]. Mice study: Protocols were reviewed and approved by the Institutional Animal Care and Use Committee at Harvard Medical School (Boston, MA).

Keywords: Chemotherapy-Induced Cardiomyopathy, Heart Failure, Genetics, Cancer

Suggested Citation

Garcia-Pavia, Pablo and Kim, Yuri and Restrepo-Cordoba, Alejandra and Lunde, Ida G. and Wakimoto, Hiroko and Smith, Amanda M. and Toepfer, Christopher N. and Getz, Kelly and Gorham, Joshua and Patel, Parth and Ito, Kaoru and Wilcox, Jonathan A. and Arany, Zoltan and Li, Jian and Owens, Anjali and Govind, Risha and Nuñez, Beatriz and Mazaika, Erica and Bayes-Genis, Antoni and Walsh, Roddy and Finkelman, Brian and Lupon, Josep and Whiffin, Nicky and Serrano, Isabel and Midwinter, William and Wilk, Alicja and Bardaji, Alfredo and Ingold, Nathan and Tayal, Upasana and Pascual-Figal, Domingo A. and Ahmad, Mian and Garcia-Pinilla, Jose Manuel and Pantazis, Antonis and Dominguez, Fernando and Baksi, John and O'Regan, Declan and Prasad, Sanjay and Lara-Pezzi, Enrique and Provencio, Mariano and Lyon, Alex and Alonso-Pulpon, Luis and Cook, Stuart A. and DePalma, Steven and Barton, Paul and Aplenc, Richard and Seidman, Jonathan G. and Ky, Bonnie and Ware, James and Seidman, Christine, Genetic Predisposing Variants Associated with Cancer Therapy-Induced Cardiomyopathy (August 28, 2018). Available at SSRN: https://ssrn.com/abstract=3244913

Pablo Garcia-Pavia (Contact Author)

Hospital Universitario Puerta de Hierro-Majadahonda, Department of Cardiology, Heart Failure and Inherited Cardiac Diseases Unit ( email )

Spain

CIBER in Cardiovascular Diseases (CIBERCV) ( email )

Spain

Francisco de Vitoria University ( email )

Spain

Yuri Kim

Harvard University - Medical School

25 Shattuck St
Boston, MA 02115
United States

Alejandra Restrepo-Cordoba

Universidad Autónoma de Madrid - Hospital Universitario Puerta de Hierro-Majadahonda

Calle Manuel de Falla, 1
Majadahonda, Madrid 28222
Spain

Ida G. Lunde

Harvard University - Medical School

25 Shattuck St
Boston, MA 02115
United States

Hiroko Wakimoto

Harvard University - Medical School

25 Shattuck St
Boston, MA 02115
United States

Amanda M. Smith

University of Pennsylvania - Perelman School of Medicine

423 Guardian Drive
Philadelphia, PA 19104
United States

Christopher N. Toepfer

Harvard University - Medical School

25 Shattuck St
Boston, MA 02115
United States

Kelly Getz

Taipei Medical University

250 Wu-Hsing Street
Taipei
Taiwan

Joshua Gorham

Harvard University - Medical School ( email )

25 Shattuck St
Boston, MA 02115
United States

Parth Patel

Harvard University - Medical School ( email )

25 Shattuck St
Boston, MA 02115
United States

Kaoru Ito

Harvard University - Medical School

25 Shattuck St
Boston, MA 02115
United States

Jonathan A. Wilcox

Harvard University - Medical School ( email )

25 Shattuck St
Boston, MA 02115
United States

Zoltan Arany

University of Pennsylvania - Perelman School of Medicine ( email )

423 Guardian Drive
Philadelphia, PA 19104
United States

Jian Li

University of Pennsylvania - Perelman School of Medicine ( email )

423 Guardian Drive
Philadelphia, PA 19104
United States

Anjali Owens

University of Pennsylvania - Perelman School of Medicine ( email )

423 Guardian Drive
Philadelphia, PA 19104
United States

Risha Govind

Imperial College London - National Heart and Lung Institute ( email )

Guy Scadding Building, Cale Street
London, SW3 6LY
United Kingdom

Beatriz Nuñez

Universidad Autónoma de Madrid - Hospital Universitario Puerta de Hierro-Majadahonda

Calle Manuel de Falla, 1
Majadahonda, Madrid 28222
Spain

Erica Mazaika

Imperial College London - National Heart and Lung Institute

Guy Scadding Building, Cale Street
London, SW3 6LY
United Kingdom

Antoni Bayes-Genis

CIBER in Cardiovascular Diseases (CIBERCV)

Spain

Roddy Walsh

Imperial College London - National Heart and Lung Institute ( email )

Guy Scadding Building, Cale Street
London, SW3 6LY
United Kingdom

Brian Finkelman

University of Pennsylvania - Perelman School of Medicine

423 Guardian Drive
Philadelphia, PA 19104
United States

Josep Lupon

CIBER in Cardiovascular Diseases (CIBERCV)

Spain

Nicky Whiffin

Imperial College London - National Heart and Lung Institute ( email )

Guy Scadding Building, Cale Street
London, SW3 6LY
United Kingdom

Isabel Serrano

Hospital Universitario de Tarragona Joan XXIII

Spain

William Midwinter

Imperial College London - National Heart and Lung Institute ( email )

Guy Scadding Building, Cale Street
London, SW3 6LY
United Kingdom

Alicja Wilk

Imperial College London - National Heart and Lung Institute ( email )

Guy Scadding Building, Cale Street
London, SW3 6LY
United Kingdom

Alfredo Bardaji

Hospital Universitario de Tarragona Joan XXIII

Spain

Nathan Ingold

Government of the United Kingdom - National Health Service (NHS)

London, SW1A 2NS
United Kingdom

Upasana Tayal

Imperial College London - National Heart and Lung Institute ( email )

Guy Scadding Building, Cale Street
London, SW3 6LY
United Kingdom

Domingo A. Pascual-Figal

CIBER in Cardiovascular Diseases (CIBERCV)

Spain

Mian Ahmad

Imperial College London - National Heart and Lung Institute ( email )

Guy Scadding Building, Cale Street
London, SW3 6LY
United Kingdom

Jose Manuel Garcia-Pinilla

CIBER in Cardiovascular Diseases (CIBERCV)

Spain

Antonis Pantazis

Government of the United Kingdom - National Health Service (NHS)

London, SW1A 2NS
United Kingdom

Fernando Dominguez

Universidad Autónoma de Madrid - Hospital Universitario Puerta de Hierro-Majadahonda

Calle Manuel de Falla, 1
Majadahonda, Madrid 28222
Spain

John Baksi

Imperial College London - National Heart and Lung Institute ( email )

Guy Scadding Building, Cale Street
London, SW3 6LY
United Kingdom

Declan O'Regan

Imperial College London ( email )

South Kensington Campus
Exhibition Road
London, Greater London SW7 2AZ
United Kingdom

Sanjay Prasad

Imperial College London - National Heart and Lung Institute ( email )

Guy Scadding Building, Cale Street
London, SW3 6LY
United Kingdom

Enrique Lara-Pezzi

CIBER in Cardiovascular Diseases (CIBERCV)

Spain

Mariano Provencio

Universidad Autónoma de Madrid - Hospital Universitario Puerta de Hierro-Majadahonda

Calle Manuel de Falla, 1
Majadahonda, Madrid 28222
Spain

Alex Lyon

Imperial College London - National Heart and Lung Institute ( email )

Guy Scadding Building, Cale Street
London, SW3 6LY
United Kingdom

Luis Alonso-Pulpon

Universidad Autónoma de Madrid - Hospital Universitario Puerta de Hierro-Majadahonda

Calle Manuel de Falla, 1
Majadahonda, Madrid 28222
Spain

Stuart A. Cook

Imperial College London - National Heart and Lung Institute ( email )

Guy Scadding Building, Cale Street
London, SW3 6LY
United Kingdom

Steven DePalma

Harvard University - Medical School ( email )

25 Shattuck St
Boston, MA 02115
United States

Paul Barton

Imperial College London - National Heart and Lung Institute ( email )

Guy Scadding Building, Cale Street
London, SW3 6LY
United Kingdom

Richard Aplenc

University of Pennsylvania - Perelman School of Medicine ( email )

423 Guardian Drive
Philadelphia, PA 19104
United States

Jonathan G. Seidman

Harvard University - Medical School ( email )

25 Shattuck St
Boston, MA 02115
United States

Bonnie Ky

University of Pennsylvania - Perelman School of Medicine ( email )

423 Guardian Drive
Philadelphia, PA 19104
United States

James Ware

Imperial College London - National Heart and Lung Institute ( email )

Guy Scadding Building, Cale Street
London, SW3 6LY
United Kingdom

Christine Seidman

Harvard University - Medical School ( email )

25 Shattuck St
Boston, MA 02115
United States

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