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      Increased Cancer Prevalence in Peripartum Cardiomyopathy

      research-article
      Author(s): , MD a , ∗ , , MS a , ∗ , , PhD a , , MD b , , MD c , , PhD a , , MS a , , MD a , , MD a , , MD a , , MD, PhD d , , MD e , , MD a , , PhD a , ∗
      Publication date (Electronic):
      Journal: JACC: CardioOncology
      Publisher: Elsevier
      Keywords: cancer, cardiotoxicity, genetics, peripartum cardiomyopathy, whole-exome sequencing, ATM, ataxia telangiectasia mutated, BMBF, Bundesministerium für Bildung und Forschung, BRCA1, breast cancer 1, CPS, cancer predisposition syndrome, DCM, dilated cardiomyopathy, DDR, DNA damage response, DFG, Deutsche Forschungsgesellschaft, ERCC5, excision repair cross-complementing rodent repair deficiency, FANCA, Fanconi anemia, complementation group, FKRP, fukutin-related protein, HCM, hypertrophic cardiomyopathy, HTX, heart transplantation, LVAD, left ventricular assist device, LVEF, left ventricular ejection fraction, PPCM, peripartum cardiomyopathy, RECQL4, ATP-dependent DNA helicase Q4, RYR1, ryanodine receptor 1, SLX4, structure-specific endonuclease subunit SLX4, TXNRD2, thioredoxin reductase 2, VUS, variants of unknown significance

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          Abstract

          Objectives

          This study was designed to analyze the prevalence and potential genetic basis of cancer and heart failure in peripartum cardiomyopathy (PPCM).

          Background

          PPCM manifests as heart failure late in pregnancy or postpartum in women without previous heart disease.

          Methods

          Clinical history and cancer prevalence were evaluated in a cohort of 236 PPCM patients from Germany and Sweden. Exome sequencing assessed variants in 133 genes associated with cancer predisposition syndromes (CPS) and in 115 genes associated with dilated/hypertrophic cardiomyopathy (DCM/HCM) in 14 PPCM patients with a history of cancer, and in 6 PPCM patients without a history of cancer.

          Results

          The prevalence of cancer was 16-fold higher (8.9%, 21 of 236 patients) in PPCM patients compared to age-matched women (German cancer registry, Robert-Koch-Institute: 0.59%; p < 0.001). Cancer before PPCM occurred in 12 of 21 patients of whom 11 obtained cardiotoxic cancer therapies. Of those, 17% fully recovered cardiac function by 7 ± 2 months of follow-up compared to 55% of PPCM patients without cancer (p = 0.015). Cancer occurred after PPCM in 10 of 21 patients; 80% had left ventricular ejection fraction of ≥50% after cancer therapy. Whole-exome sequencing in 14 PPCM patients with cancer revealed that 43% (6 of 14 patients) carried likely pathogenic (Class IV) or pathogenic (Class V) gene variants associated with DCM/HCM in CPT2, DSP, MYH7, TTN, and/or with CPS in ATM, ERCC5, NBN, RECQL4, and SLX4. All CPS variants affected DNA damage response genes.

          Conclusions

          Cardiotoxic cancer therapy before PPCM is associated with delayed full recovery. The high cancer prevalence in PPCM is linked to likely pathogenic/pathogenic gene variants associated with DCM/HCM and/or CPS/DNA damage response–related cancer risk. This may warrant genetic testing and screening for heart failure in pregnant women with a cancer history and screening for cancer in PPCM patients.

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          Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

          Sue Richards, Nazneen Aziz, Sherri Bale … (2015)
          The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants. 1 In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next generation sequencing. By adopting and leveraging next generation sequencing, clinical laboratories are now performing an ever increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes and epigenetic assays for genetic disorders. By virtue of increased complexity, this paradigm shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context, the ACMG convened a workgroup in 2013 comprised of representatives from the ACMG, the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP) to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP and CAP stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories including genotyping, single genes, panels, exomes and genomes. This report recommends the use of specific standard terminology: ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’, and ‘benign’ to describe variants identified in Mendelian disorders. Moreover, this recommendation describes a process for classification of variants into these five categories based on criteria using typical types of variant evidence (e.g. population data, computational data, functional data, segregation data, etc.). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a CLIA-approved laboratory with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or equivalent.
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            Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration

            Helga Thorvaldsdóttir, James Robinson, Jill Mesirov (2012)
            Data visualization is an essential component of genomic data analysis. However, the size and diversity of the data sets produced by today’s sequencing and array-based profiling methods present major challenges to visualization tools. The Integrative Genomics Viewer (IGV) is a high-performance viewer that efficiently handles large heterogeneous data sets, while providing a smooth and intuitive user experience at all levels of genome resolution. A key characteristic of IGV is its focus on the integrative nature of genomic studies, with support for both array-based and next-generation sequencing data, and the integration of clinical and phenotypic data. Although IGV is often used to view genomic data from public sources, its primary emphasis is to support researchers who wish to visualize and explore their own data sets or those from colleagues. To that end, IGV supports flexible loading of local and remote data sets, and is optimized to provide high-performance data visualization and exploration on standard desktop systems. IGV is freely available for download from http://www.broadinstitute.org/igv, under a GNU LGPL open-source license.
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              Analysis of protein-coding genetic variation in 60,706 humans

              , Monkol Lek, Konrad J. Karczewski … (2016)
              Summary Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. We describe the aggregation and analysis of high-quality exome (protein-coding region) sequence data for 60,706 individuals of diverse ethnicities generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of truncating variants with 72% having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human “knockout” variants in protein-coding genes.
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                Author and article information

                Contributors
                Denise Hilfiker-Kleiner: @pfeffer_tj
                Journal
                Journal ID (nlm-ta): JACC CardioOncol
                Journal ID (iso-abbrev): JACC CardioOncol
                Title: JACC: CardioOncology
                Publisher: Elsevier
                ISSN (Electronic): 2666-0873
                Publication date PMC-release: 17 December 2019
                Publication date Collection: December 2019
                Publication date (Electronic): 17 December 2019
                Volume: 1
                Issue: 2
                Pages: 196-205
                Affiliations
                [a ]Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
                [b ]Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
                [c ]Department of Human Genetics, Hannover Medical School, Hannover, Germany
                [d ]Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
                [e ]Hatter Institute for Cardiovascular Research in Africa, University of Cape Town, Cape Town, South Africa
                Author notes
                [∗ ] Address for correspondence: Dr. Hilfiker-Kleiner, Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany. hilfiker.denise@ 123456mh-hannover.de @pfeffer_tj
                [∗]

                Drs. Pfeffer and Schlothauer contributed equally to this paper.

                Article
                Publisher Item ID: S2666-0873(19)30081-X
                DOI: 10.1016/j.jaccao.2019.09.008
                PMC ID: 8352111
                PubMed ID: 34396183
                SO-VID: 61cd901c-2b6d-4eae-8cf4-31433ccfd033
                Copyright © © 2019 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 14 June 2019
                Date revision received : 23 August 2019
                Date accepted : 9 September 2019
                Categories
                Subject: Original Research

                Keywords: cancer,cardiotoxicity,genetics,peripartum cardiomyopathy,whole-exome sequencing,atm, ataxia telangiectasia mutated,bmbf, bundesministerium für bildung und forschung,brca1, breast cancer 1,cps, cancer predisposition syndrome,dcm, dilated cardiomyopathy,ddr, dna damage response,dfg, deutsche forschungsgesellschaft,ercc5, excision repair cross-complementing rodent repair deficiency,fanca, fanconi anemia, complementation group,fkrp, fukutin-related protein,hcm, hypertrophic cardiomyopathy,htx, heart transplantation,lvad, left ventricular assist device,lvef, left ventricular ejection fraction,ppcm, peripartum cardiomyopathy,recql4, atp-dependent dna helicase q4,ryr1, ryanodine receptor 1,slx4, structure-specific endonuclease subunit slx4,txnrd2, thioredoxin reductase 2,vus, variants of unknown significance
                Data availability:
                Keywords: cancer, cardiotoxicity, genetics, peripartum cardiomyopathy, whole-exome sequencing, atm, ataxia telangiectasia mutated, bmbf, bundesministerium für bildung und forschung, brca1, breast cancer 1, cps, cancer predisposition syndrome, dcm, dilated cardiomyopathy, ddr, dna damage response, dfg, deutsche forschungsgesellschaft, ercc5, excision repair cross-complementing rodent repair deficiency, fanca, fanconi anemia, complementation group, fkrp, fukutin-related protein, hcm, hypertrophic cardiomyopathy, htx, heart transplantation, lvad, left ventricular assist device, lvef, left ventricular ejection fraction, ppcm, peripartum cardiomyopathy, recql4, atp-dependent dna helicase q4, ryr1, ryanodine receptor 1, slx4, structure-specific endonuclease subunit slx4, txnrd2, thioredoxin reductase 2, vus, variants of unknown significance

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