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Genetic Factors Involved in Cardiomyopathies and in Cancer.

ABSTRACT: Cancer therapy-induced cardiomyopathy (CCM) manifests as left ventricular (LV) dysfunction and heart failure (HF). It is associated withparticular pharmacological agents and it is typically dose dependent, but significant individual variability has been observed. History of prior cardiac disease, abuse of toxics, cardiac overload conditions, age, and genetic predisposing factors modulate the degree of the cardiac reserve and the response to the injury. Genetic/familial cardiomyopathies (CMY) are increasingly recognized in general populations with an estimated prevalence of 1:250. Association between cardiac and oncologic diseases regarding genetics involves not only the toxicity process, but pathogenicity. Genetic variants in germinal cells that cause CMY (LMNA, RAS/MAPK) can increase susceptibility for certain types of cancer. The study of mutations found in cancer cells (somatic) has revealed the implication of genes commonly associated with the development of CMY. In particular, desmosomal mutations have been related to increased undifferentiation and invasiveness of cancer. In this article, the authors review the knowledge on the relevance of environmental and genetic background in CCM and give insights into the shared genetic role in the pathogenicity of the cancer process and development of CMY.

SUBMITTER: Sabater-Molina M

PROVIDER: S-EPMC7356401 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Genetic Factors Involved in Cardiomyopathies and in Cancer.

Sabater-Molina María M Navarro-Peñalver Marina M Muñoz-Esparza Carmen C Esteban-Gil Ángel Á Santos-Mateo Juan Jose JJ Gimeno Juan R JR

Journal of clinical medicine 20200602 6

Cancer therapy-induced cardiomyopathy (CCM) manifests as left ventricular (LV) dysfunction and heart failure (HF). It is associated withparticular pharmacological agents and it is typically dose dependent, but significant individual variability has been observed. History of prior cardiac disease, abuse of toxics, cardiac overload conditions, age, and genetic predisposing factors modulate the degree of the cardiac reserve and the response to the injury. Genetic/familial cardiomyopathies (CMY) are ...[more]

PMID: 32498335

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Project description:Familial hypertrophic cardiomyopathy (FHC) is associated with mild to severe cardiac problems and is the leading cause of sudden death in young people and athletes. Although the genetic basis for FHC is well-established, the molecular mechanisms that ultimately lead to cardiac dysfunction are not well understood. To obtain important insights into the molecular mechanism(s) involved in FHC, hearts from two FHC troponin T models (Ile79Asn [I79N] and Arg278Cys [R278C]) were investigated using label-free proteomics and metabolomics. Mutations in troponin T are the third most common cause of FHC, and the I79N mutation is associated with a high risk of sudden cardiac death. Most FHC-causing mutations, including I79N, increase the Ca(2+) sensitivity of the myofilament; however, the R278C mutation does not alter Ca(2+) sensitivity and is associated with a better prognosis than most FHC mutations. Out of more than 1200 identified proteins, 53 and 76 proteins were differentially expressed in I79N and R278C hearts, respectively, when compared with wild-type hearts. Interestingly, more than 400 proteins were differentially expressed when the I79N and R278C hearts were directly compared. The three major pathways affected in I79N hearts relative to R278C and wild-type hearts were the ubiquitin-proteasome system, antioxidant systems, and energy production pathways. Further investigation of the proteasome system using Western blotting and activity assays showed that proteasome dysfunction occurs in I79N hearts. Metabolomic results corroborate the proteomic data and suggest the glycolytic, citric acid, and electron transport chain pathways are important pathways that are altered in I79N hearts relative to R278C or wild-type hearts. Our findings suggest that impaired energy production and protein degradation dysfunction are important mechanisms in FHCs associated with poor prognosis and that cardiac hypertrophy is not likely needed for a switch from fatty acid to glucose metabolism.

Dataset Information

Genetic Factors Involved in Cardiomyopathies and in Cancer.

Publications

Genetic Factors Involved in Cardiomyopathies and in Cancer.

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