Apoptosis Genes as a Key to Identification of Inverse Comorbidity of Huntington’s Disease and Cancer

Abstract

Cancer and neurodegenerative disorders present overwhelming challenges for healthcare worldwide. Epidemiological studies showed a decrease in cancer rates in patients with neurodegenerative disorders, including the Huntington disease (HD). Apoptosis is one of the most important processes for both cancer and neurodegeneration. We suggest that genes closely connected with apoptosis and associated with HD may affect carcinogenesis. We applied reconstruction and analysis of gene networks associated with HD and apoptosis and identified potentially important genes for inverse comorbidity of cancer and HD. The top 10 high-priority candidate genes included APOE, PSEN1, INS, IL6, SQSTM1, SP1, HTT, LEP, HSPA4, and BDNF. Functional analysis of these genes was carried out using gene ontology and KEGG pathways. By exploring genome-wide association study results, we identified genes associated with neurodegenerative and oncological disorders, as well as their endophenotypes and risk factors. We used publicly available datasets of HD and breast and prostate cancers to analyze the expression of the identified genes. Functional modules of these genes were characterized according to disease-specific tissues. This integrative approach revealed that these genes predominantly exert similar functions in different tissues. Apoptosis along with lipid metabolism dysregulation and cell homeostasis maintenance in the response to environmental stimulus and drugs are likely key processes in inverse comorbidity of cancer in patients with HD. Overall, the identified genes represent the promising targets for studying molecular relations of cancer and HD.

Upregulated Chaperone-Mediated Autophagy May Perform a Key Role in Reduced Cancer Incidence in Huntington’s Disease

“…This was followed up by Ehrnhoefer et al who suggested that upregulation of p53 found in mHTT containing neuronal and peripheral cells lowers the apoptotic threshold [ 40 ]. In a new publication, the authors analyzed gene networks associated with HD, apoptosis, and cancer and identified genes pointing on apoptosis along with lipid metabolism dysregulation and cell homeostasis as key processes [ 41 ]. In cell and mouse models Murmann et al investigated the effects of trinucleotide repeat (TNR) siRNA in cancer cell and found the siCAG repeat to be the most toxic suggesting that RNA interference could be involved in neurodegeneration as well as cancer suppression mechanisms [ 42 ].…”

Research advances in huntingtin-associated protein 1 and its application prospects in diseases

“…Cancer is rarely reported on the death certificates of individuals with HD (Sørensen et al, 1999;Bragina et al, 2023). In those with HD, the length of the mHtt repeat sequence is negatively correlated with cancer incidence (Murmann et al, 2018a,b).…”