New genetic signatures associated with cancer cachexia as defined by low skeletal muscle index and weight loss

Abstract

BackgroundCachexia affects the majority with advanced cancer. Based on current demographic and clinical factors, it is not possible to predict who will develop cachexia or not. Such variation may, in part, be due to genotype. It has recently been proposed to extend the diagnostic criteria for cachexia to include a direct measure of low skeletal muscle index (LSMI) in addition to weight loss (WL). We aimed to explore our panel of candidate single nucleotide polymorphism (SNPs) for association with WL +/− computerized tomography‐defined LSMI. We also explored whether the transcription in muscle of identified genes was altered according to such cachexia phenotypeMethodsA retrospective cohort study design was used. Analysis explored associations of candidate SNPs with WL (n = 1276) and WL + LSMI (n = 943). Human muscle transcriptome (n = 134) was analysed using an Agilent platform.ResultsSingle nucleotide polymorphisms in the following genes showed association with WL alone: GCKR, LEPR, SELP, ACVR2B, TLR4, FOXO3, IGF1, CPN1, APOE, FOXO1, and GHRL. SNPs in LEPR, ACVR2B, TNF, and ACE were associated with concurrent WL + LSMI. There was concordance between muscle‐specific expression for ACVR2B, FOXO1 and 3, LEPR, GCKR, and TLR4 genes and LSMI and/or WL (P < 0.05).ConclusionsThe rs1799964 in the TNF gene and rs4291 in the ACE gene are new associations when the definition of cachexia is based on a combination of WL and LSMI. These findings focus attention on pro‐inflammatory cytokines and the renin–angiotensin system as biomarkers/mediators of muscle wasting in cachexia.

Relationship between TNF-α −1031T/C gene polymorphism, plasma level of TNF-α, and risk of cachexia in head and neck cancer patients

“…Recent large study performed by Johns et al examined over 100 SNPs within genes related to cancer cachexia, and these molecular alterations were associated with both weight loss and muscle wasting in about 1200 studied individuals. Basing on a study set, the new cachexia related SNPs were revealed, and among them the TNF-α −1031T/C (Johns et al 2017). The contribution of that SNP to the risk of cancer cachexia is still unknown; however, the results of the latest studies conducted in patients with various diseases demonstrated significant role of the discussed SNP in the mediation of systemic inflammatory response.…”

Contemporary publication patterns in the Journal of Cachexia, Sarcopenia and Muscle by type and sub‐speciality: facts and numbers

“…[57][58][59][60][61][62][63] As befits a series of fields that are relatively new and not the main speciality of many practitioners, there was a large number of informative review articles, 64-71 as well as the emergence of reports on patient groups, commentaries, and political campaigns. [57][58][59][60][61][62][63] As befits a series of fields that are relatively new and not the main speciality of many practitioners, there was a large number of informative review articles, 64-71 as well as the emergence of reports on patient groups, commentaries, and political campaigns.…”

“…We conducted an analysis of the types of publications in the respective medical sub-specialities that this major cachexia focussed journal, JCSM, has published in the last three calendar years and analysed trends within each sub-discipline. [57][58][59][60][61][62][63] As befits a series of fields that are relatively new and not the main speciality of many practitioners, there was a large number of informative review articles, 64-71 as well as the emergence of reports on patient groups, commentaries, and political campaigns. Furthermore, they are classified into the major medical sub-specialities (including ageing) or are considered multidisciplinary if applicable across a range of specialities.…”

Overcoming Resistance to Anabolic Selective Androgen Receptor Modulator (SARM) Therapy in Experimental Cancer Cachexia with Histone Deacetylase Inhibitor AR-42

“…Several of the genes shared across multiple over-represented pathways have been previously studied in models of muscle wasting and cachectic patients including FOS [50,60], FoxO1 [50,61,62], IL-6 receptor (IL6Ra) [63,64], MEF2C [65] and p21 (CDKN1A) [66,67]. Of note, both extensively characterized E3-ligases, MuRF-1 (TRIM63) and Atrogin-1 (Fbxo32), were among the 147 overlapping genes (Supplemental Table 1) though only MuRF-1 was part of an over-represented pathway ( Figure 5C).…”