Dataset Information

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

ABSTRACT:

Background

Cachexia 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 phenotype METHODS: A 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.

Results

Single 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).

Conclusions

The 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.

SUBMITTER: Johns N

PROVIDER: S-EPMC5356227 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Johns Neil N Stretch Cynthia C Tan Benjamin H L BH Solheim Tora S TS Sørhaug Sveinung S Stephens Nathan A NA Gioulbasanis Ioannis I Skipworth Richard J E RJ Deans D A Christopher DA Vigano Antonio A Ross James A JA Bathe Oliver F OF Tremblay Michel L ML Kaasa Stein S Strasser Florian F Gagnon Bruno B Baracos Vickie E VE Damaraju Sambasivarao S Fearon Kenneth C H KC

Journal of cachexia, sarcopenia and muscle 20160805 1

<h4>Background</h4>Cachexia 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 associ ...[more]

PMID: 27897403

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Project description:BackgroundCabozantinib, a standard of care metastatic renal cell carcinoma (mRCC), may be associated with weight and muscle loss. These effects of new generation VEGFR tyrosine kinase inhibitor on muscle mass loss are poorly described.MethodsAll cabozantinib-treated mRCC patients from January 2014 to February 2019 in our institution were included. Clinical data including weight were collected during therapy. Computed tomography images were centrally reviewed for response assessment, and axial sections at the third lumbar vertebrae were used to measure the total muscle area. Toxicities and cabozantinib outcomes were evaluated. Co-primary endpoints included skeletal muscle loss and weight loss (WL), longitudinally evaluated during treatment. WL has been classified according to CTCAEv5.0: Grade 1 (loss of 5 to <10% of baseline body weight), Grade 2 (loss of 10% to <20% of baseline body weight), and Grades 3-4 (loss >20% of baseline body weight).ResultsPatients were mostly men (70.3%), median age was 59.2 (range: 22.0-78.0) years, and median baseline body mass index was 25.0 (range: 16.4-49.3) kg/cm2 . Prognosis according to International Metastatic RCC Database Consortium score was good, intermediate, and poor for 13 (13.0%), 63 (63.0%), and 24 (24.0%) patients, respectively. Out of a total of 120 patients, 101 patients with a median follow-up of 22.3 months (range: 4.5-62.2) were eligible for analysis; 85 experienced muscle loss and muscle loss >10% increased during cabozantinib exposition, especially after 6 months of treatment. At cabozantinib baseline, 71 patients (70.3%) had sarcopenia, and 16/30 (53.3%) non-sarcopenic patients developed sarcopenia during treatment. Baseline sarcopenia was associated with lower response rates (P = 0.031) and higher grades 3-4 toxicities (P = 0.001). Out of 92 patients included in the WL analysis, 44 (47.8%) and 12 (13.0%) experienced grades 2 and 3 WL, respectively.ConclusionsWe report a high incidence of grades 3-4 WL, fourth times higher than reported in prior pivotal trials, and half of the patients developed sarcopenia while on cabozantinib treatment. Weight and muscle mass loss with cabozantinib are underreported and may require further investigations and early management.

Dataset Information

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

Background

Results

Conclusions

Publications

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

Similar Datasets

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