title: 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.
authors.affiliation: Department of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Johns
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Stretch
authors.affiliation: Department of Surgery, University Hospital Derby, Derby, UK.
authors.forename: Benjamin H L
authors.initials: BH
authors.lastname: Tan
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Tora S
authors.initials: TS
authors.lastname: Solheim
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Sveinung
authors.initials: S
authors.lastname: Sørhaug
authors.affiliation: Department of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Stephens
authors.affiliation: Department of Medical Oncology, University Hospital of Larissa, Larissa, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Gioulbasanis
authors.affiliation: Department of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Richard J E
authors.identifier: http://orcid.org/0000-0003-1349-9229
authors.initials: RJ
authors.lastname: Skipworth
authors.affiliation: Department of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: D A Christopher
authors.initials: DA
authors.lastname: Deans
authors.affiliation: University of McGill, Montreal, Canada.
authors.forename: Antonio
authors.initials: A
authors.lastname: Vigano
authors.affiliation: Department of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Ross
authors.affiliation: Department of Oncology, University of Calgary, Calgary, Alberta, Canada.|Department of Surgery, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Oliver F
authors.initials: OF
authors.lastname: Bathe
authors.affiliation: University of McGill, Montreal, Canada.
authors.forename: Michel L
authors.initials: ML
authors.lastname: Tremblay
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Stein
authors.initials: S
authors.lastname: Kaasa
authors.affiliation: Department of Family Medicine and Emergency Medicine, Laval University, Quebec, Canada.
authors.forename: Florian
authors.initials: F
authors.lastname: Strasser
authors.affiliation: Department of Internal Medicine, Cantonal Hospital, St. Gallen, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Gagnon
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Vickie E
authors.initials: VE
authors.lastname: Baracos
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Sambasivarao
authors.initials: S
authors.lastname: Damaraju
authors.affiliation: Department of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: Kenneth C H
authors.initials: KC
authors.lastname: Fearon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002100:Cachexia / Q000000981:diagnostic imaging / Q000209:etiology / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging / Q000378:metabolism; D009133:Muscular Atrophy / Q000000981:diagnostic imaging / Q000235:genetics*; D009369:Neoplasms / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D014057:Tomography, X-Ray Computed; D059467:Transcriptome; D055815:Young Adult
keywords: Cachexia; Cancer; Genetics; Polymorphisms