Urinary diagnostic proteomic markers for dynapenia in cancer patients

Abstract

Abstract. Dynapenia is defined as the age-related loss of muscle strength, and plays a significant role in the loss of physical function and increased risk of disability among older individuals. The need for an early diagnosis supports the search for a biomarker that reflects muscle 'weakening'. This has previously proven difficult due to patient heterogeneity at presentation and lack of understanding of the underlying molecular mechanisms. The aim of the present study was to identify potential urinary biomarkers of dynapenia in patients undergoing potentially curative surgery for upper gastrointestinal cancer. Maximum isometric knee extensor strength (strain gauge) and maximum leg extensor power (Nottingham power rig) measurements were taken. Cut-off values for dynapenia were based on the Allied Dunbar national fitness survey. Values below the 5th percentile for the population matched for age and sex on the Allied Dunbar national fitness survey were used to stratify the cohort into dynapenic or normal. Urine samples taken at induction of anaesthesia were analysed by SELDI-TOF mass spectrometry using CM10 and IMAC30 chip-types to establish statistically significant m/z peak fingerprint patterns, followed by in-gel LC-MS/MS to identify molecular constituents. Statistical analysis of decision-tree calculations using Biomarker Pattern software resulted in models with sensitivities of 86 and 96%, specificities of 81 and 89%, and overall correctness of 84 and 93%, when applied to the entire cohort for power and strength measurement-based stratifications using the IMAC30 chip-type and the CM10 chip-type, respectively. The molecular identities of 10 peaks of interest were further investigated. After subtraction of potentially unrelated proteins, they were identified as fragments of Annexin A1, collagen α-1 (XV), perlecan and myotrophin. These results demonstrate that urinary screening can be used to define cancer-associated muscle weakness, and the identification of potential biomarkers could be invaluable in establishing a rapid test to measure and assess dynapenia in the clinical setting.

Presence of dynapenia and association with anthropometric variables in cancer patients

“…This study identified dynapenia in 23.4% of the evaluated patients, who were mostly malnourished and had gastrointestinal tract cancer. Similar studies carried out in both adults and the elderly showed that dynapenia was present in 24.4% [36] and 44.9% [37] of cancer patients, respectively, while yet another study reported that 30.9% of the elderly population under evaluation presented dynapenia [13].…”

Gene Ontology (GO)-Driven Inference of Candidate Proteomic Markers Associated with Muscle Atrophy Conditions

“…Another mass spectrometry-based technique employed to identify potential urinary biomarkers is surface-enhanced laser desorption/ionization; together with model building using decision tree analysis, Husi et al identified prospective biomarkers of myosteatosis [ 44 ] and dynapenia (the age-associated loss of muscle strength) [ 42 ] by comparing the expression profiles of potential biomarker peaks between groups, to establish a proteomic fingerprint pattern which, upon validation, can be used in clinical diagnostics. Such an approach not only allows stratification and pattern matching to search for specific cachexia-related biomarkers in the urine of cancer patients, but also identifies key protein fragments that may be related to the pathophysiology of muscle wasting in cancer.…”

“…Such an approach not only allows stratification and pattern matching to search for specific cachexia-related biomarkers in the urine of cancer patients, but also identifies key protein fragments that may be related to the pathophysiology of muscle wasting in cancer. For example, the downregulation of fragments of CTSC, agrin, ARSA and GFAP was observed in patients with upper gastrointestinal tract cancer and myosteatotic vs. non-myosteatotic [ 44 ], whilst downregulation of annexin A1 and COL15A1 chain was observed in patients with a mixture of cancers and with leg-power measurement-based dynapenia [ 42 ].…”

Longitudinal characterisation of cachexia in patients undergoing surgical resection for cancer

“…The ease and non-invasive nature by which urine can be obtained makes it an appealing source for potential biomarkers. Previous investigation has highlighted promising target markers in patients with gastrointestinal cancers [25,26] and even links to decreased muscle power in this population [27].…”