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Title: Cancer cachexia : evaluation of body composition and identification of genetic markers
Author: Tan, Benjamin Hsiang-Loong
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2012
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Cachexia is characterised by a chronic wasting syndrome, involving loss of skeletal muscle tissue with or without adipose tissue, which is resistant to conventional nutritional support. The typical patient with advanced cachexia demonstrates loss of appetite, early satiety, severe weight loss, weakness, anaemia and fluid retention. Affected individuals are also likely to report/experience decreased quality of life, decreased levels of physical performance, increased levels of fatigue, increased risks of treatment failure (be it chemotherapy, radiotherapy or surgery), increased risks of treatment side effects, and an increased mortality rate. Cachexia is therefore an extremely important, yet often underappreciated, cause of cancer patient morbidity and mortality which requires urgent attention. However, due to the epidemic of obesity in Western Society, a substantial proportion of oncology patients at the start of palliative therapy now have a BMI in the overweight range and this can confound conventional measures used for risk stratification. Cachexia in its advanced phase (where patients may have lost 20-30% of their body weight) is easily identified. However, at this stage, the primary initiating events are frequently compounded by secondary factors (e.g. prolonged patient bed rest), and it is often impossible to attempt any realistic form of intervention, either practical or (given the patient's almost imminent demise) ethically advisable. Thus, any systematic approach to the treatment of cachexia requires early identification of patients at risk of cachexia and the institution of prophylactic measures to attenuate its progression. The main aims of this thesis are: 1) To assess if measures of body composition, specifically skeletal muscle, have any prognostic value, and to chart time course changes in regional body fat and lean tissue compartments using pancreatic cancer as a model for cancer cachexia. 2) To identify genetic variants that may be associated with susceptibility of developing cancer cachexia by means of a candidate gene association study. Using a novel method of assessing body composition using computed tomography (CT) scans, 56% of pancreatic patients (n = 111) were found to be sarcopenic at the time of diagnosis. A much greater rate of fat loss was observed as compared with muscle loss in the course of the cancer journey. The combination of sarcopenia and overweight/obesity was found to be a poor prognostic indicator (HR 2.07, 95%CI 1.23 - 3.50, p=0.006). Despite a substantial proportion of cancer patients at diagnosis now having a BMI in the overweight range, the previously noted tendency to muscle wasting continues with the majority of patients' sarcopenic at diagnosis. The combination of sarcopenia and overweight/obesity has been highlighted as a poor prognostic factor in cancer patients and should be considered in the stratification of cancer patients' entering clinical trials, systemic therapy or support care programs. The candidate gene association study was carried out based on data from two preliminary studies identifying genes involved in the pathogenesis of cancer cachexia. A systematic literature review identified 184 polymorphisms in 92 genes that have potential as susceptibility biomarkers for cancer cachexia. A gene expression array (Affymetrix) examining muscle of cachetic versus non-cachetic patients revealed an 83 gene signature correlating with weight loss. A total of 191 SNPs in 99 genes were selected for the candidate gene association analysis. The study was carried out in a cohort of 775 patients and significant results were validated in a separate cohort of 101 patients. 21 SNPs had significant associations with cachexia. However, only the C allele (minor allele frequency 10.7%) of the rs6136 (SELP) SNP was found to be associated with cachexia (weight loss >10%) both in the main study (OR 0.52, 95%C.I 0.29 - 0.93, p=0.026) and the validation study (OR 0.09, 95%C.I 0.01 - 0.98, p=0.035). Gene-group analysis was performed based on functional similarity according to gene ontology in the main study patients. Gene groups regulating appetite, glucocorticoid signalling, and mitogen activated protein kinases (MAPK) activity were associated with cachexia (weight loss >15% and CRP >10mg/l) (p=0.0008, p=0.018, and p=0.026 respectively). Patients who possess the C-allele of the P-selectin (SELP) rs6136 polymorphism appear to be at reduced risk of developing cancer cachexia. The rs6136 polymorphism may prove to be a useful susceptibility biomarker. Grouping of candidate genes according to gene ontology revealed three groupings that were associated with the development of cachexia. Genes regulating appetite, glucocorticoid signalling and MAPK activity appear to be important in the pathogenesis of cachexia and should be further investigated.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available