C-Reactive Protein Levels and Vitamin D Receptor Polymorphisms as Markers in Predicting Cachectic Syndrome in Cancer Patients

Abstract

Background and Objective: In patients with advanced cancer, cachexia correlates with low performance status and poor quality of life. In addition, cachexia may be associated with reduced response to chemoradiotherapy and a poor prognosis in cancer patients. Nearly all forms of cachexia are closely associated with chronic inflammation and elevated levels of inflammatory and pro-inflammatory circulating factors, including C-reactive protein (CRP), which is considered a valid laboratory and clinical marker. Among the different pathways involved in the production of inflammatory cytokines and chemokines, the vitamin Dvitamin D receptor (VDR) axis plays a fundamental role.In this study, we explore the possible association between CRP and key factors pertaining to the vitamin D axis -in particular, VDR gene polymorphisms -in cancer patients with cachexia. Although certain tumor types are more commonly associated with cachexia, even within the same tumor type there are significant differences in the extent and duration of cachexia. Such variations may be due to polymorphisms of the VDR gene that could lead to cachexia-prone genotypes or to cachexia-resistant genotypes. Identification of such genotypes could be very helpful in the management of cancer patients. Methods: Forty-three cancer patients were recruited by the Nutritional Unit of the Prato Hospital. Data on age, gender, type of cancer, stage of cancer, and nutritional assessment, as well as transferrin, ferritin, albumin, and CRP levels, were collected. Genomic DNA was extracted from peripheral blood leukocytes and amplified by polymerase chain reaction. BsmI, ApaI, TaqI, and FokI polymorphisms of the VDR gene were investigated using the respective restriction enzymes. For the different VDR polymorphisms, the absence or presence of the restriction sites were designated with capital or small letters, respectively. For example, for the BsmI polymorphism, the presence of the undigested fragment identified the B allele, whereas the presence of the digested fragment identified the b allele. Results: Cancer patients with cachexia have higher CRP levels compared with non-cachectic cancer patients, independently from the genotype. In cachectic patients, the presence of specific VDR BsmI and TaqI alleles was associated with higher CRP levels. In particular, the VDR b and T alleles were more frequent in cachectic cancer patients with elevated CRP levels than in cachectic patients with normal CRP levels. Conclusion: From these results, we hypothesize that there is an association between BsmI and TaqI VDR gene polymorphisms and the cachectic syndrome. In particular, we propose that in cancer patients, the concomitance of b and T alleles with elevated CRP levels may represent an early clinical predictor for the development of a more aggressive form of cachexia.

Role of Angiotensin-Converting Enzyme and Vitamin D Receptor Gene Polymorphisms in Cancer Anorexia-Cachexia Syndrome

“…C1 patients had the highest systemic inflammation, lowest nutritional status and dramatically poorest prognosis (Table 2). As previously described by our research group (Punzi et al, 2012), CRP proved to be one of the most reliable and economic blood markers for CACS that a standard clinical laboratory can study (Mahmoud and Rivera, 2002). A standard nutritional status assessment usually includes the determination of albumin serum level, despite the open discussion regarding which albumin threshold should be chosen for the diagnosis of malnutrition.…”

“…We recently demonstrated that cancer patients with CACS have higher C-Reactive Protein (CRP) levels compared with non-cachectic cancer patients (Punzi et al, 2012), thus reinforcing the hypothesis that the chronic inflammatory state commonly observed in advanced cancers is linked to the aetiology of CACS (MacDonald, 2011). Aberrant immune system activity is a crucial aspect of the chronic systemic inflammation associated with CACS and it triggers a vicious cycle leading to further tumour growth and metastases.…”

“…DNA extraction and purification were performed by QIAamp ® DNA Blood Mini Kit (QIAGEN S.p.a., Italy). Purified DNA was then examined for FokI and BsmI VDR gene polymorphism and I/D ACE gene polymorphism after polymerase chain reaction amplification (SuperMini Cycler®, Mj Research, Inc., USA) using specific primers and the AccuPrime Supermix Kit (Invitrogen, Carlsbad, CA, USA) (Punzi et al, 2012).…”

“…On the contrary, to determine the allelic characteristic of the VDR gene, each amplified DNA fragment was treated with appropriate restriction enzymes (Punzi et al, 2012). The restriction products of FokI and BsmI were sorted as F and f and B and b respectively, where capital letters indicate an absence of restriction sites and lowercase letters indicate their presence.…”

Genetic basis of interindividual susceptibility to cancer cachexia: selection of potential candidate gene polymorphisms for association studies

“…To date most of the studies on identification of SNPs involved in cancer cachexia has led to the discovery of other SNPs involved in the innate immune system, mainly in the interleukin family of cytokines (Jatoi et al 2007(Jatoi et al , 2010Knoll et al 2008;Zhang et al 2008;Deans et al 2009;Bo et al 2010;Rausch et al 2010;Sun et al 2010a, b) (table 1). SNPs in other biological processes have also been studied for their association with cancer cachexia (Solheim 2011(Solheim , 2012Punzi et al 2012) (table 1). By altering the phenotype for a degree of skeletal muscle quantification, it may be possible to identify SNPs associated with muscle tissue biology.…”