Relationship between TNF-α −1031T/C gene polymorphism, plasma level of TNF-α, and risk of cachexia in head and neck cancer patients

Abstract

BackgroundMalnutrition and cachexia are frequent among head and neck cancer (HNC) patients and these syndromes are associated with both poor quality of life and unfavorable disease prognosis. Unfortunately, there are still no established biomarkers that could predict the development of cachexia. Among potential molecular alterations related to cancer cachexia, there are single-nucleotide polymorphisms (SNPs) within genes encoding pro-inflammatory cytokines such as TNF-α.The aim of the studyTo investigate TNF-α −1031T/C SNP as a risk factor of cachexia in 62 HNC patients subjected to radiotherapy. DNA was isolated from whole blood samples and genotyping was conducted using real-time PCR method by means of TaqMan SNP Genotyping Assay. TNF-alpha Human ELISA Kit was used to determine TNF-α concentration in each extracted plasma sample. Moreover, the relationship between genotype variants of TNF-α and plasma level of TNF-α was examined. Detailed clinical–demographic and nutritional data were collected from each study participant.ResultsCC genotype carriers were at a significantly higher risk of being qualified as cachectic compared with other genotype carriers (p = 0.044; HR = 3.724). Subjects, who carried CC genotype had significantly lower body mass compared to patients with TT and CT genotype (p = 0.045). Moreover, CC individuals had the highest TNF-α plasma level (median 10.70 ± 0.72 pg/mL, p = 0.006) among the studied cases. We also noted, that CC genotype carriers had significantly higher risk of early death incidence compared to other genotype carriers [overall survival (OS): 28 vs 38 months (HR = 3.630, p = 0.013)].ConclusionDespite the differences between SGA and NRS scoring, the presence of CC genotype could be a useful objective marker allowing for the prediction of cachexia development in both parenterally nourished and non-parenterally nourished patients. Patients with CC genotype had also the highest risk of early death incidence; therefore, such individuals should be qualified for parenteral nutrition and supportive care at the time of diagnosis to improve further therapy outcomes. Moreover, this is the first study demonstrating the relationship between TNF-α −1031T/C polymorphism and plasma level of TNF-α. This is also the first paper investigating the role of TNF-α −1031T/C in cancer cachexia.

IL-6 mediated JAK/STAT3 signaling pathway in cancer patients with cachexia

“…As the molecular mechanisms underlying cachexia have not been fully elucidated yet, new molecular biomarkers of cancer cachexia are urgently explored. In the literature, single nucleotide polymorphism in different genes and cytokines, differentially expressed alternatively spliced genes (DASGs), some cytokine (IL-6, and TNF-α) serum levels and epigenetic mechanisms have been associated with cachexia in patients with gastric, head and neck, pancreatic and lung cancer (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Additionally, recent studies have indicated that high systemic IL-6 levels are linked to worse prognosis in different cancer patients (gastric, non-small lung, pancreas etc.)…”

MAPKAPK2 (MK2) inhibition mediates radiation-induced inflammatory cytokine production and tumor growth in head and neck squamous cell carcinoma

“…Downstream cytokines regulated by MK2 include IL-1, IL-6 and TNF-α and high levels of these cytokines have been linked with worse patient outcome [17,18]. High cytokine levels contribute significantly to cancer proliferation, treatment resistance and metastasis [19,21,44].…”

“…Neutrophilia and increased neutrophil-to-lymphocyte ratios (NLR) are markers of inflammation and are shown to be associated with decreased overall survival in HNSCC [14][15][16]. Furthermore, high expression of downstream inflammatory cytokines is associated with worse overall survival in HNSCC [17,18]. High serum IL-6 levels were associated with cancer recurrence and lower overall survival [17,19], and high plasma TNF-α levels were associated with high rates of cachexia and decreased survival in HNSCC patients [18].…”

“…Furthermore, high expression of downstream inflammatory cytokines is associated with worse overall survival in HNSCC [17,18]. High serum IL-6 levels were associated with cancer recurrence and lower overall survival [17,19], and high plasma TNF-α levels were associated with high rates of cachexia and decreased survival in HNSCC patients [18]. In oral squamous cell carcinoma, IL-1α enhanced cancer-associated fibroblast (CAF) proliferation in vitro, and tumor growth in vivo [20].…”

The Redox Balance: A Target for Interventions Against Muscle Wasting in Cancer Cachexia?

“…The other way round, there are studies showing that cachexia is associated with reduced expression of anti-inflammatory cytokines such as IL-10 (28). Finally, the association between cachexia and polymorphisms on genes coding for IL-8, IL-10, and TNFa has been reported in cancer patients (15,34,103).…”