Changes in cytokines and related signaling pathways in cases with cancer and familial cancer susceptibility by clinical exome sequencing analysis

Cancer, which is characterized by uncontrolled cell growth and proliferation, is a complex and multistage genetic disease dependent on many etiological factors. Although the relationship between cancer and inflammation is complex, epidemiological studies show that inflammatory and infectious diseases are associated with cancer risk. The immune system is an important regulator in formation and spreading of cancer, as well as the body's defense against pathogens. The tumor microenvironment is critical in the interaction of the immune system and cancer cells. The dynamic interaction of cytokine and oxidant molecules, which are important modulators of the immune response in the tumor microenvironment, affects tumor prognosis by mediating the formation of chronic inflammation. Current studies investigating cancer immunogenetics accept these molecular changes in the tumor microenvironment as important biomarkers in the diagnosis and prognosis of cancer patients. Therefore, in this study, it was aimed to examine the gene variants involved in cytokine and related signaling pathways and to correlate the results with clinical findings in the patient group diagnosed with cancer and in patients who underwent clinical exome sequencing analysis for screening purposes due to familial cancer history. Descriptive tests were used in the statistical analysis of the data. In our study, the indications for clinical exome sequencing analysis were invasive ductal breast cancer (40%, n=12/30), familial cancer history positivity (26.7%, n=8/30), ovarian cancer (13.3%, n=4/30), endometrial cancer (3.3%, n=1/30), ovarian and endometrial cancer (3.3%, n=1/30), breast fibroblastic hyperplasia (3.3%, n=1/30), breast and stomach cancer (3.3%, n=1/30), stomach cancer (3.3%, n=1/30) and gastrointestinal stromal tumor (3.3%, n=1) respectively. According to clinical exome sequencing analysis, the rate of variant detection in cancer-related genes in the entire cohort was 83.3% (n=25/30), while the rate of variant detection in genes containing cytokine and related signaling pathways was 40% (n=12/30). According to the results of clinical exome sequencing analysis, in addition to genes with tumor suppressor and oncogenic functions in cell growth and proliferation and DNA repair, variation was also detected in genes involved in mitochondrial and lysosomal functions (ALK, ATM, BRCA2, CDKN2A, CHEK2, ERBB2, ERCC2, IGF2R, KIT, LZTR1, MET, MN1, MSH5, MUTYH, MYH1, NF1, NOTCH, NQO1, PARK2, PDGFRA, PMS1, POLE, PTCH1, RET, RUNX1, TP53, TSC1, TYR). The gene variants involved in cytokine and related signaling pathways accompanying these gene changes were also determined. These genes include CCR9, CXCR1, ILDR1, IL-2Rɣ, IL-6R, IL-7R, IL-10/10RB, IL-21R, IRAK3, IRAK4, SMAD3/6, STAT3, TGF-β1 and TLR2 whose effects have been shown in the literature on tumor microenvironment and immune response balance. In particular, gene polymorphisms in cytokines and associated signaling pathways accompanying tumor suppressor gene and oncogene changes involved in DNA repair were detected in 7 patients diagnosed with cancer. Cytokine gene variants accompanying tumor suppressor gene and oncogene variants support the link between immunoreactive tumor microenvironment and genomic instability. Despite the limited sample size of our study, our results show that clinical exome sequencing analysis is an important molecular genetic test in elucidating cancer immunogenetics and our data should be supported by functional studies.