Role of Genetic Variants of Autophagy Genes in Susceptibility for Non-Medullary Thyroid Cancer and Patients Outcome

Abstract

Autophagy is a central process in regulation of cell survival, cell death and proliferation and plays an important role in carcinogenesis, including thyroid carcinoma. Genetic variation in autophagy components has been demonstrated to influence the capacity to execute autophagy and is associated with disease susceptibility, progression and outcome. In the present study, we assessed whether genetic variation in autophagy genes contributes to susceptibility to develop thyroid carcinoma, disease progression and/or patient outcome. The results indicate that patients carrying the ATG5 single nucleotide polymorphisms rs2245214 have a higher probability to develop thyroid carcinoma (OR 1.85 (95% CI 1.04–3.23), P = 0.042). In contrast, no significant differences could be observed for the other genetic variants studied in terms of thyroid carcinoma susceptibility. Furthermore, none of the selected genetic variants were associated with clinical parameters of disease progression and outcome. In conclusion, genetic variation in ATG5, a central player in the autophagy process, is found to be associated with increased susceptibility for thyroid carcinoma, indicating a role for autophagy in thyroid carcinogenesis.

Potentially Functional Variants of ATG16L2 Predict Radiation Pneumonitis and Outcomes in Patients with Non–Small Cell Lung Cancer after Definitive Radiotherapy

“…Potentially functional genetic variants of autophagy genes may alter the host autophagic capacity and thus influence efficiency of therapies. 28 Inspired by these findings, the present study was conducted to test the hypothesis that potentially functional genetic variants in ATG genes are prognostic and predictive for radiation-induced pneumonitis and clinical outcomes in NSCLC patients after definitive radiotherapy. In the present study, we evaluated the effects of nine functional variants in important ATG genes (e.g., ATGB2, ATG10, ATG12 , and ATG16L2) on clinical outcomes among 393 NSCLC patients in a North American population.…”

Autophagy and cancer

“…Similarly, a SNP in the ATG5 gene was associated with increased susceptibility to nonmedullary thyroid carcinoma (Plantinga et al, 2014). Loss of ATG5 expression was observed in gastric, colorectal, and hepatocellular carcinomas Cho et al, 2012).…”

“…Most of these studies are correlative; nevertheless, autophagy gene mRNA and/or protein expression changes and mutations were observed in different tumor series. (Iqbal et al, 2009;Kang et al, 2009;An et al, 2011;Plantinga et al, 2014;Rao et al, 2014;Rothe et al, 2014) BECN1 (Atg6) Reduced expression in breast cancers, nonsmall cell lung cancers, renal clear cell carcinomas, brain tumors, cervical squamous cell carcinomas, hepatocellular carcinomas, ovarian cancers, osteosarcomas, melanomas, and glioblastomas Mutations in ovarian cancers, human breast cancers, prostate cancers Reduced expression due to gene methylation in breast cancers Increased expression in CD34(+) chronic myeloid leukemia cells, colon cancers (stage IIIB), non-Hodgkin lymphomas, cholangiocarcinomas (Russell et al, 1990;Futreal et al, 1992;Cliby et al, 1993;Saito et al, 1993;Tangir et al, 1996;Aita et al, 1999;Liang et al, 1999;Qu et al, 2003;Wang et al, 2006;Lee et al, 2007;Miracco et al, 2007 ;Ding et al, 2008;Liu et al, 2008;Shen et al, 2008 ;Li et al, 2009;Zhang et al, 2009;Huang JJ et al, 2010;Huang X et al, 2010;Koukourakis et al, 2010;Lazova et al, 2010;Miracco et al, 2010;Nicotra et al, 2010;Dong et al, 2011;Liu et al, 2011;Sivridis et al, 2011;Jiang et al, 2012;Choi et al, 2013;Deng et al, 2013;Dong et al, 2013;Laddha et al...…”

Pathological processes and therapeutic advances in radioiodide refractory thyroid cancer

“…In TC specifically, autophagy has been shown to intertwine with oncogenic signaling and in vitro activation of autophagy is demonstrated to increase sensitivity of TC to treatment with chemotherapy, radiotherapy, TRAIL and mTOR kinase inhibitors (Lin et al 2010, Jin et al 2014, Morani et al 2014, Yi et al 2014, Plews et al 2015 and to promote resistance to BRAF inhibitors (Wang et al 2017). Furthermore, germline-genetic variants in autophagy genes, specifically ATG5 (rs2245214) and ATG16L1 p.Thr300Ala (rs2241880), known to functionally impair the autophagy machinery, are associated with genetic susceptibility to TC development and/or resistance to RAI treatment (Huijbers et al 2012, Plantinga et al 2014b. Accordingly, loss of autophagy activity was demonstrated to be associated with RAI resistance in TC patients .…”