The effect of the ATG16L1 Thr300Ala polymorphism on susceptibility and outcome of patients with epithelial cell-derived thyroid carcinoma

Huijbers, Angelique; Plantinga, Theo S.; Joosten, Leo A. B.; Aben, Katja K.H.; Guðmundsson, Jūlı́us; Heijer, Martin den; Kiemeney, Lambertus A.; Netea, Mihai G.; Hermus, A.R.M.M.; Netea‐Maier, Romana T.

doi:10.1530/erc-11-0302

Cited by 34 publications

(37 citation statements)

References 11 publications

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“…26 Similar important roles of ATGs have also been demonstrated in the development of other cancers. 27,28 Together, these findings indicate that autophagy plays an important role in carcinogenesis. To our knowledge, no study has focused on the association between polymorphisms in the ATG genes and the risk of BM in patients with NSCLC.…”

Section: Introductionmentioning

confidence: 79%

“…35 Similar to our findings, the presence of the ATG16L1 G allele has been associated with a protective effect against epithelial thyroid carcinoma. 28 In a recent study, ATG16L1 (T300A) was found to be associated with reduced metastasis in colorectal cancer patients. 36 Collectively, these observations indicate that our finding of an association between SNPs and BM in patients with NSCLC may be biologically plausible.…”

Section: Discussionmentioning

confidence: 96%

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The Thr300Ala variant of ATG16L1 is associated with decreased risk of brain metastasis in patients with non-small cell lung cancer

Xiao

Huang

et al. 2017

Autophagy

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Non-small cell lung cancer (NSCLC) often metastasizes to the brain, but identifying which patients will develop brain metastases (BM) is difficult. Macroautophagy/autophagy is critical for cancer initiation and progression. We hypothesized that genetic variants of autophagy-related genes may affect brain metastases (BM) in NSCLC patients. We genotyped 16 single nucleotide polymorphisms (SNPs) in 7 autophagy-related (ATG) genes (ATG3, ATG5, ATG7, ATG10, ATG12, ATG16L1, and MAP1LC3/LC3) by using DNA from blood samples of 323 NSCLC patients. Further, we evaluated the potential associations of these genes with subsequent BM development. Lung cancer cell lines stably transfected with ATG16L1: rs2241880 (T300A) were established. Mouse models of brain metastasis were developed using cells transfected with ATG16L1-300T or ATG16L1-300A. ATG10: rs10036653 and ATG16L1: rs2241880 were significantly associated with a decreased risk of BM (respective hazard ratios [HRs]D0.596, 95% confidence interval [CI] 0.398-0.894, P D 0.012; and HR D 0. 655, 95% CI 0.438-0.978, P D 0.039, respectively). ATG12: rs26532 was significantly associated with an increased risk of BM (HRD1.644, 95% CI 1.049-2.576, P D 0.030). Invasion and migration assays indicated that transfection with ATG16L1-300T (vs. 300A) stimulated the migration of A549 cells. An in vivo metastasis assay revealed that transfection with ATG16L1-300T (vs. 300A) significantly increased brain metastasis. Our results indicate that genetic variations in autophagy-related genes can predict BM and that genome analysis would facilitate stratification of patients for BM prevention trials.

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Section: Introductionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 96%

The Thr300Ala variant of ATG16L1 is associated with decreased risk of brain metastasis in patients with non-small cell lung cancer

Xiao

Huang

et al. 2017

Autophagy

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“…Indeed, it has been previously shown that the presence of inflammatory mediators in TC, including cytokines such as IL-1β and TNFα, negatively influence the expression of sodium iodine symporter, the major protein responsible for the uptake of radioactive iodide in thyroid cells which represents the main targeted therapy for patients with TC 19 . Also processes that limit inflammation such as autophagy are defective in TC 20,21 . In addition to TAMs, also the function of regulatory T cells has been shown to be dependent on glycolysis, as the induction of their suppressive function was tightly dependent on mTOR-induced glycolysis 22 .…”

Section: Discussionmentioning

confidence: 99%

Transcriptional and metabolic reprogramming induce an inflammatory phenotype in non-medullary thyroid carcinoma-induced macrophages

et al. 2016

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Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment in non-medullary thyroid cancer (TC), the most common endocrine malignancy. However, little is known regarding the regulation of their function in TC. Transcriptome analysis in a model of TC-induced macrophages identified increased inflammatory characteristics and rewiring of cell metabolism as key functional changes. This functional reprogramming was partly mediated by TC-derived lactate that induced upregulation of cytokine production through an AKT1/mTOR-dependent increase in aerobic glycolysis. This led to epigenetic modifications at the level of histone methylation, and subsequently long-term functional changes. Immunohistochemistry assessment validated the increase in glycolysis enzymes and lactate receptor in TAMs in tissue samples from patients with TC. In conclusion, Akt/mTOR-dependent glycolysis mediates TC-induced reprogramming of TAMs and inflammation, and this may represent a novel therapeutic target in TC.

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“…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 .…”

Section: Autophagymentioning

confidence: 99%

Pathological processes and therapeutic advances in radioiodide refractory thyroid cancer

Tesselaar¹,

Smit

Nagarajah³

et al. 2017

Journal of Molecular Endocrinology

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While in most patients with non-medullary thyroid cancer (TC), disease remission is achieved by thyroidectomy and ablation of tumor remnants by radioactive iodide (RAI), a substantial subgroup of patients with metastatic disease present tumor lesions that have acquired RAI resistance as a result of dedifferentiation. Although oncogenic mutations in BRAF, TERT promoter and TP53 are associated with an increased propensity for induction of dedifferentiation, the role of genetic and epigenetic aberrations and their effects on important intracellular signaling pathways is not yet fully elucidated. Also immune, metabolic, stemness and microRNA pathways have emerged as important determinants of TC dedifferentiation and RAI resistance. These signaling pathways have major clinical implications since their targeting could inhibit TC progression and could enable redifferentiation to restore RAI sensitivity. In this review, we discuss the current insights into the pathological processes conferring dedifferentiation and RAI resistance in TC and elaborate on novel advances in diagnostics and therapy to improve the clinical outcome of RAI-refractory TC patients.

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The effect of the ATG16L1 Thr300Ala polymorphism on susceptibility and outcome of patients with epithelial cell-derived thyroid carcinoma

Cited by 34 publications

References 11 publications

The Thr300Ala variant of ATG16L1 is associated with decreased risk of brain metastasis in patients with non-small cell lung cancer

The Thr300Ala variant of ATG16L1 is associated with decreased risk of brain metastasis in patients with non-small cell lung cancer

Transcriptional and metabolic reprogramming induce an inflammatory phenotype in non-medullary thyroid carcinoma-induced macrophages

Pathological processes and therapeutic advances in radioiodide refractory thyroid cancer

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