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

Epithelial cell-derived thyroid carcinoma (TC) is the most common endocrine malignancy. Increasing evidence suggests that autophagy, a complex process of autodigestion in conditions of cellular stress, plays an important role in the pathophysiology of the TC malignant process. One of the main mammalian autophagy proteins is autophagy related 16-like 1 (ATG16L1), which is essential for autophagosome formation, induction of autophagy, and modulation of inflammation (Saitoh et al. 2008). Subsequently, defective autophagy in ATG16L1 knockout mice results in an increased production of the proinflammatory cytokine interleukin 1b (IL1b; Saitoh et al. 2008) that is also known to affect the growth and differentiation of different malignant cell types (Apte & Voronov 2002). Considering the potential role of both autophagy and IL1b in the pathology of TC, we hypothesized that genetic variation in ATG16L1 influences the susceptibility for and the outcome of TC. One single nucleotide polymorphism of the ATG16L1 gene (c.898AOG, Thr300Ala, rs2241880) has been shown to affect the autophagy process (Cooney et al. 2010) and also to modulate production of IL1b in human cells (Plantinga et al. 2011). We investigated whether this ATG16L1 polymorphism is associated with the susceptibility or clinical outcome of TC. One hundred and thirty nine patients (75% women, mean age 39G13 (S.D.) years) with histologically confirmed TC (papillary (70%), follicular TC (24%), or both (6%)), who visited the outpatient clinic at the Department of Endocrinology of our centre, were included. Primary treatment consisted of (near-) total thyroidectomy in all patients and modified radical neck dissections in patients with confirmed nodal metastases, followed by ablation with radioactive iodine (I, RAI) of residual thyroid tissue. Initial cure is