Variants in autophagy-related genes and clinical characteristics in melanoma: a population-based study.

Kirsten A White ,Lynn From,Loraine D Marrett,Stefano Rosso,Marianne Berwick,Anne E Cust,Stephen B Gruber,Todd A Thompson,Terence Dwyer,Li Luo,Colin B Begg,Irene Orlow,Hoda Anton‐Culver,Nancy E Thomas,Chien‐An Andy Hu,Salina Torres,Klaus J Busam,Peter A Kanetsky,Richard P Gallagher,Lidia Sacchetto,Jenna Lilyquist

doi:10.1002/cam4.929

Abstract

Autophagy has been linked with melanoma risk and survival, but no polymorphisms in autophagy‐related (ATG) genes have been investigated in relation to melanoma progression. We examined five single‐nucleotide polymorphisms (SNPs) in three ATG genes (ATG5;ATG10; and ATG16L) with known or suspected impact on autophagic flux in an international population‐based case–control study of melanoma. DNA from 911 melanoma patients was genotyped. An association was identified between (GG) (rs2241880) and earlier stage at diagnosis (OR 0.47; 95% Confidence Intervals (CI) = 0.27–0.81, P = 0.02) and a decrease in Breslow thickness (P = 0.03). The ATG16L heterozygous genotype (AG) (rs2241880) was associated with younger age at diagnosis (P = 0.02). Two SNPs in ATG5 were found to be associated with increased stage (rs2245214 CG, OR 1.47; 95% CI = 1.11–1.94, P = 0.03; rs510432 CC, OR 1.84; 95% CI = 1.12–3.02, P = 0.05). Finally, we identified inverse associations between ATG5 (GG rs2245214) and melanomas on the scalp or neck (OR 0.20, 95% CI = 0.05–0.86, P = 0.03); ATG10 (CC) (rs1864182) and brisk tumor infiltrating lymphocytes (TILs) (OR 0.42; 95% CI = 0.21–0.88, P = 0.02), and ATG5 (CC) (rs510432) with nonbrisk TILs (OR 0.55; 95% CI = 0.34–0.87, P = 0.01). Our data suggest that ATG SNPs might be differentially associated with specific host and tumor characteristics including age at diagnosis, TILs, and stage. These associations may be critical to understanding the role of autophagy in cancer, and further investigation will help characterize the contribution of these variants to melanoma progression.

Highlights

Autophagy is one mechanism of tumorigenesis that is under intensive investigation
In separate analyses of each single-nucleotide polymorphisms (SNPs) with Breslow thickness, the ATG16L rs2241880 GG genotype was associated with a decrease in Breslow thickness (P = 0.02), earlier stage at diagnosis
Autophagy in cancer is context dependent, acting as both a tumor suppressor and tumor promotor depending on the stage of development of the tumor [31]

Summary

Introduction

Autophagy is one mechanism of tumorigenesis that is under intensive investigation. This catabolic process assists the removal of unnecessary or dysfunctional cellular components, including damaged proteins and organelles through lysosomal degradation [1]. Accumulating evidence indicates that autophagy is involved in cancer development and progression [3, 5], and the notion that melanomas are addicted to autophagy [5,6,7,8,9] has important implications for cancer development as well as management of treatment options for this difficult disease [10]. The American Cancer Society estimates that in 2016, 76,380 new melanomas will be diagnosed in the United States and 10,130 people will die from their disease [11]. The long-term prognosis for melanoma patients has not improved at the same rate as other cancers [12]

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