Genetic variants of the autophagy pathway as prognostic indicators for prostate cancer

Abstract

Autophagy is a complex process of autodigestion in conditions of cellular stress, and it might play an important role in the pathophysiology during carcinogenesis. We hypothesize that genetic variants of the autophagy pathway may influence clinical outcomes in prostate cancer patients. We genotyped 40 tagging single-nucleotide polymorphisms (SNPs) from 7 core autophagy pathway genes in 458 localized prostate cancer patients. Multivariate Cox regression was performed to evaluate the independent association of each SNP with disease progression. Positive findings were then replicated in an independent cohort of 504 advanced prostate cancer patients. After adjusting for known clinicopathologic factors, the association between ATG16L1 rs78835907 and recurrence in localized disease [hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.54–0.90, P = 0.006] was replicated in more advanced disease (HR 0.78, 95% CI 0.64–0.95, P = 0.014). Additional integrated in silico analysis suggests that rs78835907 tends to affect ATG16L1 expression, which in turn is correlated with tumor aggressiveness and patient prognosis. In conclusion, genetic variants of the autophagy pathway contribute to the variable outcomes in prostate cancer, and discovery of these novel biomarkers might help stratify patients according to their risk of disease progression.

Development of an autophagy-related gene expression signature for prognosis prediction in prostate cancer patients

“…Moreover, inhibition of RHEB can lead to the suppressed proliferation of prostate cancer cell lines [16]. Previous research analyzed the relationship between genetic variants of the autophagy pathway and clinical outcomes in 458 prostate cancer patients, which indicated that high expression of ATG16L1 was correlated with lower tumor aggressiveness and favorable prognosis [17]. Fu et al reported that high expression of FAM215A was associated with low tumor grades, early disease stages, and favorable overall survival in epithelial ovarian cancer [18].…”

The multifaceted role of autophagy in cancer and the microenvironment

“…For instance, during tumor development, the autophagic process appears to function as a tumor suppressor and limits tumorigenesis . In this respect, it is noteworthy that a single‐nucleotide polymorphism in the promoter region of the crucial autophagy‐related gene (ATG) ATG16L1, which putatively downregulates its expression level, associated with susceptibility to thyroid and colorectal cancer and has a significant negative impact on patient survival in local and advanced metastatic prostate cancer . Further, survival of patients with advanced lung adenocarcinoma upon epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment is significantly impacted by functional genetic polymorphisms in core autophagy genes, thus highlighting the potential clinical impact of autophagic signaling on cancer development and response to therapy …”

Association study of genetic variation in the autophagy lysosome pathway genes and risk of eight kinds of cancers

“…The autophagy lysosome pathway has been widely studied in human cancer and some genetic variants of autophagy lysosome genes were identified as associated with cancer risk or prognosis . However, no study has comprehensively and systematically evaluated the risk of germ‐line genetic variant of this pathway for cancer.…”

“…SNPs in certain autophagy lysosome pathway genes have been shown to be associated with the risk of breast cancer, colorectal cancer (CRC), thyroid carcinoma, gastric cancer (GC), melanoma . In addition, previous studies have also assessed associations between SNPs in the autophagy lysosome pathway and clinical outcome or other clinical characteristics of patients with cancer . However, the number of the included SNPs and the samples were relatively small in most of these studies.…”