Abstract
The Spalt-Like Transcription Factor 4 (SALL4) oncogene plays a central function in embryo-fetal development and is absent in differentiated tissues. Evidence suggests that it can be reactivated in several cancers worsening the prognosis. We aimed at investigating the risk associated with SALL4 reactivation for all-cause mortality and recurrence in cancer using the current literature. A PubMed and SCOPUS search until 1st September 2016 was performed, focusing on perspective studies reporting prognostic parameters in cancer data. In addition, 17 datasets of different cancer types from The Cancer Genome Atlas were considered. A total of 9,947 participants across 40 cohorts, followed-up for about 5 years on average, were analyzed comparing patients showing SALL4 presence (SALL4+, n = 1,811) or absence (SALL4-, n = 8,136). All data were summarised using risk ratios (RRs) for the number of deaths/recurrences and hazard ratios (HRs) for the time-dependent risk related to SALL4+, adjusted for potential confounders. SALL4+ significantly increased overall mortality (RR = 1.34, 95% confidence intervals (CI)=1.21-1.48, p<0.0001, I2=66%; HR=1.4; 95%CI: 1.19-1.65; p<0.0001; I2=63%) and recurrence of disease (RR = 1.25, 95% CI = 1.1-1.42, p=0.0006, I2=62%); HR=1.52; 95% CI: 1.22-1.89, p=0.0002; I2=69%) compared to SALL4-. Moreover, SALL4 remained significantly associated with poor prognosis even using HRs adjusted for potential confounders (overall mortality: HR=1.4; 95%CI: 1.19-1.65; p<0.0001; I2=63%; recurrence of disease: HR=1.52; 95% CI: 1.22-1.89, p=0.0002; I2=69%). These results suggest that SALL4 expression increases both mortality and recurrence of cancer, confirming this gene as an important prognostic marker and a potential target for personalized medicine.
Highlights
The stem-like phenotype in cancer is the result of epigenetic and genetic alterations leading to the expression of genes involved in cell migration, invasion, angiogenesis, self-renewal, anti-apoptosis, and immuneescape, which are fundamental for the embryo-fetal development
Spalt-Like Transcription Factor 4 (SALL4) encodes for a zinc-finger transcription factor that plays an essential role during embryo-fetal development forming a regulatory network with other stemness-related genes, such as the Octamer-Binding Transcription Factor 4 (OCT-4), the Nanog Homeobox (NANOG), and the SexDetermining Region Y-Box 2 (SOX2), [1,2,3] and gradually disappears until it remains strongly silenced in fully differentiated tissues [4, 5]
The quality of the studies, assessed through NOS score [30], was generally good without any study with possible high risk of bias (Supplementary Table 1). Most of these 22 studies were carried out in Asia (n=18), three in USA, and one in Europe, mainly focusing on hepatocellular carcinoma (HCC) (n=11) and SALL4 was mainly assayed by IHC (n=18) rather than by molecular tests (n=6)
Summary
The stem-like phenotype in cancer is the result of epigenetic and genetic alterations leading to the expression of genes involved in cell migration, invasion, angiogenesis, self-renewal, anti-apoptosis, and immuneescape, which are fundamental for the embryo-fetal development. The expression of a stem-like phenotype seems to play a central role in defining the malignant potential of different cancers. The fetal oncogene Spalt-Like Transcription Factor 4 (SALL4) has recently emerged www.impactjournals.com/oncotarget as a potential prognostic marker in many tumors. SALL4 encodes for a zinc-finger transcription factor that plays an essential role during embryo-fetal development forming a regulatory network with other stemness-related genes, such as the Octamer-Binding Transcription Factor 4 (OCT-4), the Nanog Homeobox (NANOG), and the SexDetermining Region Y-Box 2 (SOX2), [1,2,3] and gradually disappears until it remains strongly silenced in fully differentiated tissues (except for the germline cells and the hematopoietic stem/progenitor cells) [4, 5]. We presented a systematic review and meta-analysis in order to investigate the prognostic role of SALL4 presence (SALL4+) in cancer patients by considering all-cause mortality and recurrence of cancer, evaluating whether SALL4+ can be associated with a poorer prognosis with respect to the absence of SALL4 (SALL4-)
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