Abstract
Loss of the tumor suppressor gene AT-rich interactive domain-containing protein 1A (ARID1A) has been demonstrated in several cancers, but its prognostic role is unknown. We aimed to investigate the risk associated with loss of ARID1A (ARID1A-) for all-cause mortality, cancer-specific mortality and recurrence of disease in subjects with cancer. PubMed and SCOPUS search from database inception until 01/31/2015 without language restriction was conducted, contacting authors for unpublished data. Eligible were prospective studies reporting data on prognostic parameters in subjects with cancer, comparing participants with presence of ARID1A (ARID1A+) vs. ARID1A-, assessed either via immunohistochemistry (loss of expression) or with genetic testing (presence of mutation). Data were summarized using risk ratios (RR) for number of deaths/recurrences and hazard ratios (HR) for time-dependent risk related to ARID1A- adjusted for potential confounders. Of 136 hits, 25 studies with 5,651 participants (28 cohorts; ARID1A-: n = 1,701; ARID1A+: n = 3,950), with a mean follow-up period of 4.7 ± 1.8 years, were meta-analyzed. Compared to ARID1A+, ARID1A- significantly increased cancer-specific mortality (studies = 3; RR = 1.55, 95% confidence interval (CI) = 1.19-2.00, I(2) = 31%). Using HRs adjusted for potential confounders, ARID1A- was associated with a greater risk of cancer-specific mortality (studies = 2; HR = 2.55, 95%CI = 1.19-5.45, I(2) = 19%) and cancer recurrence (studies = 10; HR = 1.93, 95%CI = 1.22-3.05, I(2) = 76%). On the basis of these results, we have demonstrated that loss of ARID1A shortened time to cancer-specific mortality, and to recurrence of cancer when adjusting for potential confounders. For its role, this gene should be considered as an important potential target for personalized medicine in cancer treatment.
Highlights
Recent studies established that cancer development depends on both epigenetic and genomic alterations [1, 3]
Among the moderators considered for stratification, no significant moderators emerged explaining the absence of an association between ARID1A- and all-cause mortality, while loss of ARID1A was significantly associated with the number of recurrences of urological cancers (RR = 1.15, 95%confidence interval (CI): 1.07–1.23, p < 0.0001, I2 = 0%) and studies conducted in non-Asian countries (RR = 1.16, 95%CI: 1.04–1.28, p = 0.005) (Supplementary Table 5)
Funnel plots inspection indicated that publication bias was unlikely. This is the first meta-analysis investigating the relationship between loss of ARID1A and prognosis or outcome in patients with cancer
Summary
Recent studies established that cancer development depends on both epigenetic and genomic alterations [1, 3]. Genes involved in epigenetic mechanisms establishing chromatin structure are frequently mutated in various types of human cancers [4,5,6]. Chromatin structure is regulated by two general classes of complexes that cooperate dynamically: the first class covalently modifies histone tails and the second remodels nucleosomes in an ATP-dependent manner. SWI/SNF complexes remodel nucleosome structure and can mobilize nucleosomes both by sliding and by catalyzing the ejection and insertion of histone octamers, using the energy of ATP. These complexes have important roles in gene expression regulation, even during lineage specification, and in maintaining stem cell pluripotency
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