Abstract
TP53 mutation patterns are associated with prognosis of various cancers. This study was designed to investigate the association between TP53 mutation patterns and recurrence patterns in upper urinary tract urothelial carcinoma (UTUC) patients. A total of 165 consecutive UTUC patients who underwent nephroureterectomies were enrolled for measuring mutation patterns of TP53 gene from exome 2 to 11. Bladder recurrence, contralateral UTUC recurrence, and metastases were compared among groups by using log-rank test and Cox proportional hazard model. Single base substitution as an A:T to T:A transversion was noted in 55 (33.3%) patients (AT group). Forty-two (25.5%) patients had TP53 mutations with only other than A:T to T:A transversion (NAT group), and 68 patients (41.2%) had wide-type TP53 (WT group). AT group was predominately female (64%, 52%, 29%, respectively), had a higher incidence of end-stage renal disease (24%, 14%, 10%, respectively), and had more high-grade tumors (82%, 74%, 62%, respectively) compared to NAT and WT groups. With adjustment of tumor grade/stages, bladder and contralateral UTUC recurrence-free survival duration was shortest in NAT (p < 0.001) and AT group (p < 0.001), respectively. NAT group had a shorter metastasis-free survival duration than the other two groups combined (p = 0.018). As a result, A:T to T:A transversion increased contralateral UTUC recurrence risk, but other mutations in TP53 raised the hazard of bladder recurrence and metastases. Therefore, TP53 mutation pattern may be a useful biomarker to predict recurrence patterns of UTUC patients.
Highlights
TP53 is the most frequent gene involved in human cancers and has been widely evaluated in urothelial carcinoma (UC)
This study was designed to investigate the association between TP53 mutation patterns and recurrence patterns in upper urinary tract urothelial carcinoma (UTUC) patients
By stratifying UTUC patients according to TP53 mutation patterns, we observed that patients with an A:T to T:A transversion in the TP53 gene had a higher risk of contralateral upper urinary tract recurrence, and those with non- A:T to T:A transversion mutations had more bladder tumor recurrences and metastases than the other two groups
Summary
TP53 is the most frequent gene involved in human cancers and has been widely evaluated in urothelial carcinoma (UC). Abnormal p53 protein translated by the mutant gene has a longer half-life than the wild-type protein, resulting in cellular accumulation of abnormal p53 [4]. Based on this characteristic, immunohistochemical (IHC) staining for p53 has been widely utilized as a surrogate marker for the mutant TP53 gene [5]. A metaanalysis reviewed 7 small UTUC series and concluded that p53 overexpression as determined by IHC staining could be a biomarker for predicting poor disease outcomes [6]. We have previously shown that AA-induced UTUC, defined by A:T to T:A transversion in tumors and aristolactamDNA adducts in the renal cortex, has characteristic outcomes, including likely contralateral upper urinary tract recurrence [8]. Together with the above evidence, TP53 mutation www.impactjournals.com/oncotarget pattern may be correlated with disease outcomes and recurrence patterns of UTUC
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