Biological significance of TERT promoter mutation in papillary urothelial

neoplasm of low malignant potential

In human oncology, urothelial neoplasm is one of the neoplasms with well-established

pathogenetic models. At the genetic level, noninvasive papillary urothelial neoplasms

can be roughly divided into 2 groups: a genetically stable low-grade group and a

genetically unstable high-grade group. High-grade urothelial neoplasms are

characterized by TP53 mutations and exhibit aggressive biological behavior [2, 51–53].

By contrast, low-grade urothelial neoplasms are less likely to result in mortality.

According to the current WHO tumor classification, low-grade neoplasms include

totally benign urothelial papillomas (including exophytic papillomas and more common

inverted papillomas), PUNLMP, and low-grade NIPUC [2]. Although PUNLMP and

low-grade NIPUC are considered indolent tumors, they are not clinically insignificant

due to their frequent recurrence and the potential of progression to high-grade NIPUC

or invasive carcinoma. Between them, patients with low-grade NIPUC are more likely

to suffer from tumor recurrence than those with PUNLMP [3], and our results are

consistent with this general finding.

According to the current WHO criteria, classification of low-grade urothelial

genetic studies [2]. Some researchers have proposed the concept of “genetic grading”

for urothelial neoplasms [17, 54], but the complexity and cost of genetic studies may

hinder the feasibility of genetic grading in clinical practice. The results of our study

indicated that PUNLMP with wild-type TERT promoter had a lower recurrence rate. In

contrast, PUNLMP cases with TERT promoter mutations had significantly higher risks

of recurrence, which were similar to those in the low-grade NIPUC group. These results

suggest that PUNLMP cases can be stratified by TERT promoter mutation status for

prognostic purposes, and investigation of this mutation status may be of value for

clinical decision when treating patients with PUNLMP.

Compared with PUNLMP, our study did not show prognostic significance for

TERT promoter mutations in patients with low-grade NIPUC. Similarly, a study of

urothelial bladder cancers by Allory et al. found no association of the TERT promoter

mutation status with the clinical outcome [7]. Rachakonda et al. reported that TERT

promoter mutations are associated with poor survival and a higher recurrence rate in

bladder cancer patients without the common polymorphism rs2853669, which is located

in a preexisting Ets2 binding site in the TERT promoter. Such an association was not

found in patients with that polymorphism. The possible mechanism underlying the

association is that TERT promoter mutations affect the clinical outcome by creating de

novo Ets/TCF binding sites, and that common polymorphism may modify such effects

[55]. However, Rachakonda et al. did not include cases of PUNLMP, and further

investigation is necessary to explain the possible mechanisms of the effects of TERT

promoter mutations in PUNLMP.

Our results showed a high prevalence (76%) of HRAS mutation in inverted

papillomas. A previous study also showed HRAS mutations in 10 (91%) of 11 inverted

papillomas, and the authors postulated that isolated RAS mutations might induce cellular

senescence and result in a benign clinical course [22]. In our cohort, the three cases of

PUNLMP with HRAS mutations did not show coexistent TERT promoter or FGFR3

gene mutations. Two of them showed partially inverted growth patterns, and none of

these three tumors recurred after resection. Although these results were inconclusive due

to the limited case number, PUNLMPs with HRAS mutations might have similar

characteristics to the benign inverted papillomas. By contrast, two of the five low-grade

NIPUCs with mutated HRAS also showed TERT promoter mutation, and one additional

case had coexistent HRAS and FGFR3 mutations in our study. None of these tumors had

inverted growth in histology. The different biologic significance of HRAS mutations in

these low-grade urothelial neoplasms may worth further investigation.

Back to the issue of TERT promoter mutation, comparing our results with previous

results is potentially problematic. For survival analysis, many studies evaluating TERT

promoter mutations in bladder tumors have included cases with different grades or

stages [7, 8, 55]. In our study, the prognostic value of TERT promoter mutations fell to

an equivocal level if PUNLMP and low-grade NIPUC cases were mixed (p = .052).

Moreover, and probably more important, the actual cut-off points of histological

classification are subject to interobserver variation [56, 57]. In fact, all of the low-grade

NIPUC cases in our study were originally diagnosed as PUNLMP or even inverted

papilloma. Although our study found no TERT promoter mutation in any case of

inverted papilloma, Cheng et al. reported TERT promoter mutations in 15% (4/26) cases

of inverted papillomas [8]. Such discrepancy might result from the ethnic factor or other

causes; however, the potential interobserver variation may influence the accuracy of

metanalysis among these studies.

There are three potential limitations in our study. First, tumor progression was

uncommon in our study cohort and thereby limiting the analysis of PFS. Secondly, we

met technical problems about TERT promoter mutation analysis in three cases,

including one PUNLMP. This incident did not affect the statistical significance in our

study, but it might hamper the clinical application of TERT promoter mutation analysis.

Finally, to minimize the potential heterogeneity in our study cohort, we only selected

the primary (initial) specimen for each patient with tumor recurrence(s). The recurrent

tumors might exhibit different mutation patterns from their primary counterparts, but

investigations of such difference and possible clinical importance were beyond our

scope in this study.