Genetic Polymorphisms of the Telomerase Reverse Transcriptase Gene in Relation to Prostate Tumorigenesis, Aggressiveness and Mortality: A Cross-Ancestry Analysis

Abstract

Background:
Telomerase reverse transcriptase (TERT) has been consistently associated with prostate cancer (PCa) risk. However, few studies have explored the association between TERT variants and PCa aggressiveness.

Methods:
Individual and genetic data were obtained from UK Biobank and a Chinese PCa cohort (Chinese Consortium for Prostate Cancer Genetics).

Results:
A total of 209,694 Europeans (14,550 PCa cases/195,144 controls) and 8873 Chinese (4438 cases/4435 controls) were involved. Nineteen susceptibility loci with five novel ones (rs144704378, rs35311994, rs34194491, rs144020096, and rs7710703) were detected in Europeans, whereas seven loci with two novel ones (rs7710703 and rs11291391) were discovered in the Chinese cohort. The index SNP for the two ancestries was rs2242652 (odds ratio [OR] = 1.16, 95% confidence interval [CI]:1.12-1.20, p = 4.12 × 10-16) and rs11291391 (OR = 1.73, 95%CI:1.34-2.25, p = 3.04 × 10-5), respectively. SNPs rs2736100 (OR = 1.49, 95%CI:1.31-1.71, p = 2.91 × 10-9) and rs2853677 (OR = 1.74, 95%CI:1.52-1.98, p = 3.52 × 10-16) were found significantly associated with aggressive PCa, while rs35812074 was marginally related to PCa death (hazard ratio [HR] = 1.61, 95%CI:1.04-2.49, p = 0.034). Gene-based analysis showed a significant association of TERT with PCa (European: p = 3.66 × 10-15, Chinese: p = 0.043) and PCa severity (p = 0.006) but not with PCa death (p = 0.171).

Conclusion:
TERT polymorphisms were associated with prostate tumorigenesis and severity, and the genetic architectures of PCa susceptibility loci were heterogeneous among distinct ancestries.

Full text

Citation: Zhan, Y.; Ruan, X.; Liu, J.;
Huang, D.; Huang, J.; Huang, J.;
Chun, T.T.S.; Ng, A.T.-L.; Wu, Y.; Wei,
G.; et al. Genetic Polymorphisms of
the Telomerase Reverse Transcriptase
Gene in Relation to Prostate
Tumorigenesis, Aggressiveness and
Mortality: A Cross-Ancestry
Analysis. Cancers 2023,15, 2650.
https://doi.org/10.3390/
cancers15092650
Academic Editor: Cagatay Günes
Received: 27 March 2023
Revised: 23 April 2023
Accepted: 3 May 2023
Published: 8 May 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
cancers
Article
Genetic Polymorphisms of the Telomerase Reverse
Transcriptase Gene in Relation to Prostate Tumorigenesis,
Aggressiveness and Mortality: A Cross-Ancestry Analysis
Yongle Zhan 1,† , Xiaohao Ruan 2,† , Jiacheng Liu 2, Da Huang 2, Jingyi Huang 2, Jinlun Huang 2,
Tsun Tsun Stacia Chun 1, Ada Tsui-Lin Ng 1,3, Yishuo Wu 4, Gonghong Wei 5, Haowen Jiang 4,*, Danfeng Xu 2
and Rong Na 1, *
1Division of Urology, Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong,
Hong Kong, China
2Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine,
Shanghai 200025, China
3Division of Urology, Department of Surgery, Queen Mary Hospital, Hong Kong, China
4Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China
5Fudan University Shanghai Cancer Center & MOE Key Laboratory of Metabolism and Molecular Medicine
and Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Shanghai
Medical College of Fudan University, Shanghai 200032, China
*Correspondence: yungna@hku.hk or narong.hs@gmail.com (R.N.); oncouro_jhw@126.com (H.J.);
Tel.: +852-22554853 (R.N.)
† These authors contributed equally to this work.
Simple Summary:
Mutation in telomerase reverse transcriptase (TERT) has been reportedly related
to risks of prostate cancer (PCa). However, prior genome-wide association studies (GWAS) were
limited to inconsistency, small-scale, one-outcome phenotype, or single ancestry. In this study, we
used two large-scale population datasets from European and Chinese ancestries to comprehensively
estimate the association of TERT loci polymorphisms with prostate tumorigenesis and severity.
Results of this study showed that (1) over half of the risk variants were located at the intron 2 region
in both populations; (2) seven novel loci situated at intron 2, intron 6, intron 9, and intron 12 were first
identified to be related to PCa risk; (3) SNPs rs2736100 and rs2853677 were significantly associated
with aggressive PCa, whereas rs35812074 was marginally related to PCa death; (4) most identified
loci were different between Europeans and Chinese. These findings support the evidence regarding
TERT polymorphisms in relation to PCa risk and prognosis, and indicate the heterogeneous genetic
architectures of PCa susceptibility loci among distinct ancestries.
Abstract:
Background: Telomerase reverse transcriptase (TERT) has been consistently associated with
prostate cancer (PCa) risk. However, few studies have explored the association between TERT vari-
ants and PCa aggressiveness. Methods: Individual and genetic data were obtained from UK Biobank
and a Chinese PCa cohort (Chinese Consortium for Prostate Cancer Genetics). Results: A total of
209,694 Europeans (14,550 PCa cases/195,144 controls) and 8873 Chinese (4438 cases/4435 controls)
were involved. Nineteen susceptibility loci with five novel ones (rs144704378, rs35311994, rs34194491,
rs144020096, and rs7710703) were detected in Europeans, whereas seven loci with two novel ones
(rs7710703 and rs11291391) were discovered in the Chinese cohort. The index SNP for the two ances-
tries was rs2242652 (odds ratio [OR] = 1.16, 95% confidence interval [CI]:1.12–1.20, p=
4.12 ×10−16
)
and rs11291391 (OR = 1.73, 95%CI:1.34–2.25, p= 3.04
×
10
−5
), respectively. SNPs rs2736100 (OR = 1.49,
95%CI:1.31–1.71, p= 2.91
×
10
−9
) and rs2853677 (OR = 1.74, 95%CI:1.52–1.98, p= 3.52
×
10
−16
) were
found significantly associated with aggressive PCa, while rs35812074 was marginally related to PCa
death (hazard ratio [HR] = 1.61, 95%CI:1.04–2.49, p= 0.034). Gene-based analysis showed a significant
association of TERT with PCa (European: p= 3.66
×
10
−15
, Chinese: p= 0.043) and PCa severity
(p= 0.006) but not with PCa death (p= 0.171). Conclusion: TERT polymorphisms were associated
with prostate tumorigenesis and severity, and the genetic architectures of PCa susceptibility loci were
heterogeneous among distinct ancestries.
Cancers 2023,15, 2650. https://doi.org/10.3390/cancers15092650 https://www.mdpi.com/journal/cancers

Cancers 2023,15, 2650 2 of 12
Keywords:
prostate cancer; aggressive prostate cancer; prostate cancer death; telomerase reverse
transcriptase; single nucleotide polymorphism; cross-ancestry; European; Chinese
1. Introduction
Prostate cancer (PCa) has become the second most common male cancer and the
fifth leading cause of male cancer death worldwide based on the estimated number from
GLOBOCAN 2020 [
1
]. The incidence and mortality of PCa have been increasing in past
decades. In the US, PCa incidence increases by 3% annually, with an estimated
288,300 new
cases and 34,700 deaths expected in 2023 [
2
]. In European countries, the estimated new
cases and deaths were 473,300 and 108,100, respectively, in 2020 [
3
]. In China, up to
125,646 new
cases and 56,239 deaths were reported in 2022 [
4
]. To date, only a few risk
factors for PCa have been established. Among them, genetic susceptibility is one of the
most critical risk factors.
Telomerase, a ribonucleoprotein complex to prevent telomere shortening, is essential
for maintaining chromosomal integrity and stability during cell division. Telomerase
reverse transcriptase (TERT), a key determinant of the enzymatic activity of telomerase, is
reportedly related to both aging and carcinogenesis [
5
]. Thus, mutations in the TERT regions
(5p15.33) in relation to tumorigenesis have long intrigued researchers. Prior genome-wide
association studies (GWAS) have found polymorphisms in TERT were associated with risks
of multiple cancers, such as breast, lung, glioma, bladder, testicular, pancreas, prostate, and
skin cancer [
6
,
7
]. In prostate cancer, single nucleotide polymorphisms (SNPs), including
rs4449583, rs10069690, rs13172201, and rs2736098, were identified to be associated with
disease risks in the European population [
7
], while rs2736100 and rs10069690 were found
to be associated in the Chinese population [
8
]. Results from previous studies were limited
to either inconsistency or their small scale. For the validation of PCa-related TERT SNPs in
multiple ancestries, only a cross-ancestry meta-analysis found that rs7726159 and rs2736098
were significantly associated with PCa risk in at least two ancestries [
7
]. Furthermore, there
is a research gap on the association of TERT variants with PCa severity and prognosis.
Given a paucity of investigation regarding the genetic architecture of susceptibility
loci of prostate tumorigenesis and prognosis across TERT regions in distinct ancestries, we,
therefore, utilize two large-scale population datasets from European and Chinese ancestries
to validate the association of TERT loci polymorphisms with PCa, PCa aggressiveness, and
PCa death, and to explore the genetic heterogeneity effect among distinct ethnic populations.
The primary objective of this study is to provide comparable and comprehensive evidence
on TERT genetic variations in prostate cancer risk in two different ethnic populations.
2. Materials and Methods
2.1. Study Population
The study population in this study comprised patients of European and Chinese
ancestries. Data from European participants were obtained from the UK Biobank (UKB), a
large-scale biomedical database containing a prospective cohort with a wealth of genetic
and phenotypic information. Around 0.5 million individuals between 40 and 69 years old
were recruited from 2006 to 2010 across the UK [
9
]. Participants with PCa were recorded
through the cancer registry, hospital electronic system and self-report. Data from Chinese
participants were obtained from the Chinese Consortium for Prostate Cancer Genetics
(ChinaPCa), an ongoing case-control study in which 5000 pathologically diagnosed PCa
patients were recruited from the local hospitals in the south-eastern region in mainland
China, whereas the 5000 cancer-free controls were recruited from the local community or
physical examination centers [
10
,
11
]. All participants were collected with informed consent,
and the study was approved by the regional ethics committee.

Cancers 2023,15, 2650 3 of 12
2.2. Outcome Phenotype Ascertainment
In UKB, participants were followed up for prostate cancer (C61) and PCa-specific death
using records linkage with the regional system of disease surveillance, chronic disease
management, and electronic health records (EHRs) based on diagnostic codes from the
International Classification of Diseases, 10th revision (ICD-10). Cancer survival time was
ascertained from the date of cancer diagnosis to the date of death, loss to follow-up, or
15 November 2022, whichever came first.
In ChinaPCa, malignant neoplasm of the prostate was ascertained by pathological
diagnosis from the local hospital. Aggressive PCa was defined as PCa with Gleason score
(GS)
≥
8 or prostate-specific antigen (PSA) value > 20 ng/mL according to the National
Comprehensive Cancer Network (NCCN) guideline.
2.3. SNPs Selection and Genotyping
To ensure the probable regulatory regions of the TERT were included, we extended
the upstream and downstream of the initial gene region to 100 kb. SNPs located at
chr5:1,150,000–1,400,000 were selected according to the HapMap database. Germline DNA
samples of the two datasets were extracted from blood samples via whole blood genomic
DNA extraction kit and were further genotyped by using the UK Biobank Axiom array
in the UKB dataset [
12
] and Illumina Human OmniExpress BeadChips in the ChinaPCa
dataset [10].
2.4. Phasing, Imputation and Quality Control
Pre-phasing and imputation in UKB genotyping data were performed via the SHAPEIT
and IMPUTE4 program using the Haplotype Reference Consortium and the merged
UK10K and 1000 Genome Phase III reference panels [
12
]. For ChinaPCa genotyping
data,
pre-phasing
analysis was conducted by Eagle v2.4, and imputation was performed
using the Michigan Imputation Server using the minimac4 imputation algorithm [
13
].
Although different imputation algorithms were used on two populations, the imputation
accuracy of these two algorithms was deemed highly consistent in accordance with previ-
ous
research [13]
. A posterior probability of >0.90 was applied to call genotypes during
the course of imputation. Poorly imputed SNPs were further excluded on the basis of
(a) genotype call rate less than 95%, (b) minor allele frequency (MAF) below 0.01, and
(c) p-value for the Hardy–Weinberg Equilibrium (HWE) test amid controls lower than
1.0 ×10−6.
2.5. Statistical Analysis
The association of each SNP with PCa and aggressive PCa was estimated by odds
ratio (OR), 95% CI, and corresponding p-value, using logistic regression analysis with
adjustment for age based on an additive model. The association of each SNP with PCa
death for the UKB sample was estimated by hazard ratio (HR), 95% confidence interval
(CI) and corresponding p-value, using Cox regression analysis with adjustment for age,
family history, and Charlson Comorbidity Index (CCI), based on an additive model. In
order to evaluate the combined effect of the significant SNPs on PCa risk, a polygenic
risk score (PRS) was additionally calculated by summing the number of each significant
risk allele carried (0, 1, or 2) for each individual, with every single variant weighted
by its effect size (log [OR] for binary traits). Gene-based analysis was performed based
on the remission and percentage improvement GWAS p-values using MAGMA v1.10
software [
14
]. The analysis was conducted according to genetic variants and linkage dis-
equilibrium (LD) in two ethnic reference data sets (1000 Genomes European panel and
1000 Genomes
East Asian panel), and then SNPs were assigned to genes using the MAGMA
NCBI37.3.gene.loc file with a 10-kb window. The
gene-based
association was estimated
using Z statistics and the corresponding p-value. Regional plots were generated from
LocusZoom (http://csg.sph.umich.edu/locuszoom/ (accessed on 20 March 2023)). LD
heatmap was created using LDBlockShow v1.39
software [15]
. All statistical analyses were

Cancers 2023,15, 2650 4 of 12
performed under PLINK v1.90 software. Two-tailed Bonferroni corrected
p< 7.35 ×10−4
(0.05/68) for UKB and p< 5.32
×
10
−4
(0.05/94) for ChinaPCa were considered statisti-
cally significant, while the p-value between Bonferroni correction and 0.05 was deemed
marginally significant on SNP association analysis. A two-tailed p< 0.05 was considered
significant in gene-based analysis.
3. Results
3.1. Participant Characteristics
A total of 209,694 Europeans (14,550 PCa cases/195,144 controls) and 8873 Chinese
(4438 cases/4435 controls) were involved in this study (Table 1). Briefly, PCa patients
were of older age and had a higher proportion of a positive PCa family history in both
populations. The median comorbidity index was higher in Europeans with PCa than in
controls (median CCI: 2.0 vs. 0.0, p< 0.001). In the Chinese population, PCa patients
had an elevated PSA value compared with their control counterparts (median PSA value:
21.8 vs. 9.8 ng/mL
,p< 0.001). 52.1% and 37.6% of the cancer patients had high levels of
PSA (>20 ng/mL) and GS (≥8), respectively.
Table 1. Characteristics of prostate cancer cases and controls in European and Chinese populations.
Cases Controls p-Value
European
N 14,550 195,144
Age, years (mean ±SD) 62.1 ±5.5 56.6 ±8.1 <0.001
Family history 12.4% 8.8% <0.001
CCI (median, IQR) 2.0 (0.0–3.0) 0.0 (0.0–1.0) <0.001
Chinese
N 4438 4435
Age, years
(mean ±SD) 70.3 ±8.0 64.5 ±9.1 <0.001
Family history 4.2% 3.0% 0.110
PSA value, ng/mL (median, IQR) 21.8 (11.0–71) 9.8 (6.6–14.6) <0.001
PSA category <0.001
<1 ng/mL 1.1% 1.6%
1–4 ng/mL 1.9% 5.4%
4–10 ng/mL 18.8% 46.6%
10–20 ng/mL 26.1% 33.6%
>20 ng/mL 52.1% 12.8%
Gleason score (median, IQR) 7.0 (7.0–8.0)
GS category
2–5 2.1%
6–7 60.3%
8–10 37.6%
SD, standard deviation; IQR, interquartile range; PSA, prostate-specific antigen; PCa, prostate cancer; GS,
Gleason score.
3.2. Associations between TERT SNPs and PCa Risk
Nineteen SNPs were identified to be significantly related to PCa risk in European
ancestry under an additive effect assumption (Table 2). These SNPs were located in three
regions (Figure 1A), spanning a 6.8-kb region from the promoter (rs2736109) to intron 2
(rs74682426), a 1.8-kb region from intron 2 (rs4449583) to intron 3 (rs7726159), and a 0.9-kb
region from intron 3 (rs4975538) to intron 4 (rs10054203) of the TERT. The index SNPs in
these regions were rs7712562 (OR = 1.16, 95%CI: 1.11–1.20, p= 1.17
×
10
−12
), rs7725218
(OR = 1.12, 95%CI: 1.09–1.15, p= 1.34
×
10
−14
), and rs2242652 (OR = 1.16, 95%CI: 1.12–1.20,
p= 4.12
×
10
−16
), respectively. Among these SNPs, five loci (rs144704378, rs35311994,
rs34194491, rs144020096, and rs7710703) were first discovered to be related to PCa risk in
European ancestry. The combined effect of all the marginal-to-significant SNPs showed a
two-fold higher risk of PCa among the European population (OR = 1.99, 95%CI: 1.77–2.25,
p< 0.001).

Cancers 2023,15, 2650 5 of 12
Table 2. Significant associations between TERT SNPs and prostate cancer in European ancestry.
SNP ID Position * Location Alleles #EAF OR (95% CI) p-Value
rs144704378 †1259489 Intron 12 T/C 0.049 1.14 (1.07–1.21) 1.60 ×10−5
rs35311994 †1260514 Intron 12 T/C 0.029 1.22 (1.14–1.32) 1.18 ×10−7
rs34194491 †1267213 Intron 9 C/T 0.025 1.22 (1.12–1.32) 2.50 ×10−6
rs144020096 †1278447 Intron 6 C/A 0.989 1.30 (1.12–1.50) 4.12 ×10−4
rs10069690 1279790 Intron 4 C/T 0.743 1.12 (1.09–1.16) 2.58 ×10−13
rs10054203 1279964 Intron 4 G/C 0.606 1.08 (1.05–1.11) 1.52 ×10−8
rs2242652 1280028 Intron 4 G/A 0.810 1.16 (1.12–1.20) 4.12 ×10−16
rs4975538 1280830 Intron 3 G/C 0.648 1.09 (1.06–1.12) 1.57 ×10−9
rs7726159 1282319 Intron 3 C/A 0.676 1.12 (1.09–1.15) 3.16 ×10−14
rs7725218 1282414 Intron 3 G/A 0.666 1.12 (1.09–1.15) 1.34 ×10−14
rs72709458 1283755 Intron 2 C/T 0.799 1.15 (1.11–1.19) 1.57 ×10−14
rs4449583 1284135 Intron 2 C/T 0.678 1.12 (1.09–1.15) 7.73 ×10−14
rs7705526 1285974 Intron 2 C/A 0.680 1.06 (1.03–1.09) 8.62 ×10−5
rs7710703 †1287505 Intron 2 C/T 0.874 1.10 (1.06–1.15) 4.30 ×10−6
rs74682426 1289975 Intron 2 C/A 0.867 1.15 (1.11–1.20) 1.04 ×10−11
rs2736098 1294086 Exon 2 T/C 0.280 1.10 (1.07–1.14) 2.60 ×10−11
rs2853669 1295349 Promoter G/A 0.314 1.09 (1.06–1.12) 7.41 ×10−10
rs7712562 1296072 Promoter G/A 0.862 1.16 (1.11–1.20) 1.17 ×10−12
rs2736109 1296759 Promoter T/C 0.407 1.06 (1.03–1.09) 2.52 ×10−5
* Locate in Chromosome 5;
#
Risk allele/Reference allele;
†
Novel susceptibility loci. SNP, single nucleotide
polymorphism; EAF, effect allele frequency; OR, odds ratio; CI, confidence interval.
In terms of Chinese ancestry, seven SNPs were found to be significantly associated
with PCa risk in the additive model (Table 3). These SNPs were situated in
two regions
(
Figure 1B
), spanning a 12.0-kb region from the promoter (rs7712562) to intron 2 (rs530443350)
and a 27.5-kb region from intron 2 (rs530443350) to intron 7 (rs2853687) of the TERT.
The index SNPs in these two regions were rs11291391 (OR = 1.73, 956% CI: 1.34–2.25,
p= 3.04 ×10−5
) and rs530443350 (OR = 3.08, 95%CI: 1.21–7.82, p= 0.018), respectively.
Among these SNPs, two loci (rs7710703 and rs11291391) were first detected to be associated
with PCa risk in Chinese ancestry. The combined effect of all the marginal-to-significant
SNPs showed a 16% higher risk of PCa among the Chinese population (OR = 1.16, 95%CI:
1.03–1.22, p< 0.001).
Three SNPs were identified to be associated with PCa risk in both ancestries, including
rs7712562 (OR = 1.16, 95% CI: 1.11–1.20, p= 1.17
×
10
−12
for Europeans; OR = 1.72, 95%
CI: 1.29–2.29, p= 2.15
×
10
−4
for Chinese), rs74682426 (OR = 1.15, 95% CI: 1.11–1.20,
p= 1.04 ×10−11
for Europeans; OR = 1.70, 95% CI: 1.27–2.27, p= 3.25
×
10
−4
for Chinese),
and rs7710703 (OR = 1.10, 95% CI: 1.06–1.15, p= 4.30
×
10
−6
for Europeans; OR = 1.72, 95%
CI: 1.28–2.31, p= 3.08
×
10
−4
for Chinese), among which, the first SNP was located in the
promoter region whereas the latter two were situated in intron 2 region (Figure 2).
3.3. Associations between TERT SNPs and Aggressive PCa Risk
Two TERT SNPs were found to be significantly associated with aggressive PCa
risk among PCa cases sample from Chinese ancestry (Figure 1C), including rs2736100
(OR: 1.49, 95%CI: 1.31–1.71, p= 2.91
×
10
−9
) and rs2853677 (OR: 1.74, 95%CI: 1.52–1.98,
p= 3.52 ×10−16
). These two SNPs were both located in intron 2 of TERT. The combined
effect of all the marginal-to-significant SNPs showed a 34% increased risk of aggressive
PCa among the Chinese population (OR = 1.34, 95%CI: 1.05–1.70, p= 0.017).

Cancers 2023,15, 2650 6 of 12
Cancers 2023, 14, x FOR PEER REVIEW 6 of 12
Figure 1. Prostate cancer-related SNPs in the TERT locus and their linkage disequilibrium status.
(A) Prostate cancer-related SNPs in European ancestry; (B) Prostate cancer-related SNPs in Chinese
ancestry; (C) Aggressive prostate cancer-related SNPs in Chinese ancestry; (D) Prostate cancer-spe-
cic death-related SNPs in European ancestry.
Figure 1.
Prostate cancer-related SNPs in the TERT locus and their linkage disequilibrium status.
(
A
) Prostate cancer-related SNPs in European ancestry; (
B
) Prostate cancer-related SNPs in Chinese
ancestry; (
C
) Aggressive prostate cancer-related SNPs in Chinese ancestry; (
D
) Prostate cancer-specific
death-related SNPs in European ancestry.

Cancers 2023,15, 2650 7 of 12
Table 3. Significant associations between TERT SNPs and prostate cancer in Chinese ancestry.
SNP ID Position * Location Alleles #EAF OR (95% CI) p-Value
rs2736100 1286516 Intron 2 A/C 0.540748 1.49 (1.31–1.71) †2.91 ×10−9
rs2853677 1287194 Intron 2 A/G 0.549014 1.74 (1.52–1.98) †3.52 ×10−16
rs7710703 ‡1287505 Intron 2 T/C 0.898 1.72 (1.28–2.31) 3.08 ×10−4
rs11291391 ‡1287612 Intron 2 CA/C 0.860 1.73 (1.34–2.25) 3.04 ×10−5
rs2853676 1288547 Intron 2 T/C 0.818 1.53 (1.22–1.92) 2.67 ×10−4
rs74682426 1289975 Intron 2 A/C 0.893 1.70 (1.27–2.27) 3.25 ×10−4
rs7712562 1296072 Promoter A/G 0.890 1.72 (1.29–2.29) 2.15 ×10−4
* Locate in Chromosome 5;
#
Risk allele/Reference allele;
†
Association with aggressive PCa;
‡
Novel susceptibility
loci. SNP, single nucleotide polymorphism; EAF, effect allele frequency; OR, odds ratio; CI, confidence interval.
Cancers 2023, 14, x FOR PEER REVIEW 7 of 12
In terms of Chinese ancestry, seven SNPs were found to be signicantly associated
with PCa risk in the additive model (Table 3). These SNPs were situated in two regions
(Figure 1B), spanning a 12.0-kb region from the promoter (rs7712562) to intron 2
(rs530443350) and a 27.5-kb region from intron 2 (rs530443350) to intron 7 (rs2853687) of
the TERT. The index SNPs in these two regions were rs11291391 (OR = 1.73, 956% CI: 1.34–
2.25, p = 3.04 × 10−5) and rs530443350 (OR = 3.08, 95%CI: 1.21–7.82, p = 0.018), respectively.
Among these SNPs, two loci (rs7710703 and rs11291391) were rst detected to be associ-
ated with PCa risk in Chinese ancestry. The combined eect of all the marginal-to-signif-
icant SNPs showed a 16% higher risk of PCa among the Chinese population (OR = 1.16,
95%CI: 1.03–1.22, p < 0.001).
Three SNPs were identied to be associated with PCa risk in both ancestries, includ-
ing rs7712562 (OR = 1.16, 95% CI: 1.11–1.20, p = 1.17 × 10−12 for Europeans; OR = 1.72, 95%
CI: 1.29–2.29, p = 2.15 × 10−4 for Chinese), rs74682426 (OR = 1.15, 95% CI: 1.11–1.20, p = 1.04
× 10−11 for Europeans; OR = 1.70, 95% CI: 1.27–2.27, p = 3.25 × 10−4 for Chinese), and
rs7710703 (OR = 1.10, 95% CI: 1.06–1.15, p = 4.30 × 10−6 for Europeans; OR = 1.72, 95% CI:
1.28–2.31, p = 3.08 × 10−4 for Chinese), among which, the rst SNP was located in the pro-
moter region whereas the laer two were situated in intron 2 region (Figure 2).
Table 3. Significant associations between TERT SNPs and prostate cancer in Chinese ancestry.
SNP ID
Position *
Location
Alleles #
EAF
OR (95% CI)
p-Value
rs2736100
1286516
Intron 2
A/C
0.540748
1.49 (1.31–1.71) †
2.91 × 10−9
rs2853677
1287194
Intron 2
A/G
0.549014
1.74 (1.52–1.98) †
3.52 × 10−16
rs7710703 ‡
1287505
Intron 2
T/C
0.898
1.72 (1.28–2.31)
3.08 × 10−4
rs11291391 ‡
1287612
Intron 2
CA/C
0.860
1.73 (1.34–2.25)
3.04 × 10−5
rs2853676
1288547
Intron 2
T/C
0.818
1.53 (1.22–1.92)
2.67 × 10−4
rs74682426
1289975
Intron 2
A/C
0.893
1.70 (1.27–2.27)
3.25 × 10−4
rs7712562
1296072
Promoter
A/G
0.890
1.72 (1.29–2.29)
2.15 × 10−4
* Locate in Chromosome 5; # Risk allele/Reference allele; † Association with aggressive PCa; ‡ Novel
susceptibility loci. SNP, single nucleotide polymorphism; EAF, eect allele frequency; OR,
odds ratio; CI, condence interval.
Figure 2. Common susceptibility loci of prostate cancer in European and Chinese ancestry (OR, odds
ratio; CI, condence interval).
Figure 2.
Common susceptibility loci of prostate cancer in European and Chinese ancestry (OR, odds
ratio; CI, confidence interval).
3.4. Associations between TERT SNPs and PCa Death
One SNP, rs35812074, was identified to be marginally related to PCa death among PCa
cases sample from European ancestry (Figure 1D). The risk allele (C) of rs35812074 was
associated with a 61% increased risk of PCa death (HR = 1.61, 95%CI: 1.04–2.49, p= 0.034)
with adjustment for age, family history and comorbidity index (Figure 3).
3.5. Gene-Based Analysis
Gene-based analysis using 56 SNPs from European ancestry and 79 SNPs from Chinese
ancestry showed that TERT was significantly associated with PCa among the two ancestries
(Z = 7.78, p= 3.66
×
10
−15
for European; Z = 1.72, p= 0.043 for Chinese). This gene was also
found to be related to aggressive PCa (Z = 2.54, p= 0.006). However, we did not observe a
gene-based association between TERT and PCa death (Z = 0.95, p= 0.171) (Table 4).

Cancers 2023,15, 2650 8 of 12
Cancers 2023, 14, x FOR PEER REVIEW 8 of 12
3.3. Associations between TERT SNPs and Aggressive PCa Risk
Two TERT SNPs were found to be signicantly associated with aggressive PCa risk
among PCa cases sample from Chinese ancestry (Figure 1C), including rs2736100 (OR:
1.49, 95%CI: 1.31–1.71, p = 2.91 × 10−9) and rs2853677 (OR: 1.74, 95%CI: 1.52–1.98, p = 3.52 ×
10−16). These two SNPs were both located in intron 2 of TERT. The combined eect of all
the marginal-to-signicant SNPs showed a 34% increased risk of aggressive PCa among
the Chinese population (OR = 1.34, 95%CI: 1.05–1.70, p = 0.017).
3.4. Associations between TERT SNPs and PCa Death
One SNP, rs35812074, was identied to be marginally related to PCa death among
PCa cases sample from European ancestry (Figure 1D). The risk allele (C) of rs35812074
was associated with a 61% increased risk of PCa death (HR = 1.61, 95%CI: 1.04–2.49, p =
0.034) with adjustment for age, family history and comorbidity index (Figure 3).
Figure 3. Prostate cancer survival curve of rs35812074 polymorphism. (The survival curve suggested
a negative correlation between the C allele of rs35812074 and the survival rate. HR, hazard ratio; CI,
condence interval).
3.5. Gene-Based Analysis
Gene-based analysis using 56 SNPs from European ancestry and 79 SNPs from Chi-
nese ancestry showed that TERT was signicantly associated with PCa among the two
ancestries (Z = 7.78, p = 3.66 × 10−15 for European; Z = 1.72, p = 0.043 for Chinese). This gene
was also found to be related to aggressive PCa (Z = 2.54, p = 0.006). However, we did not
observe a gene-based association between TERT and PCa death (Z = 0.95, p = 0.171) (Table
4).
Figure 3.
Prostate cancer survival curve of rs35812074 polymorphism. (The survival curve suggested
a negative correlation between the C allele of rs35812074 and the survival rate. HR, hazard ratio; CI,
confidence interval).
Table 4.
Gene-based association between TERT and prostate cancer in European and
Chinese ancestries.
Gene Chr Start Stop nSNPs Z stat p-Value
European ancestry
PCa TERT 5
1253282 1295178
56 7.78 3.66 ×10−15
PCa mortality TERT 5
1253282 1295178
55 0.95 0.171
Chinese ancestry
PCa TERT 5
1253282 1295178
79 1.72 0.043
Aggressive PCa TERT 5
1253282 1295178
54 2.54 0.006
Chr, chromosome; nSNPs, number of single nucleotide polymorphisms included in gene region; PCa, prostate
cancer; TERT, Telomerase reverse transcriptase.
4. Discussion
The present study including two ethnic population datasets shows that polymor-
phisms in TERT are associated with prostate tumorigenesis, aggressiveness, and PCa death.
This study is the first to comprehensively illustrate the genetic architectures of PCa suscep-
tibility loci across the TERT region among distinct ancestries. Specifically, we found that
(1) over half of the variants significantly associated with PCa risk or aggressiveness were
located at the intron 2 region in both populations; (2) seven novel loci situated at intron 2,
intron 6, intron 9 and intron 12 were first identified to be related to PCa risk; (3) rs35812074
located in intron 9 was observed marginally associated with PCa death.
TERT, located at 5p15.33 with 16 exons and 15 introns, has been reported to harbor
several susceptibility loci that could influence prostate carcinogenesis. A fine-mapping
study using 22,301 PCa cases and 22,320 controls identified multiple risk loci, including
rs2853669, rs2853676, rs7725218, and rs2242652, which were situated at the promoter,
intron 2, intron 3, and intron 4 regions, respectively [
16
]. Another recent fine-mapping
study using European ancestry population additionally found that rs2853677, rs11414507,

Cancers 2023,15, 2650 9 of 12
rs7705526, and rs35334674 at the intron 2 region, rs10069690 at intron 4 region, as well
as rs35033501 at exon 16 region were significant SNPs related to PCa risk [
17
]. Several
susceptibility loci, such as rs7712562 at the promoter region and rs7726159 at the intron
3 region, were identified by some case-control studies [18,19]. In this study, we confirmed
the aforementioned SNPs to be associated with PCa.
To the best of our knowledge, the present study was the first to comprehensively
evaluate the effect of polymorphisms across the TERT on PCa severity and PCa-specific
death. SNP rs2736100, located in intron 2, was found to be associated with significant
PCa aggressiveness in our study, consistent with the finding from a prior case-case study
involving 1210 Chinese PCa patients [
8
]. SNP rs10069690, another susceptibility locus
discovered by that study, however, was not confirmed in our study. In terms of prostate
cancer-specific death, we first found a potential susceptibility locus (rs35812074) (p= 0.034).
This SNP was reported to be associated with lung cancer by a recent GAWS [
20
]. However,
the finding of rs35812074 in relation to PCa death in our study should be treated with
caution because the risk allele of rs35812074 was detected as the major allele, and the minor
allele frequency of this SNP was lower than 5%. Although the current imputation method
ensures the imputation accuracy for the genotypes, result interpretation remains further
validated in other GWASs and functional experiments.
In the present study, we found that most of the risk loci were located in intron regions,
particularly intron 2 in both ancestries. Introns, at present, have been paid increasing regard
to gene regulation, such as genome organization, transcription regulation, and alternative
splicing [
21
]. The intron 2 of TERT has been presumed to harbor a putative regulatory
region [
22
] and thus is likely to play a significant role in biological functions. As reported by
prior functional studies involving polymorphisms in the intron 2 region of TERT, rs2853677
was found located within the Snail1 binding site in a TERT enhancer, the risk allele of which
disrupted the Snail1 binding site, and the resultant derepressed TERT expression increased
cancer susceptibility [
23
]. Confirmed by ex vivo luciferase gene assays, SNP rs2736100 was
found situated at an intronic enhancer and could pose a genotype-specific impact on TERT
expression [24].
Since promoter activity is essential for gene expression, the mechanisms between poly-
morphisms in the TERT promoter region and tumorigenesis merit further investigations. A
previous functional investigation revealed that the switch with risk allele at TERT promoter
variant (rs2853669) was pivotal in regulating TERT expression by influencing MYC and
E2F1 expression. The resultant synergistic effects of MYC/E2F1/TERT expression with the
rs2853669 polymorphism further deteriorated the prognosis of prostate cancer [25].
Two synonymous variants at the exon region of TERT were identified in this study.
SNP rs2736098 was previously found located in an open chromatin region with gene
regulatory elements and was reported to correlate with a higher prostate-specific antigen
level [
26
]. The aberrant activation of the related transcriptional factors caused by the
variation in this SNP may drive the potential signaling pathways of tumorigenesis [
27
].
Another synonymous SNP, rs35033501, was reportedly associated with splicing patterns
alteration and cancer susceptibility increase by disrupting certain splice sites [28].
Our study identified several novel genetic variants of TERT in relation to PCa risk in
different ancestries. In European ancestry, five novel SNPs involving intron 12, intron 9,
intron 6, and intron 2 regions were discovered, while two novel SNPs situated at intron
2 were discovered in those of Chinese ancestry. This finding can strongly broaden the
evidence base on the genetic predisposition of prostate cancer and can refine the genetic
architectures of PCa susceptibility loci across the TERT region among distinct ancestries.
One plausible explanation underlying the association between these novel SNPs and PCa
risk may be attributable to a high linkage disequilibrium with adjacent polymorphisms
with biological function.
This study supports the evidence of different genetic variants between Europeans
and Chinese, which can furnish insights into public health practice, such as different
population-based risk stratification and ethnic-specific target screening. According to the

Cancers 2023,15, 2650 10 of 12
findings of our prior research, the precision of risk estimate decreased when applying
European-specific PCa polygenic risk score as a risk stratification tool to other ancestry
populations [
29
]. In addition, compared with the large sample size of European GWASs,
the small sample size of the East Asian studies led to an imbalance in the risk variants
identification and a decrease in the risk estimate precision in this group [
30
]. Therefore, it is
necessary to identify more ethnic-specific risk variants in non-Europeans for a precisely
targeted screening and early diagnosis.
There are several limitations in the present study. First, survival data are not available
in the Chinese population. However, the Gleason score is associated with PCa survival
which may provide some evidence. Second, gene-based analysis is estimated based on
the germline loci, whereas the actual function of TERT in each individual is unclear. For
example, the expression level of TERT from each participant is unable to be captured based
on the gene-based analysis. Future studies in the biospecimen are considered to address
this issue. Finally, subsequent functional experiments are warranted to assess the present
findings, as well as to evaluate the different functions between the loci in promoter and
intron 2 regions in the TERT.
5. Conclusions
In conclusion, this study, including a large set of SNPs and two ethnic populations,
supports the existing evidence regarding TERT polymorphisms in relation to PCa risk
and prognosis, discovers some novel PCa-related genetic variants in the TERT region, and
indicates the heterogeneous genetic architectures of PCa susceptibility loci among distinct
ancestries. Further functional studies of TERT polymorphisms are required to validate the
present findings and reveal the underlying mechanisms.
Author Contributions:
Y.Z. designed the research, undertook the statistical analyses and drafted the
manuscript. X.R. designed the research, conducted data collection, and provided technical support.
J.L. conducted data collection and provided administrative support. D.H. provided the funding and
provided administrative support. J.H. (Jingyi Huang), J.H. (Jinlun Huang), T.T.S.C. and A.T.-L.N.
provided administrative support. Y.W. and G.W. provided data access. H.J. and D.X. provided data
access and supervised the study. R.N. provided the funding, supervised the study and revised the
manuscript. All authors have read and agreed to the published version of the manuscript.
Funding:
This work was supported by grants from the National Natural Science Foundation of China
[grant number 81972645], an innovative research team of high-level local universities in Shanghai,
the Shanghai Youth Talent Support Program, an intramural grant of The University of Hong Kong
to Rong Na, and the Shanghai Sailing Program [grant number 22YF1440500] to Da Huang. All the
funders had no role in the design and conduct of the study; collection, management, analysis, and
interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit
the manuscript for publication.
Institutional Review Board Statement:
The study was conducted in accordance with the Declaration
of Helsinki, and was approval by the Institutional Review Board of each hospital. Data of this study
are secondary data from UK Biobank and ChinaPCa, whose ethnical approval information have been
published in their research [10,12].
Informed Consent Statement:
Informed consent has been obtained from all subjects in the UKB
and ChinaPCa.
Data Availability Statement:
UKB Data used in this research are publicly available to qualified
researchers on application to the UK Biobank (www.ukbiobank.ac.uk (accessed on 15 November
2022)). The study protocol, statistical analysis plan, and analytical code of this study will be available
from the time of publication in response to any reasonable request to the corresponding author.
Acknowledgments:
We thank all the subjects included in this study (ChinaPCa). We thank the
Chinese PCa consortium and UK Biobank (Access Number: 66813) for access to the data.
Conflicts of Interest: The authors declare no conflict of interest.

Cancers 2023,15, 2650 11 of 12
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