<scp><i>TERT</i></scp> gene harbors multiple variants associated with pancreatic cancer susceptibility

Campa, Daniele; Rizzato, Cosmeri; Stolzenberg-Solomon, Rachael; Pacetti, Paola; Vodička, Pavel; Cleary, Sean P.; Capurso, Gabriele; Bueno-de-Mesquita, H. Bas; Werner, Jens; Gazouli, Maria; Butterbach, Katja; Ivanauskas, Audrius; Giese, Nathalia A.; Petersen, Gloria M.; Fogar, Paola; Wang, Zhaoming; Bassi, Claudio; Ryska, Miroslav; Theodoropoulos, George; Kooperberg, Charles; Li, Donghui; Greenhalf, William; Pasquali, Claudio; Hackert, Thilo; Fuchs, Charles S.; Mohelníková-Duchoňová, Beatrice; Sperti, Cosimo; Funel, Niccola; Dieffenbach, Aida Karina; Wareham, Nicholas J.; Buring, Julie E.; Holcátová, Ivana; Costello, Eithne; Zambon, Carlo–Federico; Kupčinskas, Juozas; Risch, Harvey A.; Kraft, Peter; Bracci, Paige M.; Pezzilli, Raffaele; Olson, Sara H.; Sesso, Howard D.; Hartge, Patricia; Strobel, Oliver; Małecka‐Panas, Ewa; Visvanathan, Kala; Arslan, Alan A.; Pedrazzoli, Sergio; Souček, Pavel; Gioffreda, Domenica; Key, Timothy J.; Talar-Wojnarowska, Renata; Scarpa, Aldo; Mambrini, Andrea; Jacobs, Eric J.; Jamroziak, Krzysztof; Klein, Alison P.; Tavano, Francesca; Bambi, Franco; Landi, Stefano; Austin, Melissa A.; Vodičková, Ľudmila; Brenner, Hermann; Chanock, Stephen J.; Fave, Gianfranco Delle; Piepoli, Ada; Cantore, Maurizio; Wang, Zheng; Wolpin, Brian M.; Ámundadóttir, Laufey T.; Canzian, Federico

doi:10.1002/ijc.29590

Cited by 62 publications

(44 citation statements)

References 51 publications

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“…A second independent signal on 5p15.33 was identified in PanScan III, tagged by a synonymous SNP (rs2736098) in the second exon of TERT [12]. Recently, a third risk locus, marked by rs2853677, was identified in this genomic region through a candidate gene analysis of the TERT and TERC genes [62]; however this variant did not attain GWAS significance in our study (PanScan I-III, P = 4.2×10 −4 ). The TERT gene encodes the catalytic subunit of telomerase, known for its critical role in maintaining telomere ends and the increased telomerase activity frequently seen in human cancers [63–65].…”

Section: Discussionmentioning

confidence: 99%

Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21

et al. 2016

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Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88×10−15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22×10−9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70×10−8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L-TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7×10−8). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5×10−4-2.0×10−3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.

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Section: Discussionmentioning

confidence: 99%

Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21

et al. 2016

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“…Campa D, et al . identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio = 0.85; 95% confidence interval = 0.80–0.90, P = 8.3 × 10 −8 )35. Our study, for the first time, combined rs2853677 and rs2242652 polymorphisms with ischemic stroke risk.…”

Section: Discussionmentioning

confidence: 51%

Polymorphisms in Telomere Length Associated TERC and TERT predispose for Ischemic Stroke in a Chinese Han population

Zhang

Liang

et al. 2017

Sci Rep

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The role of telomere in genomic stability is an established fact. Variation in leukocyte telomere length (LTL) has been considered a crucial factor that associated with age-associated diseases. To elucidate the association between LTL variation and ischemic stroke (IS) risk, we selected ten single nucleotide polymorphisms (SNPs) in three genes (TERC, TERT and RTEL1) that previously reported link to LTL, and genotyped SNPs of these genes in a case-control study. The association between polymorphisms and IS risk were tested by Chi squared test and haplotype analysis. In allele association analysis, allele “C” in rs10936599 of TERC gene and allele “G” in rs2853677 of TERT gene were found to have an increased risk of IS when compared with allele “T” and “A”, respectively. Model association analysis showed that genotype “G/A” in the overdominant model and genotypes “G/A” and “A/A” in the dominant model of rs2242652 presented a more likelihood to have IS. Another TERT locus (rs2853677) with genotype “G” was also found IS-related risky in the log-additive model. Taken together, our results suggest a potential association between LTL related TERC, TERT gene variants and ischemic stroke risk.

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“…PanScan III reported a second independent risk locus on chromosome 5p15.33, tagged by a synonymous variant within the second exon of TERT (rs2736098) 105 . A third independent risk locus located in the first intron of TERT gene (rs2853677) was discovered through a candidate gene analysis in 5,550 pancreatic cancer cases and 7,585 control subjects from PANDoRA (PANcreatic Disease ReseArch) consortium and PanScan 123 . Recently, imputation of PanScan I–III and replication in PANDoRA and PanC4 found a fourth risk locus for pancreatic cancer in this genomic region (rs35226131), which is located about 200bps upstream of the transcriptional start site of TERT 107 .…”

Section: Common Low-risk Susceptibility Locimentioning

confidence: 99%

Inherited pancreatic cancer

Chen¹,

Roberts²,

Klein³

2017

Chin. Clin. Oncol.

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Pancreatic cancers arise through a series of genetic events both inherited and acquired. Inherited genetic changes, both high penetrance and low penetrance, are an important component of pancreatic cancer risk, and may be used to characterize populations who will benefit from early detection. Furthermore, pancreatic cancer patients with inherited mutations may be particularly sensitive to certain targeted agents, providing an opportunity to personalized treatment. Family history of pancreatic cancer is one of the strongest risk factors for the disease, and is associated with an increased risk of caners at other sites, including but not limited to breast, ovarian and colorectal cancer. The goal of this chapter is to discuss the importance of family history of pancreatic cancer, and the known genes that account for a portion of the familial clustering of pancreatic cancer.

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TERT gene harbors multiple variants associated with pancreatic cancer susceptibility

Cited by 62 publications

References 51 publications

Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21

Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21

Polymorphisms in Telomere Length Associated TERC and TERT predispose for Ischemic Stroke in a Chinese Han population

Inherited pancreatic cancer

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