A polymorphic variant in telomere maintenance is associated with worrisome features and high-risk stigmata development in IPMNs

Abstract

Intraductal papillary mucinous neoplasms (IPMNs) are non-obligatory precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The identification of molecular biomarkers able to predict the risk of progression of IPMNs toward malignancy is largely lacking and sorely needed. Telomere length (TL) is associated with the susceptibility of developing cancers, including PDAC. Moreover, several PDAC risk factors have been shown to be associated with IPMN transition to malignancy. TL is genetically determined, and the aim of this study was to use 11 SNPs, alone or combined in a score (teloscore), to estimate the causal relation between genetically determined TL and IPMNs progression. For this purpose, 173 IPMN patients under surveillance were investigated. The teloscore did not show any correlation, however, we observed an association between PXK-rs6772228-A and an increased risk of IPMN transition to malignancy (HR=3.17; 95%CI 1.47-6.84; P=3.24x10 -3). This effect was also observed in a validation cohort of 142 IPMNs even though the association was not statistically significant. The combined analysis was consistent showing an association between PXK-rs6772228-A and increased risk of progression. The A allele of this SNP is strongly associated with shorter LTL that in turn have been reported to be associated with increased risk of developing PDAC. These results clearly highlight the importance of looking for genetic variants as potential biomarkers in this setting in order to further our understanding the etiopathogenesis of PDAC and suggest that genetically determined TL might be an additional marker of IPMN prognosis.

Role of pancreatic ductal adenocarcinoma risk factors in intraductal papillary mucinous neoplasm progression

“…Thus, the results suggest the absence of a shared genetic background between PDAC risk and IPMN progression. This conclusion agrees with our previous results, which identified a germline variant associated with clinical IPMN progression that is not associated with PDAC risk ( 33 ).…”

“…Several lines of evidence suggest that lifestyle and genetic factors play a role in transforming IPMN into PDAC ( 32 – 36 ). Since carcinogenesis is a complex and multifactorial process, the only viable way to predict individuals’ risks is to analyse them with a comprehensive approach ( 33 , 34 ). Additionally, it has been proposed that PDAC risk factors may play a role in IPMN progression.…”

GWAS-identified telomere length associated genetic variants predict risk of recurrence of HPV-positive oropharyngeal cancer after definitive radiotherapy

“… 73 Multiple genes, such as RTEL1 , LRRC31 , TERF1 , TERT , ATM , PXK , ACYP2 , POT1 , and CTC1 , can influence TL through SNPs, which are the most common form of stable genetic variation in the genome. 34 , 35 , 36 , 37 , 39 , 74 , 75 , 76 , 77 , 78 Studies have shown that LTL is affected by clinical, lifestyle, and risk factors, but these factors alone cannot explain variations in LTL. TL-related genetic variants may affect LTL and cancer prognosis.…”

Modern aspects of the management of pancreatic intraductal papillary mucinous neoplasms: a narrative review

“…It is genetically determined by single nucleotide polymorphisms (SNPs) using 11 variants alone or combined [acylphosphatase 2 (ACYP2)-rs11125529, PX serine/threonine kinase (PXK)-rs6772228, telomerase ribonucleic acid (RNA) component (TERC)-rs10936599, nuclear assembly factor 1 ribonucleoprotein (NAF1)-rs7675998, telomerase reverse transcriptase (TERT)-rs2736100, oligonucleotide/oligosaccharide-binding fold containing 1 (OBFC1)-rs9420907, CST telomere replication complex component 1 (CTC1)-rs3027234, zinc finger protein 208 (ZNF208)-rs8105767, zinc finger protein 676 (ZNF676)-rs412658, DEAH-box helicase 35 (DHX35)-rs6028466, zinc finger and BTB domain containing 46 (ZBTB46)-rs755017] that affect telomere length (teloscore). This teloscore showed no association with progression to pancreatic cancer, except the PXK-rs6772228-A variant that had an increased risk of such progression [ 28 ].…”