Department of Biology, University of Pisa, Pisa, Italy,
Digestive and Liver Disease Unit, S. Andrea Hospital, "Sapienza" University of Rome, Rome, Italy.
Neuroendocrinology. 2022;112(12):1168-1176. doi: 10.1159/000524659. Epub 2022 Apr 26.
Telomere length (TL) is a potential indicator of cancer predisposition; however, the multitude of techniques used to measure it causes the results to be heterogeneous and, in some cases, controversial. In the last years, several studies adopted a strategy based on TL-associated genetic variants to generate a polygenic score, often referred as teloscore, used in lieu of direct TL measurement. For pancreatic neuroendocrine neoplasms (PanNEN), this strategy has not been attempted yet.
A teloscore was generated using 11 SNPs (NAF1-rs7675998, ZNF676-rs409627, TERC-rs10936599, CTC1-rs3027234, PXK-rs6772228, DHX35-rs6028466, OBFC1-rs9420907, ZNF208-rs8105767, ACYP2-rs11125529, TERT-rs2736100, and ZBTB46-rs755017), and 291 PanNEN cases and 1,686 controls collected by the PANcreatic Disease ReseArch (PANDoRA) consortium were genotyped to analyse the association of the teloscore and its individual SNPs with the risk of developing PanNEN.
An association between genetically determined long telomeres and the risk of developing PanNEN (OR = 1.99, CI: 1.33-2.98, p = 0.0008) for highest versus median (third) quintile was observed. In addition, two novel SNPs associated with PanNEN risk were identified: ZNF676-rs409627 (ORC/C_vs_G/G = 2.27, CI: 1.58-3.27, p = 8.80 × 10-6) and TERT-rs2736100 (ORC/A_vs_C/C = 2.03, CI: 1.42-2.91, p = 1.06 × 10-4).
In conclusion, this study provides for the first time a clear indication of the association between long genetically determined telomeres and increased risk of developing PanNEN.
端粒长度（TL）是癌症易感性的潜在指标；然而，用于测量 TL 的多种技术导致结果存在异质性，在某些情况下存在争议。在过去的几年中，一些研究采用了基于与 TL 相关的遗传变异的策略来生成多基因评分，通常称为 teloscore，用于替代直接 TL 测量。对于胰腺神经内分泌肿瘤（PanNEN），尚未尝试这种策略。
使用 11 个 SNP（NAF1-rs7675998、ZNF676-rs409627、TERC-rs10936599、CTC1-rs3027234、PXK-rs6772228、DHX35-rs6028466、OBFC1-rs9420907、ZNF208-rs8105767、ACYP2-rs11125529、TERT-rs2736100 和 ZBTB46-rs755017）生成了一个 teloscore，并对 PANcreatic Disease ReseArch（PANDoRA）协会收集的 291 例 PanNEN 病例和 1686 例对照进行基因分型，以分析 teloscore 及其个体 SNP 与 PanNEN 发病风险的关联。
观察到遗传决定的长端粒与 PanNEN 发病风险之间存在关联（OR=1.99，CI：1.33-2.98，p=0.0008），最高与中位数（第三）五分位数相比。此外，还鉴定出两个与 PanNEN 风险相关的新 SNP：ZNF676-rs409627（ORC/C_vs_G/G=2.27，CI：1.58-3.27，p=8.80×10-6）和 TERT-rs2736100（ORC/A_vs_C/C=2.03，CI：1.42-2.91，p=1.06×10-4）。
总之，这项研究首次提供了明确的证据表明遗传决定的长端粒与 PanNEN 发病风险增加之间存在关联。
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