Gentiluomo Manuel, Corradi Chiara, Apadula Laura, Comandatore Annalisa, Lauri Gaetano, Rossi Gemma, Peduzzi Giulia, Crippa Stefano, Rizzato Cosmeri, Falconi Massimo, Arcidiacono Paolo Giorgio, Morelli Luca, Capurso Gabriele, Campa Daniele
Department of Biology, University of Pisa, Pisa, Italy.
Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Cancer. 2025 Jan 1;131(1):e35678. doi: 10.1002/cncr.35678. Epub 2024 Dec 5.
Intraductal papillary mucinous neoplasms (IPMNs) are precursors to pancreatic cancer, but not all IPMNs progress to cancer. The objective of this study was to identify the germline genetic variants associated with IPMN clinical progression by conducting the first genome-wide association study (GWAS) and computing a polygenic hazard score (PHS) in 338 patients with IPMN.
The study population was divided into two subsets, and a Cox analysis adjusted for sex, age, cyst size at diagnosis, and the top 10 principal components was performed. A PHS was calculated using the genotypes of common variants associated with IPMN progression identified.
Eight loci with significant associations (p < 5 × 10) were identified, and the most significant was 7q21.11-rs117620617 (hazard ratio, 16.35; 95% confidence interval, 6.93-38.60; p = 1.80 × 10). All variants were associated with inflammatory processes, suggesting that alleles that predispose to an inflammatory prone phenotype may promote progression. The PHS indicated a statistically significant association (hazard ratio, 18.05; 95% confidence interval, 7.96-45.80; p = 6.18 × 10) with IPMN progression among individuals who had the highest number of effect alleles (fourth quartile) compared with those who had the lowest number (first quartile).
The current results study advance the understanding of individual predisposition to IPMN progression and underscore the potential use of genetics in the stratification of patients who have IPMN.
导管内乳头状黏液性肿瘤（IPMN）是胰腺癌的癌前病变，但并非所有IPMN都会进展为癌症。本研究的目的是通过开展首例全基因组关联研究（GWAS）并计算338例IPMN患者的多基因风险评分（PHS），来确定与IPMN临床进展相关的种系基因变异。
将研究人群分为两个亚组，并进行了一项针对性别、年龄、诊断时囊肿大小和前10个主成分进行校正的Cox分析。使用所确定的与IPMN进展相关的常见变异的基因型计算PHS。
确定了8个具有显著关联的基因座（p < 5×10），其中最显著的是7q21.11-rs117620617（风险比，16.35；95%置信区间，6.93 - 38.60；p = 1.80×10）。所有变异均与炎症过程相关，这表明易患炎症倾向表型的等位基因可能促进疾病进展。PHS显示，在具有最高数量效应等位基因的个体（第四四分位数）中，与具有最低数量效应等位基因的个体（第一四分位数）相比，与IPMN进展存在统计学显著关联（风险比，18.05；95%置信区间，7.96 - 45.80；p = 6.18×10）。
当前研究结果增进了对IPMN进展个体易感性的理解，并强调了遗传学在IPMN患者分层中的潜在应用。
