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Laura Pistoni, Manuel Gentiluomo, Ye Lu, Evangelina López de Maturana, Viktor Hlavac, Giuseppe Vanella, Erika Darvasi, Anna Caterina Milanetto, Martin Oliverius, Yogesh Vashist, Milena Di Leo, Beatrice Mohelnikova-Duchonova, Renata Talar-Wojnarowska, Cristian Gheorghe, Maria Chiara Petrone, Oliver Strobel, Paolo Giorgio Arcidiacono, Ludmila Vodickova, Andrea Szentesi, Gabriele Capurso, László Gajdán, Giuseppe Malleo, George E Theodoropoulos, Daniela Basso, Pavel Soucek, Hermann Brenner, Rita T Lawlor, Luca Morelli, Audrius Ivanauskas, Emanuele Federico Kauffmann, Angelica Macauda, Maria Gazouli, Livia Archibugi, Michael Nentwich, Martin Loveček, Giulia Martina Cavestro, Pavel Vodicka, Stefano Landi, Francesca Tavano, Cosimo Sperti, Thilo Hackert, Juozas Kupcinskas, Raffaele Pezzilli, Angelo Andriulli, Luca Pollina, Edita Kreivenaite, Domenica Gioffreda, Krzysztof Jamroziak, Péter Hegyi, Jakob R Izbicki, Sabrina Gloria Giulia Testoni, Raffaella Alessia Zuppardo, Dania Bozzato, John P Neoptolemos, Núria Malats, Federico Canzian, Daniele Campa
Department of Biology, University of Pisa, Pisa, Italy.
Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Carcinogenesis. 2021 Aug 19;42(8):1037-1045. doi: 10.1093/carcin/bgab057.
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Its poor prognosis is predominantly due to the fact that most patients remain asymptomatic until the disease reaches an advanced stage, alongside the lack of early markers and screening strategies. A better understanding of PDAC risk factors is essential for the identification of groups at high risk in the population. Genome-wide association studies (GWAS) have been a powerful tool for detecting genetic variants associated with complex traits, including pancreatic cancer. By exploiting functional and GWAS data, we investigated the associations between polymorphisms affecting gene function in the pancreas (expression quantitative trait loci, eQTLs) and PDAC risk. In a two-phase approach, we analysed 13 713 PDAC cases and 43 784 controls and identified a genome-wide significant association between the A allele of the rs2035875 polymorphism and increased PDAC risk (P = 7.14 × 10-10). This allele is known to be associated with increased expression in the pancreas of the keratin genes KRT8 and KRT18, whose increased levels have been reported to correlate with various tumour cell characteristics. Additionally, the A allele of the rs789744 variant was associated with decreased risk of developing PDAC (P = 3.56 × 10-6). This single nucleotide polymorphism is situated in the SRGAP1 gene and the A allele is associated with higher expression of the gene, which in turn inactivates the cyclin-dependent protein 42 (CDC42) gene expression, thus decreasing the risk of PDAC. In conclusion, we present here a functional-based novel PDAC risk locus and an additional strong candidate supported by significant associations and plausible biological mechanisms.
胰腺导管腺癌 (PDAC) 是最致命的癌症之一。其预后不良主要是由于大多数患者在疾病达到晚期之前仍然没有症状，同时缺乏早期标志物和筛查策略。更好地了解 PDAC 的危险因素对于确定人群中的高危人群至关重要。全基因组关联研究 (GWAS) 一直是检测与复杂特征相关的遗传变异的有力工具，包括胰腺癌。通过利用功能和 GWAS 数据，我们研究了影响胰腺基因功能的多态性 (表达数量性状基因座，eQTLs) 与 PDAC 风险之间的关联。在两阶段方法中，我们分析了 13713 例 PDAC 病例和 43784 例对照，发现 rs2035875 多态性的 A 等位基因与 PDAC 风险增加之间存在全基因组显著关联 (P = 7.14×10-10)。已知该等位基因与角蛋白基因 KRT8 和 KRT18 的胰腺表达增加有关，其水平升高与各种肿瘤细胞特征相关。此外，rs789744 变体的 A 等位基因与 PDAC 发病风险降低相关 (P = 3.56×10-6)。该单核苷酸多态性位于 SRGAP1 基因中，A 等位基因与该基因的高表达相关，进而使细胞周期蛋白依赖性蛋白 42 (CDC42) 基因的表达失活，从而降低 PDAC 的风险。总之，我们在这里提出了一个基于功能的新的 PDAC 风险位点和另一个强有力的候选基因，该候选基因得到了显著关联和合理的生物学机制的支持。
