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Christos Dimitrakopoulos, Bart Vrugt, Renata Flury, Peter Schraml, Uwe Knippschild, Peter Wild, Simon Hoerstrup, Doris Henne-Bruns, Peter Wuerl, Rolf Graf, Stefan Breitenstein, Gareth Bond, Niko Beerenwinkel, Lukasz Filip Grochola
Computational Biology Group, Department of Biosystems Science and Engineering, ETH Zurich, Zurich, Switzerland.
Swiss Institute of Bioinformatics, Basel, Switzerland.
JAMA Surg. 2019 Jun 1;154(6):e190484. doi: 10.1001/jamasurg.2019.0484. Epub 2019 Jun 19.
Surgery currently offers the only chance for a cure in pancreatic ductal adenocarcinoma (PDAC), but it carries a significant morbidity and mortality risk and results in varying oncologic outcomes. At present, to our knowledge, there are no tests available before surgical resection to identify tumors with an aggressive biological phenotype that could guide personalized treatment strategies.
Identification of noninvasive genetic biomarkers that could direct therapy in patients whose cases are amenable to pancreatic cancer resection.
DESIGN, SETTING, AND PARTICIPANTS: This multicenter study combined a prospective European cohort of patients with PDAC who underwent pancreatic resection (from University Hospital of Zurich, Zurich, Switzerland; Cantonal Hospital of Winterthur, Winterthur, Switzerland; and University Clinic of Ulm, Ulm, Germany) with data from the Cancer Genome Atlas database in the United States, which includes prospectively registered patients with PDAC. A genome-wide screening for functional single-nucleotide polymorphisms (SNPs) that affect PDAC survival was conducted using the European cohort for identification and the Cancer Genome Atlas cohort for validation. We used Cox proportional hazards models to screen for high-frequency polymorphic variants that are associated with allelic differences in tumor-associated survival and either result in an altered protein structure and function or reside in known regulatory noncoding genomic regions. The false-discovery rate method was applied for multiple hypothesis-testing corrections. Data analysis occurred from November 2017 to May 2018.
Pancreatic resection.
Tumor-associated survival.
A total of 195 patients in the European cohort were included, as well as 136 patients in the Cancer Genome Atlas cohort (overall median [range] age, 66 [19-87] years; 156 [47.1%] were women, and 175 [52.9%] were men). Two SNPs in noncoding, functional regions of genes that regulate cancer progression, invasion, and metastasis were identified (CHI3L2 SNP rs684559 and CD44 SNP rs353630). These were associated with survival after PDAC resection; patients who carry the risk alleles at 1 of both SNP loci had a 2.63-fold increased risk for tumor-associated death compared with those with protective genotypes (hazard ratio for survival, 0.38 [95% CI, 0.27-0.53]; P = 1.0 × 10-8).
The identified polymorphisms may serve as a noninvasive biomarker signature of prospective survival after pancreatic resection that is readily available at the time of PDAC diagnosis. This signature can be used to identify a subset of high-risk patients with PDAC with very low survival probability who might be eligible for inclusion in clinical trials of new therapeutic strategies, including neoadjuvant chemotherapy protocols. In addition, the biological knowledge about these SNPs could help guide the development of individualized genomic strategies for PDAC therapies.
目前，手术是治疗胰腺导管腺癌（PDAC）的唯一方法，但它存在较高的发病率和死亡率，并导致不同的肿瘤学结果。目前，据我们所知，在手术切除前，还没有可以识别具有侵袭性生物学表型的肿瘤的检测方法，这些肿瘤可以指导个体化的治疗策略。
鉴定非侵入性的遗传生物标志物，以指导那些适合胰腺癌切除术的患者的治疗。
设计、地点和参与者：这项多中心研究结合了一个前瞻性的欧洲 PDAC 患者队列，这些患者接受了胰腺切除术（来自瑞士苏黎世大学医院、瑞士温特图尔州立医院和德国乌尔姆大学诊所），并结合了美国癌症基因组图谱数据库的数据，该数据库包括前瞻性登记的 PDAC 患者。使用欧洲队列进行全基因组功能单核苷酸多态性（SNP）筛选，以鉴定影响 PDAC 生存的 SNP，并使用癌症基因组图谱队列进行验证。我们使用 Cox 比例风险模型筛选与肿瘤相关的生存存在等位基因差异的高频多态性变异，这些变异要么导致蛋白结构和功能改变，要么位于已知的调控非编码基因组区域。应用错误发现率方法进行多重假设检验校正。数据分析于 2017 年 11 月至 2018 年 5 月进行。
胰腺切除术。
包括欧洲队列中的 195 名患者和癌症基因组图谱队列中的 136 名患者（总体中位[范围]年龄为 66[19-87]岁；156[47.1%]为女性，175[52.9%]为男性）。在调节癌症进展、侵袭和转移的基因的非编码、功能区域中鉴定出了两个 SNP（CHI3L2 SNP rs684559 和 CD44 SNP rs353630）。这些 SNP 与 PDAC 切除术后的生存相关；与保护性基因型相比，携带这两个 SNP 位点中 1 个风险等位基因的患者肿瘤相关死亡风险增加 2.63 倍（生存风险比，0.38[95%CI，0.27-0.53]；P=1.0×10-8）。
鉴定出的多态性可能作为胰腺切除术后前瞻性生存的非侵入性生物标志物特征，在 PDAC 诊断时即可获得。该特征可用于识别具有极低生存概率的 PDAC 高危患者亚组，这些患者可能有资格参加新治疗策略的临床试验，包括新辅助化疗方案。此外，这些 SNP 的生物学知识可能有助于指导 PDAC 治疗的个体化基因组策略的发展。
