Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD.
Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD.
J Clin Oncol. 2024 Jun 20;42(18):2196-2206. doi: 10.1200/JCO.23.01573. Epub 2024 Mar 8.
Circulating carbohydrate antigen 19-9 (CA19-9) levels reflect FUT3 and FUT2 fucosyltransferase activity. Measuring the related glycan, DUPAN-2, can be useful in individuals unable to synthesize CA19-9. We hypothesized that similar to CA19-9, FUT functional groups determined by variants in and influence DUPAN-2 levels, and having tumor marker reference ranges for each functional group would improve diagnostic performance.
Using a training/validation study design, / genotypes were determined in 938 individuals from Johns Hopkins Hospital: 607 Cancer of the Pancreas Screening (CAPS) study subjects with unremarkable pancreata and 331 with pancreatic ductal adenocarcinoma (PDAC). Serum DUPAN-2 and CA19-9 levels were measured by immunoassay.
In controls, three functional FUT groups were identified with significant differences in DUPAN-2 levels: FUT3-intact, FUT3-null/FUT2-intact, and FUT3-null/FUT2-null. DUPAN-2 training set diagnostic cutoffs for each FUT group yielded higher diagnostic sensitivity in the validation set for patients with stage I/II PDAC than uniform cutoffs (60.4% [95% CI, 50.2 to 70.0] 39.8% [30.0 to 49.8]), at approximately 99% (96.7 to 99.6) specificity. Combining FUT/CA19-9 and FUT/DUPAN-2 tests yielded 78.4% (72.3 to 83.7) sensitivity for stage I/II PDAC, at 97.7% (95.3 to 99.1) specificity in the combined sets, with higher AUC (stage I/II: 0.960 0.935 for CA19-9 + DUPAN-2 without the FUT test; < .001); for stage I PDAC, sensitivity was 62.0% (49.1 to 73.2; AUC, 0.919 0.883; = .03). CA19-9 levels in FUT3-null/FUT2-null PDAC subjects were higher than in FUT3-null/FUT2-intact subjects (median/IQR; 24.9/57.4 <1/2.3 U/mL; = .0044). In a simulated CAPS cohort, AUC precision recall (AUC) scores were 0.51 for CA19-9 alone, 0.64 for FUT/CA19-9, 0.73 for CA19-9/DUPAN-2, and 0.84 for FUT/CA19-9/DUPAN-2.
Using a tumor marker gene test to individualize CA19-9 and DUPAN-2 reference ranges achieves high diagnostic performance for stage I/II pancreatic cancer.
循环碳水化合物抗原 19-9（CA19-9）水平反映了 FUT3 和 FUT2 岩藻糖基转移酶的活性。测量相关聚糖 DUPAN-2 在无法合成 CA19-9 的个体中可能很有用。我们假设与 CA19-9 类似，由 和 中的变体决定的 FUT 功能群会影响 DUPAN-2 水平，并且为每个功能群建立肿瘤标志物参考范围将提高诊断性能。
使用培训/验证研究设计，在来自约翰霍普金斯医院的 938 个人中确定了 / 基因型：607 名癌症胰腺筛查（CAPS）研究对象的胰腺无异常，331 名患有胰腺导管腺癌（PDAC）。通过免疫测定法测量血清 DUPAN-2 和 CA19-9 水平。
在对照组中，确定了三种具有显着 DUPAN-2 水平差异的功能性 FUT 组：FUT3 完整，FUT3 缺失/FUT2 完整和 FUT3 缺失/FUT2 缺失。对于每个 FUT 组，DUPAN-2 训练集诊断截止值在验证集中用于 I/II 期 PDAC 患者的诊断敏感性高于统一截止值（60.4% [95%CI，50.2 至 70.0] 39.8% [30.0 至 49.8]），特异性约为 99%（96.7 至 99.6）。结合 FUT/CA19-9 和 FUT/DUPAN-2 检测，在联合组中，I/II 期 PDAC 的敏感性为 78.4%（72.3 至 83.7），特异性为 97.7%（95.3 至 99.1），AUC 更高（I/II 期：0.960 0.935 用于 CA19-9 + DUPAN-2 而不进行 FUT 测试； <.001）；对于 I 期 PDAC，敏感性为 62.0%（49.1 至 73.2；AUC，0.919 0.883； =.03）。FUT3 缺失/FUT2 缺失 PDAC 患者的 CA19-9 水平高于 FUT3 缺失/FUT2 完整的患者（中位数/四分位距；24.9/57.4 <1/2.3 U/mL； =.0044）。在模拟的 CAPS 队列中，AUC 精度召回（AUC）评分分别为 CA19-9 单独为 0.51，FUT/CA19-9 为 0.64，CA19-9/DUPAN-2 为 0.73，FUT/CA19-9/DUPAN-2 为 0.84。
使用肿瘤标志物基因检测对 CA19-9 和 DUPAN-2 参考范围进行个体化，可实现 I/II 期胰腺癌的高诊断性能。
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