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Abstract：
OBJECTIVE: 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 FUT3 and FUT2 influence DUPAN-2 levels, and having tumor marker reference ranges for each functional group would improve diagnostic performance.
METHODS: Using a training/validation study design, FUT2/FUT3 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.
RESULTS: 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] v 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 v 0.935 for CA19-9 + DUPAN-2 without the FUT test; P < .001); for stage I PDAC, sensitivity was 62.0% (49.1 to 73.2; AUC, 0.919 v 0.883; P = .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 v <1/2.3 U/mL; P = .0044). In a simulated CAPS cohort, AUC precision recall (AUCPR) 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.
CONCLUSIONS: 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.
METHODS: Using a training/validation study design, FUT2/FUT3 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.
RESULTS: 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] v 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 v 0.935 for CA19-9 + DUPAN-2 without the FUT test; P < .001); for stage I PDAC, sensitivity was 62.0% (49.1 to 73.2; AUC, 0.919 v 0.883; P = .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 v <1/2.3 U/mL; P = .0044). In a simulated CAPS cohort, AUC precision recall (AUCPR) 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.
CONCLUSIONS: 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.
摘要：
目的：循环糖抗原19-9（CA19-9）水平反映FUT3和FUT2岩藻糖基转移酶活性。测量相关的聚糖，DUPAN-2可用于不能合成CA19-9的个体。我们假设与CA19-9相似，FUT功能组由FUT3和FUT2中的变体决定影响DUPAN-2水平，并且具有每个官能团的肿瘤标志物参考范围将改善诊断性能。
方法：使用培训/验证研究设计，在约翰霍普金斯医院的938名个体中确定了FUT2/FUT3基因型：607名胰腺癌筛查（CAPS）研究对象的胰腺不明显，331名胰腺导管腺癌（PDAC）。采用免疫分析法检测血清DUPAN-2和CA19-9水平。
结果：在对照中，三个功能性FUT组在DUPAN-2水平上有显著差异：FUT3完整，FUT3-null/FUT2-完整,和FUT3-null/FUT2-null。每个FUT组的DUPAN-2训练集诊断截止值在I/II期PDAC患者的验证集中产生了比均匀截止值更高的诊断灵敏度(60.4%[95%CI,50.2至70.0]v39.8%[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测试对I/II级PDAC的灵敏度为78.4%(72.3至83.7),在组合组中的97.7%(95.3至99.1)的特异性，具有较高的AUC（I/II期：无FUT测试的CA19-9DUPAN-2的0.960v0.935；P<.001）；对于I期PDAC，灵敏度为62.0%（49.1至73.2；AUC，0.919v0.883；P=0.03）。FUT3-null/FUT2-nullPDAC受试者的CA19-9水平高于FUT3-null/FUT2-完整受试者(中位数/IQR;24.9/57.4v<1/2.3U/mL;P=.0044)。在模拟的CAPS队列中，仅CA19-9的AUC精确召回率（AUCPR）评分为0.51，FUT/CA19-9为0.64，CA19-9/DUPAN-2为0.73，FUT/CA19-9/DUPAN-2为0.84。
结论：使用肿瘤标记基因测试来个体化CA19-9和DUPAN-2参考范围可实现I/II期胰腺癌的高诊断性能。
方法：使用培训/验证研究设计，在约翰霍普金斯医院的938名个体中确定了FUT2/FUT3基因型：607名胰腺癌筛查（CAPS）研究对象的胰腺不明显，331名胰腺导管腺癌（PDAC）。采用免疫分析法检测血清DUPAN-2和CA19-9水平。
结果：在对照中，三个功能性FUT组在DUPAN-2水平上有显著差异：FUT3完整，FUT3-null/FUT2-完整,和FUT3-null/FUT2-null。每个FUT组的DUPAN-2训练集诊断截止值在I/II期PDAC患者的验证集中产生了比均匀截止值更高的诊断灵敏度(60.4%[95%CI,50.2至70.0]v39.8%[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测试对I/II级PDAC的灵敏度为78.4%(72.3至83.7),在组合组中的97.7%(95.3至99.1)的特异性，具有较高的AUC（I/II期：无FUT测试的CA19-9DUPAN-2的0.960v0.935；P<.001）；对于I期PDAC，灵敏度为62.0%（49.1至73.2；AUC，0.919v0.883；P=0.03）。FUT3-null/FUT2-nullPDAC受试者的CA19-9水平高于FUT3-null/FUT2-完整受试者(中位数/IQR;24.9/57.4v<1/2.3U/mL;P=.0044)。在模拟的CAPS队列中，仅CA19-9的AUC精确召回率（AUCPR）评分为0.51，FUT/CA19-9为0.64，CA19-9/DUPAN-2为0.73，FUT/CA19-9/DUPAN-2为0.84。
结论：使用肿瘤标记基因测试来个体化CA19-9和DUPAN-2参考范围可实现I/II期胰腺癌的高诊断性能。
