Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Clin Gastroenterol Hepatol. 2013 Jun;11(6):719-30.e5. doi: 10.1016/j.cgh.2012.11.016. Epub 2012 Nov 28.
BACKGROUND & AIMS: Imaging tests can identify patients with pancreatic neoplastic cysts but not microscopic dysplasia. We investigated whether mutant TP53 can be detected in duodenal samples of secretin-stimulated pancreatic juice, and whether this assay can be used to screen for high-grade dysplasia and invasive pancreatic cancer.
We determined the prevalence of mutant TP53 in microdissected pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), and invasive adenocarcinomas. TP53 mutations were quantified by digital high-resolution melt-curve analysis and sequencing of secretin-stimulated pancreatic juice samples, collected from duodena of 180 subjects enrolled in Cancer of the Pancreas Screening trials; patients were enrolled because of familial and/or inherited predisposition to pancreatic cancer, or as controls.
TP53 mutations were identified in 9.1% of intermediate-grade IPMNs (2 of 22), 17.8% of PanIN-2 (8 of 45), 38.1% of high-grade IPMNs (8 of 21), 47.6% of PanIN-3 (10 of 21), and 75% of invasive pancreatic adenocarcinomas (15 of 20); no TP53 mutations were found in PanIN-1 lesions or low-grade IPMNs. TP53 mutations were detected in duodenal samples of pancreatic juice from 29 of 43 patients with pancreatic ductal adenocarcinoma (67.4% sensitivity; 95% confidence interval, 0.52-0.80) and 4 of 8 patients with high-grade lesions (PanIN-3 and high-grade IPMN). No TP53 mutations were identified in samples from 58 controls or 55 screened individuals without evidence of advanced lesions.
We detected mutant TP53 in secretin-stimulated pancreatic juice samples collected from duodena of patients with high-grade dysplasia or invasive pancreatic cancer. Tests for mutant TP53 might be developed to improve the diagnosis of and screening for pancreatic cancer and high-grade dysplasia. Clinical Trial numbers: NCT00438906 and NCT00714701.
影像学检查可用于识别胰腺肿瘤性囊肿患者，但无法识别显微镜下的胰腺异型增生。我们研究了是否可在受促胰液素刺激的十二指肠胰液样本中检测到突变型 TP53，以及该检测是否可用于筛查高级别异型增生和侵袭性胰腺癌。
我们确定了微切割胰腺上皮内瘤变（PanINs）、胰管内乳头状黏液性肿瘤（IPMNs）和侵袭性腺癌中突变型 TP53 的发生率。通过数字高分辨率熔解曲线分析和促胰液素刺激的胰液样本测序来定量检测 TP53 突变，这些样本来自参加胰腺癌筛查试验的 180 例受试者的十二指肠；患者入组的原因是家族性和/或遗传性胰腺癌易感性，或作为对照。
在 22 例中等级别 IPMN 中发现了 9.1%（2 例）、45 例 PanIN-2 中有 17.8%（8 例）、21 例高级别 IPMN 中有 38.1%（8 例）、21 例 PanIN-3 中有 47.6%（10 例）和 20 例侵袭性胰腺腺癌中有 75%（15 例）存在 TP53 突变；PanIN-1 病变或低级别 IPMN 中未发现 TP53 突变。在 43 例胰腺导管腺癌患者（67.4%的敏感性；95%置信区间，0.52-0.80）和 8 例高级别病变（PanIN-3 和高级别 IPMN）患者的十二指肠胰液样本中检测到 TP53 突变。在 58 例对照者或 55 例无高级别病变证据的筛查者的样本中未发现 TP53 突变。
我们在高级别异型增生或侵袭性胰腺癌患者的十二指肠胰液样本中检测到了突变型 TP53。检测突变型 TP53 可能有助于提高胰腺癌和高级别异型增生的诊断和筛查。临床试验编号：NCT00438906 和 NCT00714701。
