Diagnosis of pancreaticobiliary malignancy by detection of minichromosome maintenance protein 5 in bile aspirates

Abstract

Biliary brush cytology is the standard method of sampling a biliary stricture but has a low sensitivity for the detection of malignancy. We have previously shown that minichromosome maintenance (MCM) replication proteins (Mcm2 -7) are markers of dysplasia and have utilised these novel biomarkers of growth for the diagnosis of cervical and bladder cancer. We aimed to determine if MCM proteins are dysregulated in malignant pancreaticobiliary disease and if levels in bile are a sensitive marker of malignancy. In 30 tissue specimens from patients with malignant/benign biliary strictures, we studied Mcm2 and -5 expression by immunohistochemistry. Bile samples were also collected prospectively at endoscopic retrograde cholangiopancreatography from 102 consecutive patients with biliary strictures of established (n ¼ 42) or indeterminate aetiology (n ¼ 60). Patients with indeterminate strictures also underwent brush cytology as part of standard practice. Bile sediment Mcm5 levels were analysed using an automated immunofluorometric assay. In benign biliary strictures, Mcm2 and -5 protein expression was confined to the basal epithelial proliferative compartment -in contrast to malignant strictures where expression was seen in all tissue layers. The percentage of nuclei positive for Mcm2 was higher in malignant tissue (median 76.5%, range 42 -92%) than in benign tissue (median 5%, range 0 -33%) (Po0.0005), with similar results for Mcm5. Minichromosome maintenance protein 5 levels in bile were significantly more sensitive than brush cytology (66 vs 20%; P ¼ 0.004) for the detection of malignancy in patients with an indeterminate stricture, with a comparable positive predictive value (97 vs 100%; P ¼ ns). In this study, we demonstrate that Mcm5 in bile detected by a simple automated test is a more sensitive indicator of pancreaticobiliary malignancy than routine brush cytology.

Prognostic value of minichromosome maintenance mRNA expression in early-stage pancreatic ductal adenocarcinoma patients after pancreaticoduodenectomy

“… 47 Immunohistochemical detection of MCM5 in human secretions also has a diagnostic value for cancers of the corresponding organs, such as urine sediments for prostate cancer, 13 gastric aspirates for esophageal cancer, 14 and bile aspirates or biliary brush cytology for pancreaticobiliary malignancy. 48 , 49 Moreover, the levels of MCM6 mRNA and protein in the plasma are also markedly increased, and significantly associated with tumor stage progression and lymph node metastasis in hepatocellular carcinoma (HCC). 50 Similar to previous studies, by using the GEPIA online analysis tool, we observed that MCM2–7 were upregulated in the majority of human tumor tissues, as well as in PC tumor tissue.…”

The BMI1 inhibitor PTC-209 is a potential compound to halt cellular growth in biliary tract cancer cells

“…Interestingly, a study by Bracken and coworkers showed that siRNA-mediated knockdown of BMI1 resulted in diminished expression levels of CDC6 [ 30 ], making CDC6 a potential BMI1 target. Increased expression of MCM genes has been found in various types of cancer and has been associated with short survival rates [ 31 - 33 ]. In gallbladder cancer, MCM2 has been shown to serve as an independent predictor of poor outcome, since expression of MCM2 was correlated with larger tumor mass, poor differentiation, lymph node metastasis and shorter survival [ 34 ].…”

Plasma minichromosome maintenance complex component 6 is a novel biomarker for hepatocellular carcinoma patients

“…13 Recent reports have showed that increased expression of MCM family proteins are related to several tumors including HCC. [14][15][16][17] For example, detection of stool MCM can be used for detection of colorectal cancer, 14 MCM5 is used in diagnosis of pancreaticobiliary malignancy in bile aspirates, 15 expression of MCM6 protein in meningiomas is strongly correlated with histological grade and clinical outcome, 16 MCM7 expression also predicts postoperative prognosis for HCC. 17 Our previous results also indicated that MCM6 is overexpressed in HCC tissues.…”