Gallbladder and Bile Duct Cancer

2004 News Archive

New Diagnostic Marker of Biliary Tract Carcinoma Discovered at Hopkins

As we all know too well, biliary tract carcinoma (cancers of the bile ducts and gallbladder) is a deadly disease. At this point, the best chance for cure is to detect the disease early, where surgical resection can be effective. Early detection has helped decrease morbidity and mortality from several other cancers. For example, the Pap smear detects cervical cancer at its pre-invasive stage, allowing patients to be treated before the cancer can metastasize. The serum PSA test is an effective marker in prostate cancer and allows it to be detected before patients become symptomatic and the tumor is advanced. Such a screening test is not currently available for biliary tract carcinoma, which contributes to its poor prognosis. To begin to develop such a marker, Koopmann et al. at Johns Hopkins have analyzed a novel protein, Mac-2-Binding Protein (Mac-2BP). This protein was first identified in a recent proteomic analysis of a bile sample from a patient with biliary tract carcinoma (Molecular and Cellular Proteomics 2004;7:715-728). In the current study, Koopmann et al. evaluate the sensitivity and specificity of this marker in biliary tract disease. These authors showed that biliary Mac-2BP levels were elevated by a factor of approximately three in biliary carcinoma patients compared to patients with primary sclerosing cholangitis or other non-neoplastic biliary tract disease. By immunohistochemistry, Mac-2BP was expressed in 34 of 36 biliary tract carcinomas (94.4% sensitivity). Mac-2BP levels in bile were as accurate as biliary CA19-9 levels, but use of these markers in combination led to better diagnostic accuracy.

It is clear that further studies involving larger patient populations will be needed to thoroughly evaluate the diagnostic accuracy of Mac-2BP, particularly in patients at high risk of developing biliary carcinoma, such as those with primary sclerosing cholangitis. However, this study demonstrates that screening for this tumor may be possible using bile, the bodily fluid in direct contact with tumor cells. Examination of the proteins within bile in addition to the routine brush cytology obtained from patients who undergo ERCP (endoscopic retrograde cholangiopancreatography) for suspected biliary tract tumors may improve diagnostic accuracy, and allow biliary malignancies to be detected at an early and thus potentially curable stage. These studies also show the power of new technologies (in this case proteomics) in identifying new diagnostic and potential therapeutic targets in biliary tract carcinoma.

Koopmann et al. Cancer 2004;101:1609-1615.
Kristiansen et al. Molecular and Cellular Proteomics 2004;3: 715-728.

~October 2004

Progression of Gene Hypermethylation in Gallstone Disease Leading to Gallbladder Cancer

The alteration of function of several types of genes can promote the development of cancer. Genes that promote growth are usually termed "oncogenes" these are often overexpressed or hyperactive in the cancer. Inactivation of genes that promote DNA repair creates genetic instability, which selects for tumor growth in other cancers. Other genes that normally block cell growth are inactivated in cancers; these are called tumor suppressor genes. Tumor suppressor genes can be inactivated by several mechanisms, including direct damage to the DNA (mutation), or by overt loss of the coding DNA (gene deletion). A more novel mechanism of inactivation of tumor suppressor genes is that of DNA methylation. Here, the DNA is reversibly altered such that the expression of the gene is lost, even though the coding DNA remains intact. Hence, methylation is the functional equivalent of mutation or deletion, with the exception that it is potentially reversible. Methylation of and inactivation of tumor suppressor genes is a known cancer-promoting mechanism in a variety of different cancers, including pancreas, breast, lung, and gastric carcinomas. Very little is known about methylation and its role in the development of gallbladder cancer.

To address this, our group at Hopkins, led by Dr. House, studied 54 gallbladder tumors from both the United States and Chile, where gallbladder carcinoma is endemic. Six candidate tumor suppressor genes (p16, APC, methylguanine methyltransferase, hMLH1, retinoic acid receptor beta-2 and p73) were studied. We found that while only 1 of 15 normal gallbladder controls showed methylation of these genes, 28% of gallbladders with chronic cholecystitis and 72% of gallbladder neoplasms demonstrated aberrant methylation. The most commonly methylated genes in gallbladder cancers were p16 (56%), p73 (28%), APC (27%), and hMLH1 (14%). Interestingly, significant differences in methylation were discovered between gallbladder cancers from the United States and those from Chile. APC gene methylation was more common in cancers from the United States, whereas p73 gene methylation was more common in Chilean cancers.

This study shows that the acquisition of hypermethylation at multiple tumor-suppressor gene-promoter sites may contribute to tumor formation and progression from chronic cholecystitis to gallbladder cancer. These findings open up the potential for screening for aberrant methylated genes in bile specimens, with the goal of detecting gallbladder cancers when they are small and are curable. Also, since methylation can be reversed with certain drugs, one could envision treating these tumors with these drugs to try to re-express the tumor suppressor genes, and thereby block the growth of the tumor. Since gallbladder cancers from Chile and the United States demonstrated genetic differences; it is possible that the identical cancers arising in two different parts of the world have a different and unique biology.

PubMed Abstract
House MG, Wistuba H, Argani P, Guo M, Schulick RD, Hruban RH, Herman JG, Maitra A. Ann Surg Oncol. 2003 Oct;10(8):882-9.

~April 2004