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K-ras mutations in the bile of patients with primary sclerosing cholangitis
  1. S Kubickaa,
  2. F Kühnela,
  3. P Flemmingb,
  4. B Haina,
  5. N Kezmica,
  6. K L Rudolpha,
  7. M Mannsa,
  8. P N Meiera
  1. aDepartment of Gastroenterology and Hepatology, Medizinische Hochschule Hannover, Germany, bDepartment of Pathology, Medizinische Hochschule Hannover, Germany
  1. Professor MP Manns, Department of Gastroenterology and Hepatology, Medizinische Hochschule Hannover, Carl Neubergstraβe 1, 30625 Hannover, Germany. manns.michael{at}mh-hannover.de

Abstract

BACKGROUND AND AIMS The development of cholangiocarcinoma (CCC) is a complication of primary sclerosing cholangitis (PSC). To date, no reliable factors have been described which can define those PSC patients at high risk for the development of CCC and the clinical diagnosis of CCC in PSC patients is difficult. Therefore, molecular markers of cholangiocarcinogenesis, such as K-ras mutations, may improve the early diagnosis of CCC or the timing of liver transplantation.

METHODS K-ras mutations were analysed by enriched polymerase chain reaction/restriction fragment length polymorphism in the bile fluid of 56 PSC patients and 20 patients with other cholestatic diseases. To assess the value of K-ras mutations as a risk factor for cholangiocarcinogenesis, patients were prospectively investigated over a mean period of 31.5 months.

RESULTS In contrast with the control group, 17 (30%) patients with PSC revealed K-ras mutations in bile fluid. The mean Mayo score was not significantly different between PSC patients with (mean score 0.70) and without (mean score 0.13; p=0.2) K-ras mutations. In contrast with the group of PSC patients without K-ras mutations, four CCCs and two dysplasia were diagnosed in the group of patients with K-ras mutations during the follow up investigation (p<0.001).

CONCLUSIONS Our results indicate that K-ras mutations in bile fluid of PSC patients represent frequent early events during cholangiocarcinogenesis. However, most of the PSC patients with K-ras mutations remained tumour free after a long follow up investigation which is in agreement with the fact that these mutations are not specific for malignancy but may also occur in normal bile duct mucosa or in dysplasias. Therefore, analysis of K-ras mutations in bile should not be used for diagnosis of CCC in PSC patients. However, the results of our prospective follow up investigation indicate that K-ras mutations in bile fluid of PSC patients have to be considered as risk factors for the development of CCC which may have implications for the timing of liver transplantation.

  • K-ras mutations
  • cholangiocarcinogenesis
  • molecular diagnosis
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Footnotes

  • Abbreviations used in this paper:
    CCC
    cholangiocarcinoma
    OLT
    orthotopic liver transplantation
    PSC
    primary sclerosing cholangitis
    ERC
    endoscopic retrograde cholangiography
    PCR-RFLP
    polymerase chain reaction-restriction fragment length polymorphism

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