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BRAF mutations in cholangiocarcinoma

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Intrahepatic cholangiocarcinoma is the second most common primary hepatic malignant neoplasm, after hepatocellular carcinoma. Retrovirus-associated DNA sequences (RAS), controlled by RAS oncogenes, works at least in part through the mitogen activated protein kinase (MAPK) signal transduction cascade. Signalling through this cascade leads to activation of RAF kinase. Mammalian cells contain three RAF isoforms, A-RAF, B-RAF, and C-RAF. Mutations of BRAF have been found in around 15% of all human cancers, especially in malignant melanomas. Now researchers in Leipzig have studied the role of BRAF in liver tumours.

They looked for BRAF and KRAS mutations in 25 hepatocellular carcinomas and 69 cholangiocarcinomas by direct DNA sequencing after microdissection. MAPK pathway active intermediates were detected using immunohistochemistry. Activating BRAF missense mutations were found in 15 cholangiocarcinomas (22%) and in none of the hepatocellular carcinomas. The mutations were not found in non-neoplastic liver tissue. All BRAF mutations were within exons 11 and 15 and 11 of 15 mutations were in nucleotide 1796 leading to substitution of valine by glutamic acid at position 599.

KRAS mutations were found in 31 cholangiocarcinomas (45%) and none of the hepatocellular carcinomas. Twenty four mutations were of codon 12 and seven of codon 11. Ten were G→A transitions. Two KRAS mutations were found in non-neoplastic tissue. No correlations were observed between BRAF or KRAS mutations and histological or clinical features. Disruption of the Raf/MEK/ERK (MAPK) kinase pathway by either KRAS or BRAF mutation was detected in approximately 62% of all cholangiocarcinomas.

BRAF and KRAS mutations were common in cholangiocarcinoma but were not found in hepatocellular carcinoma.

Gut 2003;52:706–12.

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