Editors' ChoiceCancer

The many faces of hepatocellular carcinoma

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Science Translational Medicine  04 Feb 2015:
Vol. 7, Issue 273, pp. 273ec20
DOI: 10.1126/scitranslmed.aaa5558

Hepatocellular carcinoma is the third most common cause of cancer mortality worldwide. Interestingly, this tumor type is known to have differences in morphologic appearance within the same tumor. However, the importance and the molecular drivers of these differences were not well understood. A recent study by Friemel et al. dissected different layers of heterogeneity in 23 hepatocellular carcinomas by matching cell and tissue morphology with immunohistochemical staining of common markers such as CK7, CD44, AFP, EpCAM, and glutamine synthetase, and mapped driver mutations in TP53 and CTNNB1 through targeted and Sanger sequencing in different areas of each tumor.

The study revealed substantial intratumor heterogeneity in at least one of these features in 20 out of 23 of the sampled hepatocellular carcinomas. Heterogeneity based only on morphology was found in 6 of 23 cases (26%), whereas when both the microscopic appearance and the immunohistochemical markers were combined, the number of cases showing heterogeneity rose up to 9 of 23 cases. In 22% of tumors, the mutational status of TP53 and CTNNB1 was heterogeneous, suggesting that CTNNB1, which is generally considered a “driver” mutation, may be absent in some tumor areas. These findings suggest that genomic instability may underlie the heterogeneity of hepatocellular carcinoma.

This study demonstrates the challenges of accurate molecular and clinicopathologic classification of hepatocellular carcinoma. The substantial heterogeneity demonstrated in this tumor also has implications for selection of targeted therapies, which are only effective when their molecular targets are enriched in the tumor.

J. Friemel et al., Intratumor heterogeneity in hepatocellular carcinoma. Clin. Cancer Res. 10.1158/1078-0432.CCR-14-0122 (2014). [Abstract]

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