Cholestasis is a marker for hepatocellular carcinomas displaying β‐catenin mutations

Abstract

The Wnt/beta-catenin signalling pathway is activated in many human hepatocellular carcinomas (HCC). Identification of beta-catenin mutation relies mostly on sequence analysis and/or immunohistochemistry. beta-catenin mutation may also be detected by analysing the expression of its target genes. The GLUL gene encoding glutamine synthetase (GS), for example, appears to be a pertinent marker. The aim of this study was to correlate GS immunostaining and beta-catenin mutations with clinicopathological features in HCC. We found that GS immunostaining had a sensitivity of 90% for the detection of beta-catenin mutations, with 98% specificity, whereas beta-catenin immunostaining had a sensitivity of 63% with 98% specificity. We used the sensitive GS marker to characterize 190 HCC cases. Sixty-eight (36%) cases displayed Wnt/beta-catenin activation. In addition to their well-differentiated pattern, these tumours exhibited significant features such as a homogeneous microtrabeculo-acinar pattern, low-grade cellular atypia, and cholestasis. As these tumours exhibited cholestasis, we hypothesized that beta-catenin acts on specific bile synthesis and/or transport pathways. In conclusion, we propose that GS immunostaining and a cholestatic pattern are relevant criteria for the identification of HCC with beta-catenin mutations.

Pathologic diagnosis of early hepatocellular carcinoma: A report of the international consensus group for hepatocellular neoplasia

“…51 Most importantly, GS is a target gene of ␤-catenin so that its overexpression is associated with mutations of ␤-catenin or with activation of this pathway. [52][53][54] Up-regulation of GS messenger RNA, protein, and activity were shown by Christa et al 52 in human HCC, while Osada et al 55 reported the stepwise increase in GS immunoreactivity from precancerous lesions to early HCC to progressed HCC. The monoclonal antibody from Chemicon International (clone MB302) at a dilution of 1/500 to 1/1000 and amplified with a new short polymer system yields reliable results.…”

“…29 New immunohistochemical and molecular markers are still under investigation and are likely to prove useful. 46,54,56 Role of Liver Biopsy. Regarding the application of biopsy for small nodules, the American Association for the Study of Liver Diseases recommends that biopsy should be performed for nodules less than 2 cm if their radiologic findings are not characteristic of HCC, whereas biopsy is not needed for lesions showing characteristic radiologic findings.…”

Organ-Specific Cancer Metabolism and Its Potential for Therapy

“…The liver-type glutaminase 2, which catalyzes the conversion of glutamine to glutamate is almost absent or significantly decreased in human HCC [91]. Consistently, the expression of glutamine synthetase, which catalyzes the opposite reaction, is increased in HCC patients with β-catenin mutations [92][93][94]. Glutamine synthetase is a target gene of β-catenin and overexpression of glutamine synthetase is highly correlated with β-catenin mutations [92], which in turn is related to early-stage HCC [95].…”

“…Consistently, the expression of glutamine synthetase, which catalyzes the opposite reaction, is increased in HCC patients with β-catenin mutations [92][93][94]. Glutamine synthetase is a target gene of β-catenin and overexpression of glutamine synthetase is highly correlated with β-catenin mutations [92], which in turn is related to early-stage HCC [95]. Moreover, glutamine synthetase expression is correlated with HCC progression [93,96].…”

“…Another enzyme involved in glutamine metabolism is the β-catenin target gene glutamine synthetase. Overexpression of glutamine synthetase is highly correlated with β-catenin mutation [92]. Mutant EGFR has been shown in other cancer types to activate Stat3 pathway by means of IL-6 upregulation [110].…”