Friday, August 12, 2011

Chromatin remodelling gene ARID2 is mutated in hepatocellular carcinoma

Chromatin remodelling gene ARID2 is mutated in hepatocellular carcinoma
by ecancer reporter Clare Sansom

Hepatocellular carcinoma (HCC) is the commonest form of liver cancer. It is relatively rare in most Western countries but is the most commonly-occurring tumour in some parts of Africa and South-East Asia.

It has a generally poor prognosis and causes well over half a million deaths worldwide each year, about half in China. These contrasting incidence patterns have been attributed to differences in the prevalence of hepatitis B (HBV) and hepatitis C (HCV) infection, which are the most important risk factors for this disease.

The genetic changes leading to the development of hepatocellular carcinoma are still unclear, and in particular, the extent to which HBV-associated, HCV-associated and non-viral liver cancers are associated with distinct molecular pathways is unknown.

A team of Chinese and American researchers led by Kenneth Kinzler and Michael Torbenson from Johns Hopkins School of Medicine, Baltimore, Maryland, USA and Jianqiang Cai from Peking Union Medical College, Beijing, China has now sequenced the exomes, or protein-coding genomes, from ten hepatocellular carcinoma patients known to be infected by HCV.

They sequenced the protein-coding sequences of about 18,000 genes from tumour and matched normal tissue from each individual using massively parallel Illlumina technology.

A total of 429 non-synonymous somatic mutations were observed in the tumours in this set, with a range of 17-85 mutations per tumour.

The researchers selected five genes found to be mutated in more than one tumour for further analysis: CTNNB1, TP53, ARID2, DMXL1, and NLRP1. Only the first two of these had previously been observed to be mutated in HCC.

These five genes were then sequenced in a further 23 hepatocellular cancer cases. Of the three not previously associated with HCC, ARID2 was mutated in the highest proportion (18.3%) of the complete set of HCC tumours tested.

All these mutations were predicted to inactivate the gene, indicating that it is a novel tumour suppressor gene.

The protein encoded by this gene forms part of a chromatin re-modelling complex that facilitates activation of transcription by nuclear receptors. All the inactivated mutations discovered were in zinc-finger domains and would have prevented the protein from binding to its target DNA.

The group then sequenced all five genes with multiple mutations in the original ten tumours in a total of 106 further tumour samples where the cancers were known to be associated with infection with HBV, HCV, both HBV and HCV, or neither virus. Mutations in ARID2 were found to be present in a significantly higher proportion of HCV-associated tumours (six out of 43, or 14%) compared to HBV-associated tumours (one out of 50).

It is likely, but cannot be proven, that this difference is directly due to the type of viral infection.

Mutations in this gene were also seen to be correlated with CTNNB1 mutations, but mutually exclusive with those in TP53.

The researchers conclude by speculating on the mechanism through which ARID2 inactivation might promote carcinoma development in HCC-infected individuals. They suggest that inactivation of this gene might repress interferon-induced signalling in the Jak-STAT pathway, subversion of which is thought to promote the persistence of HCV infection.

Source: Li, M., Zhao, H., Zhang, X. and 16 others (2011). Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nature Genetics, published online ahead of print 7 August 2011. 10.1038/ng.903

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