Biomarkers that can predict the severity of disease, or that can act as targets for new forms of treatment, are very important in tailoring treatment for individuals, and improving both diagnostics and therapeutics overall. Gene expression analysis, which involves the polymerase chain reaction (PCR), plays an important role in identifying and validating genetic markers, as shown by a study in aggressive liver cancer led by researchers from the Cancer Science Institute (CSI) of Singapore and published in New England Journal of Medicine.
According to GLOBOCAN 2008, liver cancer is the third most common cause of death from cancer worldwide. Because of late diagnosis, the five-year survival rate can be as little as 10%. The researchers focused on hepatocellular carcinoma, the most common subtype of liver cancer.
“Surgical resection is the most viable treatment option for liver cancer. However, only early stage liver tumours are resectable, and most hepatocellular carcinoma present at late stage and are not resectable,” explains Daniel Tenen, Director of CSI Singapore. “Combination chemotherapy has been used for the treatment of liver cancer for many years, yet the overall survival rate has not seen much improvement. What urgently needs to be addressed is the development of more effective targeted therapies, and this is where our research comes in.”
Amongst the different forms of hepatocellular carcinoma, those that show characteristics of progenitor-cell gene expression and carry the oncofetal gene SALL4, a gene that is silenced in healthy adults, have poor outcomes.
To confirm the role of SALL4, a stem cell gene, the researchers took specimens from nearly 400 liver cancer patients with primary hepatocellular carcinoma and screened them for SALL4 expression. Of these liver cancer patients, 10-20% expressed high levels of SALL4, while 50% expressed low levels of the gene.
Using gene expression analysis, the researchers found gene signatures showing overexpression of proliferative and metastatic genes in SALL4-positive hepatocellular carcinomas. Clinicopathologic analysis of hepatocellular carcinoma specimens confirmed that SALL4 expression was linked with worse prognosis.
These results point to SALL4 being an independent marker for prognosis for HCC, and could mean that patients who express SALL4 should be given a more aggressive treatment regimen. However, this will have to be confirmed in prospective clinical trials, as this was just a retrospective study.
Stopping the expression of SALL4 in loss-of-function studies also showed that the gene has an important role in cell survival and tumorigenicity. Blocking its activity inhibited tumour formation in animal models. These suggest that SALL4 could be a target for drug treatment, and the team is developing a screening assay to find potential small molecule therapeutics. Two patents have already been filed on this research.
SALL4 is also linked with ovarian, endometrial, gastric, breast and lung cancers and leukaemia, and so knowing more about the gene and its role could help improve the diagnosis and treatment of other cancers as well.
Suzanne Elvidge is a freelance science, biopharma, business and health writer with more than 20 years of experience. She has written for a range of online and print publications including FierceBiomarkers, FierceDrugDelivery, European Life Science, the Journal of Life Sciences (now the Burrill Report), In Vivo, Life Science Leader, Nature Biotechnology, New Scientist, PR Week and Start-Up. She specialises in writing on pharmaceuticals, biotechnology, healthcare, science, lifestyle and green living, but can write on any topic given enough tea and chocolate biscuits. She lives just beyond the neck end of nowhere in the Peak District with her second-hand bookseller husband and two second-hand cats.