Identifying Hepatocellular Carcinoma (HCC) Diagnostic and Prognostic Genetic Markers

By Maia Poon
Senior Category (Grades 11-12)
Study | Biology

OBJECTIVE
To identify genetic markers for the diagnosis and prognosis of hepatocellular carcinoma (HCC).

INTRODUCTION
Hepatocellular carcinoma (HCC) is the fifth most common cancer globally, representing 75–85% of primary liver cancers and the fastest rising cause of cancer-related death in Canada and the U.S. HCC is often caused by chronic liver diseases, including hepatitis B, hepatitis C, and liver cirrhosis, resulting in the uncontrolled proliferation of hepatocytes. As cancer cells, these hepatocytes possess DNA modifications (mutation or methylation) resulting in over– and underexpression of genes.
Despite numerous studies on the potential of DNA modifications to be diagnostic markers for HCC, genetic markers cannot be applicable to diagnosis or surveillance unless they can be detected in the peripherals (blood or urine), so that liver biopsy is not required. Liver biopsies result in high risk of complications including tumour seeding and bleeding, which lead to cancer metastasis and worsened prognosis for individuals with HCC. Furthermore, in contrast to most solid tumors lacking in liver cirrhosis, complications from liver cirrhosis in HCC make prognosis much more difficult to predict. Therefore, novel biomarkers are needed to better predict prognosis in HCC patients.

RELEVANT APPLICATION
Diagnostic biomarkers are used to determine whether a patient has a cancer or other disease, and subsequently, which treatment should be used. An increasing number of disease subtypes with significantly different prognoses and responses to specific types of treatment are being discovered; for instance, HCC is one subtype of liver cancer. Genetic markers can thus be used to determine a person’s susceptibility to a cancer, whether a person has a cancer, the prognosis of a cancer patient, and how to treat the cancer. Genetic markers include harmful variants inherited in an autosomal dominant fashion that results in familial cancer susceptibility syndromes. Other inherited genetic markers are not correlated with named syndromes, but can increase cancer risk. This study aimed to find genetic markers that could be identified in the peripherals, and thus, be used to help diagnose HCC. In addition, it sought to find genetic markers correlated with certain prognoses, to be used to better predict the outcomes of HCC. A potential finding was also a genetic marker that could help determine a person’s susceptibility to HCC.

EXPERIMENTAL DESIGN
This study compiles GEO Datasets that analyze gene expression of HCC tumours compared to paired normal liver tissue to identify significantly differentially expressed genes in cancer tissue vs. normal tissue. This study then used Human Protein Atlas (HPA) protein expression analysis, and a PubMed literature review, to determine whether these identified genes produce proteins that could be detected in the peripherals and be diagnostic or prognostic markers. HPA data also helped determine whether these differentially expressed genes could be prognostic markers.

RESULTS AND INTERPRETATION
All sixteen differentially expressed genes were expressed at similar levels in both Geo DataSet studies. Two potential diagnostic markers were identified: CLEC1B and FCN3. Six potential prognostic markers were identified: CLEC1B, CLEC4M, ECM1, FCN3, and RACGAP1. Fifteen of the sixteen genes were under-expressed in HCC tissue. Therefore, an advantage of RACGAP1 is it is generally over-expressed in HCC, and thus, easier to identify. Of the sixteen genes, RACGAP1 and ECM1 were the most versatile prognostic markers for HCC: their expression is associated with worse clinical outcomes, overall and disease-free survival, recurrence, and metastatic potential. An advantage of ECM1 is it is found in the blood, meaning liver biopsy is not needed to identify it. CLEC1B and FCN3 both have calcium-independent lectin activity, and are strong diagnostic markers that are expressed in the blood. Thus, other genes with calcium-independent lectin activity may also be significant HCC markers.

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