SOX9 Expression Is Superior to Other Stem Cell Markers K19... : The American Journal of Surgical Pathology (original) (raw)

Original Articles

SOX9 Expression Is Superior to Other Stem Cell Markers K19 and EpCAM in Predicting Prognosis in Hepatocellular Carcinoma

Ruzinova, Marianna B. MD, PhD*; Ma, Changqing MD, PhD*; Brunt, Elizabeth M. MD*; Goss, Charles W. PhD†; Vachharajani, Neeta MBBS‡; Chapman, William C. MD‡; Liu, Ta-Chiang MD, PhD*

Departments of *Pathology and Immunology

‡Surgery

†Division of Biostatistics, Washington University School of Medicine, Saint Louis, MO

Conflicts of Interest and Source of Funding: Supported in part by Digestive Disease Research Core Center at Washington University by grant P30DK052574 from the NIH. T.-C.L. was funded by NIH grants R01 DK125296 and R01 DK124274. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Marianna B. Ruzinova, MD, PhD, Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8118, Saint Louis, MO 63110 (e-mail: [email protected]).

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Abstract

Various stem cell markers (eg, epithelial cell adhesion molecule [EpCAM], cytokeratin 19 [K19]) have been reported as predictors of poor prognosis in hepatocellular carcinoma (HCC). However, the data remain limited, particularly in Western populations, and are often contradictory. In this study, the prognostic value of positive SOX9 immunohistochemistry was compared with that of more established markers EpCAM and K19 in a large cohort (n=216) of North American patients. The independent HCC cohort in The Cancer Gene Atlas (n=360) was utilized to validate our findings. Finally, molecular signatures associated with _SOX9_-high HCC were determined. We found that the expression of SOX9, but not EpCAM or K19, was associated with worse overall survival and disease-free survival (DFS) and was an independent prognostic factor for DFS in our North American cohort, in which hepatitis C infection was the most common underlying etiology. High SOX9 mRNA level, but not increased expression of EpCAM mRNA or K19 mRNA, was also associated with worse DFS and was an independent prognostic factor for DFS in The Cancer Gene Atlas cohort. This group had underlying causes, including an increased incidence of hepatitis B, significantly different from our initial cohort. High SOX9 mRNA level is associated with molecular pathways important in HCC pathogenesis. Increased SOX9 expression is clinically and biologically relevant for HCC arising in patients with a variety of underlying etiologies. Immunohistochemistry for SOX9 is a reliable proxy for increased SOX9 mRNA and can be used to predict prognosis in HCC cases.