Abstract Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. The lack of effective therapeutic options combined with an increasing incidence rate in the past 20 years calls for the identification of early stage HCC molecular markers. SH2D4A maps to human chromosome 8p21.3 and encodes for SH(2)A. The chromosomal region containing SH2D4A has been shown to be frequently lost in colorectal, lung and HCC cancers. Using a combination of gene expression, protein level and clinical data, our study aimed to investigate the SH2D4A involvement in HCC pathogenesis. Transcriptome analysis (Affymetrix) performed on 37 HCC samples (matched with their corresponding non-neoplastic liver parenchyma) and 5 normal liver donors revealed that SH2D4A is downregulated in HCC. These results were validated by qPCR in fresh frozen tissues [25 out of 37 samples (67.6%) showed SH2D4A downregulation; p<0.026]. Furthermore, the combination of qPCR data and immunohistochemistry staining performed on corresponding formalin-fixed paraffin embedded (FFPE) needle biopsies demonstrated a direct correlation between the SH2D4A mRNA expression and SH(2)A protein levels. Additional data obtained from the analysis of a tissue microarray (TMA) containing 336 informative specimens confirmed that SH(2)A protein levels are frequently reduced in HCC and additionally in cirrhosis nodules compared to normal liver samples. To conclude, our study revealed that SH2D4A is frequently downregulated in HCC samples thus corroborating its putative role as tumor suppressor gene. In addition, we provide new evidence for SH2D4A involvement in HCC pathogenesis demonstrating for the first time its deregulation also in cirrhotic nodules. Citation Format: Mariacarla Andreozzi, Luca Quagliata, Michal Kovac, Luigi Tornillo, Zuzanna Makowska, Marcus Heim, Karl Heinimann, Salvatore Piscuoglio, Luigi Maria Terracciano. SH2D4A is frequently downregulated in hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4685. doi:10.1158/1538-7445.AM2013-4685 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.