Genomic landscape of hepatocellular carcinoma in Egyptian patients by whole exome sequencing.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Chronic hepatitis and liver cirrhosis lead to accumulation of genetic alterations driving HCC pathogenesis. This study is designed to explore genomic landscape of HCC in Egyptian patients by whole exome sequencing. METHODS: Whole exome sequencing using Ion Torrent was done on 13 HCC patients, who underwent surgical intervention (7 patients underwent living donor liver transplantation (LDLT) and 6 patients had surgical resection}. RESULTS: Mutational signature was mostly S1, S5, S6, and S12 in HCC. Analysis of highly mutated genes in both HCC and Non-HCC revealed the presence of highly mutated genes in HCC (AHNAK2, MUC6, MUC16, TTN, ZNF17, FLG, MUC12, OBSCN, PDE4DIP, MUC5b, and HYDIN). Among the 26 significantly mutated HCC genes-identified across 10 genome sequencing studies-in addition to TCGA, APOB and RP1L1 showed the highest number of mutations in both HCC and Non-HCC tissues. Tier 1, Tier 2 variants in TCGA SMGs in HCC and Non-HCC (TP53, PIK3CA, CDKN2A, and BAP1). Cancer Genome Landscape analysis revealed Tier 1 and Tier 2 variants in HCC (MSH2) and in Non-HCC (KMT2D and ATM). For KEGG analysis, the significantly annotated clusters in HCC were Notch signaling, Wnt signaling, PI3K-AKT pathway, Hippo signaling, Apelin signaling, Hedgehog (Hh) signaling, and MAPK signaling, in addition to ECM-receptor interaction, focal adhesion, and calcium signaling. Tier 1 and Tier 2 variants KIT, KMT2D, NOTCH1, KMT2C, PIK3CA, KIT, SMARCA4, ATM, PTEN, MSH2, and PTCH1 were low frequency variants in both HCC and Non-HCC. CONCLUSION: Our results are in accordance with previous studies in HCC regarding highly mutated genes, TCGA and specifically enriched pathways in HCC. Analysis for clinical interpretation of variants revealed the presence of Tier 1 and Tier 2 variants that represent potential clinically actionable targets. The use of sequencing techniques to detect structural variants and novel techniques as single cell sequencing together with multiomics transcriptomics, metagenomics will integrate the molecular pathogenesis of HCC in Egyptian patients.

Impact of circ-0000221 in the Pathogenesis of Hepatocellular via Modulation of miR-661-PTPN11 mRNA Axis.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in Egypt. A deep understanding of the molecular events occurring in HCC can facilitate the development of novel diagnostic and/or therapeutic approaches. In the present study, we describe a novel axis of hsa-circ-0000221-miR-661-PTPN11 mRNA proposed by in silico and in vitro analysis and its role in HCC pathogenesis. We observe a reduction in the expression levels of hsa-circ-0000221 and PTPN11 mRNA in HCC patients' sera tested compared with control subjects. The reduction occurs with a concomitant increase in the expression of miR-661. Furthermore, the introduction of exogenous hsa-circ-0000221 into Hep-G2 or SNU449 cell lines results in detectable decrease in cellular viability and an increase in apoptotic manifestations that is associated with G1 accumulation and CCDN1 overexpression. Altogether, these findings indicate the tumor-suppressive role of hsa-circ-0000221 in HCC, which acts through miR-661 inhibition, along with a subsequent PTPN11 mRNA increase, where PTPN11 is known to inhibit cell proliferation in many forms of cancer. Our study encourages further investigation of the role of circRNAs in cancer and their potential use as molecular biomarkers.

Efficacy of loco-regional treatment for hepatocellular carcinoma prior to living donor liver transplantation: a report from a single center in Egypt.

BACKGROUND AND AIM: The number of loco-regional therapies (LRTs) for hepatocellular carcinoma (HCC) has increased dramatically during the past decade, bridging or downstaging patients on the waiting list for liver transplantation. This study aimed to analyze the outcomes of LRTs prior to living donor liver transplantation in patients with HCC. METHODS: Sixty-two HCC patients received living donor liver transplantation at Ain Shams Center for Organ Transplantation over a 2-year period. Data from 29 HCC patients were analyzed. Twenty patients (68.97%) met the Milan Criteria and 4 patients (13.8%) exceeded the Milan Criteria, but met the University of California, San Francisco Criteria. Five patients (17.2%) exceeded the University of California, San Francisco Criteria. All patients underwent preoperative LRTs. The protocol of bridging/downstaging, methods, duration of follow-up, the number of patients who were successfully downstaged before liver transplantation (LT), and their outcomes after LT were recorded. RESULTS: There was a decrease in the mean overall size of focal lesions (from mean 5.46 to 4.11 cm) in the last abdominal computed tomography (CT) scan after LRT (p=0.0018). Discrepancies between the radiological findings and histopathology were as follows: in 16 patients (55.17%) the CT findings were consistent with the histopathological examination of the explanted liver. Underestimated tumor stage was documented in 10 patients (34.48%), and was overestimated by CT scan findings in 3 patients (10.34%). The 1-year survival rate was 93%. No patient had HCC recurrence after median follow-up of 21 months (range 1-46 months). CONCLUSION: These results encouraged tumor bridging/downstaging as a potential treatment option among carefully selected patients with HCC beyond conventional criteria for LT. Further studies on a large number of patients are necessary.