{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T07:46:00Z","timestamp":1769759160743,"version":"3.49.0"},"reference-count":31,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T00:00:00Z","timestamp":1645401600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicines"],"abstract":"<jats:p>CD44 has been demonstrated to play a pivotal role in regulating tumor cell progression, including hepatocellular carcinoma (HCC) development. Here, we aimed to establish a scoring system to evaluate the risk of developing HCC utilizing CD44-rs187115 SNP polymorphism. A prospective cohort of 120 individuals was enrolled in four groups: 19 non-metastatic HCC patients, 21 metastatic, 40 patients with hepatitis C-related cirrhosis, and 40 controls. Allelic discrimination of the CD44-rs187115 gene polymorphism was assessed using TaqMan genotyping assay. HCC patients with CT\/CC genotypes were more likely to have aggressive malignancy compared to TT carriers. A significant correlation was noted between the existence of CT\/CC genotypes and tumor size, multicentricity, infiltration, portal vein thrombosis, and metastasis. A CD44-incorporated Hepatocellular Carcinoma Risk Index Scoring Tool (CHRIST) was formulated utilizing clinical and genetic variables. A score &gt; 3 for HCC development demonstrated 87.5% sensitivity, 72.5% specificity, and a 76% positive predictive value (PPV) and 85% negative predictive value (NPV). Furthermore, a score &gt; 5 for HCC metastasis demonstrated 90.4% sensitivity, 68.4% specificity, a 76% PPV and 86% NPV. A similarly significant score was noted following a six-month re-evaluation. We conclude that CD44-rs187115 may serve as a reliable prognostic biomarker for HCC and that the CHRIST prognostic model is highly predictive of the development of HCC and metastatic HCC.<\/jats:p>","DOI":"10.3390\/medicines9020014","type":"journal-article","created":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T20:47:45Z","timestamp":1645476465000},"page":"14","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["CHRIST: CD44-Incorporated Hepatocellular Carcinoma Risk Index Scoring Tool\u2014A Novel Prognostic Scoring System for Hepatocellular Carcinoma Development and Aggressiveness"],"prefix":"10.3390","volume":"9","author":[{"given":"Ahmed Ali","family":"Khalifa","sequence":"first","affiliation":[{"name":"Department of Tropical Medicine, Clinical Pathology, Alexandria Faculty of Medicine, Alexandria 21433, Egypt"},{"name":"Department of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nermeen","family":"Abdeen","sequence":"additional","affiliation":[{"name":"Department of Tropical Medicine, Clinical Pathology, Alexandria Faculty of Medicine, Alexandria 21433, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neveen L.","family":"Mikhael","sequence":"additional","affiliation":[{"name":"Department of Tropical Medicine, Clinical Pathology, Alexandria Faculty of Medicine, Alexandria 21433, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sawsan","family":"Elmalah","sequence":"additional","affiliation":[{"name":"Department of Tropical Medicine, Clinical Pathology, Alexandria Faculty of Medicine, Alexandria 21433, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayman","family":"Elshayeb","sequence":"additional","affiliation":[{"name":"Department of Tropical Medicine, Clinical Pathology, Alexandria Faculty of Medicine, Alexandria 21433, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1002\/hep.30297","article-title":"Estimating Prevalence of Hepatitis C Virus Infection in the United States, 2013\u20132016","volume":"69","author":"Hofmeister","year":"2019","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1200\/JCO.2015.64.7412","article-title":"Future of Hepatocellular Carcinoma Incidence in the United States Forecast through 2030","volume":"34","author":"Petrick","year":"2016","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1111\/liv.13452","article-title":"Improved survival of patients with hepatocellular carcinoma and compensated hepatitis C virus-related cirrhosis who attained sustained virological response","volume":"37","author":"Bruno","year":"2017","journal-title":"Liver Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e33","DOI":"10.1016\/j.dld.2014.01.078","article-title":"SVR is associated with no risk reduction of HCC development in patients with HCV-related cirrhosis. A prospective, up-to 23 years, cohort follow-up study","volume":"46","author":"Crosignani","year":"2014","journal-title":"Dig. Liver Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1053\/j.seminoncol.2012.05.011","article-title":"Clinical implications of cancer stem cell biology in hepatocellular carcinoma","volume":"39","author":"Ji","year":"2012","journal-title":"Semin Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/onc.2013.260","article-title":"Alternative CD44 splicing in intestinal stem cells and tumorigenesis","volume":"33","author":"Guo","year":"2014","journal-title":"Oncogene"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1038\/nrc3023","article-title":"CD44: Can a cancer-initiating cell profit from an abundantly expressed molecule?","volume":"11","author":"Zoller","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1073\/pnas.0610117104","article-title":"Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma","volume":"104","author":"Prince","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/nm.2304","article-title":"The cancer stem cell: Premises, promises and challenges","volume":"17","author":"Clevers","year":"2011","journal-title":"Nat. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/nrc2620","article-title":"Transitions between epithelial and mesenchymal states: Acquisition of malignant and stem cell traits","volume":"9","author":"Polyak","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1002\/hep.23221","article-title":"Comprehensive analysis of the independent effect of twist and snail in promoting metastasis of hepatocellular carcinoma","volume":"50","author":"Yang","year":"2009","journal-title":"Hepatology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1172\/JCI40665","article-title":"CHD1L promotes hepatocellular carcinoma progression and metastasis in mice and is associated with these processes in human patients","volume":"120","author":"Chen","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1016\/j.ajpath.2010.11.077","article-title":"Role of hyaluronan-mediated CD44 signaling in head and neck squamous cell carcinoma progression and chemoresistance","volume":"178","author":"Wang","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"784","DOI":"10.2174\/156652408786733667","article-title":"CD44 and EpCAM: Cancer-initiating cell markers","volume":"8","author":"Marhaba","year":"2008","journal-title":"Curr. Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2087204","DOI":"10.1155\/2016\/2087204","article-title":"The Importance of CD44 as a Stem Cell Biomarker and Therapeutic Target in Cancer","volume":"2016","author":"Thapa","year":"2016","journal-title":"Stem Cells Int."},{"key":"ref_16","first-page":"941","article-title":"Role of TGF-beta1 and C-Kit Mutations in the Development of Hepatocellular Carcinoma in Hepatitis C Virus-Infected Patients: In vitro Study","volume":"84","author":"Ismail","year":"2019","journal-title":"Biochemistry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"13143","DOI":"10.1038\/s41598-018-31421-6","article-title":"The osteopontin-CD44 axis in hepatic cancer stem cells regulates IFN signaling and HCV replication","volume":"8","author":"Shirasaki","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_18","first-page":"1","article-title":"Surgery and portal hypertension","volume":"1","author":"Child","year":"1964","journal-title":"Major Probl. Clin. Surg."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1002\/hep.21563","article-title":"The model for end-stage liver disease (MELD)","volume":"45","author":"Kamath","year":"2007","journal-title":"Hepatology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1055\/s-2007-1007122","article-title":"Prognosis of hepatocellular carcinoma: The BCLC staging classification","volume":"19","author":"Llovet","year":"1999","journal-title":"Semin Liver Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1007\/978-1-60327-411-1_19","article-title":"The TaqMan method for SNP genotyping","volume":"578","author":"Shen","year":"2009","journal-title":"Methods Mol. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"S136","DOI":"10.1016\/S0168-8278(02)00432-4","article-title":"Hepatocellular carcinoma: Present status and future prospects","volume":"38","author":"Llovet","year":"2003","journal-title":"J. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4708","DOI":"10.19082\/4708","article-title":"Evaluation of CD44 and CD133 as markers of liver cancer stem cells in Egyptian patients with HCV-induced chronic liver diseases versus hepatocellular carcinoma","volume":"9","author":"Rozeik","year":"2017","journal-title":"Electron. Phys."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/S0168-8278(00)80192-0","article-title":"Protein expression of CD44 (standard and variant isoforms) in hepatocellular carcinoma: Relationships with tumor grade, clinicopathologic parameters, p53 expression, and patient survival","volume":"32","author":"Endo","year":"2000","journal-title":"J. Hepatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"231474","DOI":"10.1155\/2014\/231474","article-title":"CD44 gene polymorphisms on hepatocellular carcinoma susceptibility and clinicopathologic features","volume":"2014","author":"Chou","year":"2014","journal-title":"Biomed Res. Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"47431","DOI":"10.18632\/oncotarget.10164","article-title":"Prognostic value of the expression of cancer stem cell-related markers CD133 and CD44 in hepatocellular carcinoma: From patients to patient-derived tumor xenograft models","volume":"7","author":"Zhao","year":"2016","journal-title":"Oncotarget"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s12935-016-0325-2","article-title":"Prognostic value of CD44 expression in patients with hepatocellular carcinoma: Meta-analysis","volume":"16","author":"Luo","year":"2016","journal-title":"Cancer Cell Int."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1007\/s00595-009-4065-y","article-title":"Prognostic nutritional index: A tool to predict the biological aggressiveness of gastric carcinoma","volume":"40","author":"Nozoe","year":"2010","journal-title":"Surg. Today"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2633","DOI":"10.1016\/j.ejca.2011.03.028","article-title":"A comparison of inflammation-based prognostic scores in patients with cancer. A Glasgow Inflammation Outcome Study","volume":"47","author":"Proctor","year":"2011","journal-title":"Eur. J. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"S206","DOI":"10.1111\/j.1872-034X.2007.00186.x","article-title":"Cancer of the Liver Italian Program (CLIP) score for staging hepatocellular carcinoma","volume":"37","author":"Daniele","year":"2007","journal-title":"Hepatol. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1053\/j.gastro.2013.03.051","article-title":"A hepatocellular carcinoma 5-gene score associated with survival of patients after liver resection","volume":"145","author":"Nault","year":"2013","journal-title":"Gastroenterology"}],"container-title":["Medicines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2305-6320\/9\/2\/14\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:23:41Z","timestamp":1760135021000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2305-6320\/9\/2\/14"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,21]]},"references-count":31,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["medicines9020014"],"URL":"https:\/\/doi.org\/10.3390\/medicines9020014","relation":{},"ISSN":["2305-6320"],"issn-type":[{"value":"2305-6320","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,21]]}}}