{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:52:57Z","timestamp":1791175977818,"version":"4.1.0"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Hepatocellular carcinoma (HCC) exhibits significant morphological heterogeneity that has traditionally been attributed to etiological, environmental, and biological factors. Recent evidence suggests, however, that genetic background may influence tumor characteristics and behavior in HCC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>To investigate associations between established HCC genetic risk factors and first-order radiomic features.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We evaluated a retrospective cohort of 210 patients with HCC who underwent contrast-enhanced MRI and genetic profiling for three established HCC risk variants (PNPLA3 rs738409-G, TM6SF2 rs58542926-T, and MAU2 rs58489806-T). We screened first-order radiomic features in the full cohort and then focused the primary analysis on 77 treatment-naive patients whose tumor morphology had not been modified by therapy. Patients were stratified into at-risk (\u22651 risk allele, n=52) and wild-type (no risk alleles, n=25) groups. Eighteen first-order radiomic features were screened using the Mann-Whitney U test and AUC analysis. The leading feature, kurtosis, was then subjected to univariate and multivariate analysis for clinical and imaging features to identify any confounding effect. In addition, a 10-fold cross-validated cutpoint stability, sensitivity analysis, and Cox\/Kaplan-Meier survival analysis were also conducted.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 18 features, kurtosis best distinguished at-risk from wild-type genotypes in treatment-naive patients (AUC\u00a0=\u00a00.67, p=0.014), with wild-type tumors showing more uniform, sharply peaked intensity patterns. Tumor volume correlated modestly with kurtosis (Spearman\u2019s \u03c1=0.45, p&amp;lt;0.0001), but volume alone did not discriminate genotype (Mann-Whitney U, p=0.3994). The genotype-kurtosis association remained significant after adjusting for volume and shape (ANCOVA, p=0.029) and strengthened after adjusting for nine clinical\/demographic covariates (p=0.003), indicating kurtosis reflects biological information beyond tumor size. The empirical cutpoint was stable across 10-fold cross-validation (mean=3.35, SD\u00a0=\u00a00.05), and results were unchanged in sensitivity analysis. Kurtosis was not associated with overall survival (Cox HR\u00a0=\u00a01.19, p=0.13). No genotype-related discrimination was observed in the pooled full cohort, consistent with treatment-related alteration of tumor texture.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In a cohort of 210 genetically profiled patients with HCC, genotype-related radiomic features were not apparent when treated and untreated tumors were analyzed together. However, restricting the analysis to the treatment-naive subgroup (n=77) revealed tumor kurtosis as a reproducible, biologically plausible first-order imaging correlate of established HCC genetic risk status.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1754407","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:32:11Z","timestamp":1791174731000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic risk stratification reveals distinct first-order radiomic phenotypes in hepatocellular carcinoma"],"prefix":"10.3389","volume":"16","author":[{"given":"Mohamed","family":"Eltaher","sequence":"first","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaina","family":"Boriek","sequence":"additional","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohan","family":"Amare","sequence":"additional","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Awj","family":"Twam","sequence":"additional","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prasun","family":"Jalal","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Long","sequence":"additional","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene","family":"Koay","sequence":"additional","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khaled M.","family":"Elsayes","sequence":"additional","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rikita","family":"Hatia","sequence":"additional","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manal","family":"Hassan","sequence":"additional","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Fuentes","sequence":"additional","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(22)01200-4","article-title":"Hepatocellular carcinoma","volume":"400","author":"Vogel","year":"2022","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.cld.2022.08.004","article-title":"Hepatocellular carcinoma: New developments","volume":"27","author":"Ganesan","year":"2023","journal-title":"Clin Liver Dis"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001624","article-title":"Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis","volume":"11","author":"Singal","year":"2014","journal-title":"PLoS Med"},{"key":"B4","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1097\/hep.0000000000000800","article-title":"Genome-wide association study identifies high-impact susceptibility loci for HCC in North America","volume":"80","author":"Hassan","year":"2024","journal-title":"Hepatology"},{"key":"B5","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1016\/j.jhep.2016.03.011","article-title":"PNPLA3 gene in liver diseases","volume":"65","author":"Tr\u00e9po","year":"2016","journal-title":"J Hepatol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"97","DOI":"10.4261\/1305-3825.Dir.5973-12.1","article-title":"Quantitative morphometric analysis of hepatocellular carcinoma: Development of a programmed algorithm and preliminary application","volume":"19","author":"Yap","year":"2013","journal-title":"Diagn Interv Radiol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"4006","DOI":"10.1038\/ncomms5006","article-title":"Decoding tumour phenotype by noninvasive imaging using a quantitative radiomics approach","volume":"5","author":"Aerts","year":"2014","journal-title":"Nat Commun"},{"key":"B8","doi-asserted-by":"publisher","first-page":"43","DOI":"10.3748\/wjg.v29.i1.43","article-title":"Current status and future perspectives of radiomics in hepatocellular carcinoma","volume":"29","author":"Miranda","year":"2023","journal-title":"World J Gastroenterol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1226","DOI":"10.1053\/j.gastro.2015.05.061","article-title":"Genetic landscape and biomarkers of hepatocellular carcinoma","volume":"149","author":"Zucman-Rossi","year":"2015","journal-title":"Gastroenterology"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2006.01.015","article-title":"User-guided 3D active contour segmentation of anatomical structures: Significantly improved efficiency and reliability","volume":"31","author":"Yushkevich","year":"2006","journal-title":"NeuroImage"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0230798","article-title":"Applying univariate vs. multivariate statistics to investigate therapeutic efficacy in (pre)clinical trials: A Monte Carlo simulation study on the example of a controlled preclinical neurotrauma trial","volume":"15","author":"Todorov","year":"2020","journal-title":"PLoS One"},{"key":"B12","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1148\/radiology.143.1.7063747","article-title":"The meaning and use of the area under a receiver operating characteristic (ROC) curve","volume":"143","author":"Hanley","year":"1982","journal-title":"Radiology"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/s0895-4356(96)00236-3","article-title":"A simulation study of the number of events per variable in logistic regression analysis","volume":"49","author":"Peduzzi","year":"1996","journal-title":"J Clin Epidemiol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28638","article-title":"Genotype-phenotype correlation of CTNNB1 mutations reveals different \u03b2-catenin activity associated with liver tumor progression","volume":"64","author":"Rebouissou","year":"2016","journal-title":"Hepatology"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1007\/s00261-023-03876-3","article-title":"Can MRI features predict clinically relevant hepatocellular carcinoma genetic subtypes","volume":"48","author":"Liu","year":"2023","journal-title":"Abdom Radiol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.118.222893","article-title":"Introduction to radiomics","volume":"61","author":"Mayerhoefer","year":"2020","journal-title":"J Nucl Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.crad.2016.01.023","article-title":"Heterogeneity of non-cancerous liver parenchyma on gadoxetic acid-enhanced MRI: An imaging biomarker for hepatocellular carcinoma development in chronic liver disease","volume":"71","author":"Asayama","year":"2016","journal-title":"Clin Radiol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1186\/s12880-017-0212-x","article-title":"Texture-based classification of different single liver lesion based on SPAIR T2W MRI images","volume":"17","author":"Li","year":"2017","journal-title":"BMC Med Imaging"},{"key":"B19","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s12880-019-0321-9","article-title":"Radiomics-based classification of hepatocellular carcinoma and hepatic haemangioma on precontrast magnetic resonance images","volume":"19","author":"Wu","year":"2019","journal-title":"BMC Med Imaging"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2018.e00987","article-title":"MRI texture analysis for differentiation of malignant and benign hepatocellular tumors in the non-cirrhotic liver","volume":"4","author":"Stocker","year":"2018","journal-title":"Heliyon"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics16142266","article-title":"Why radiomics rarely reaches the clinic: Reproducibility, validation, and evidence gap\u2014a critical narrative review","volume":"16","author":"Pozzi","year":"2026","journal-title":"Diagnostics"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1754407\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:32:17Z","timestamp":1791174737000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1754407\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,5]]},"references-count":21,"alternative-id":["10.3389\/fonc.2026.1754407"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1754407","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,5]]},"article-number":"1754407"}}