Aim: Increased serum alpha-fetoprotein (AFP) levels are associated with specific molecular subclasses of hepatocellular carcinoma (HCC), supporting AFP as a predictive or therapeutic biomarker for precision treatment ...Aim: Increased serum alpha-fetoprotein (AFP) levels are associated with specific molecular subclasses of hepatocellular carcinoma (HCC), supporting AFP as a predictive or therapeutic biomarker for precision treatment of this disease. Considering recent efforts to validate HCC molecular classification systems across different populations, we applied existing signature-based classification templates to Hawaii cohorts and examined whether associations between HCC molecular sub-class, AFP levels, and clinical features found elsewhere can also be found in Hawaii, a region with a unique demographic and risk factor profile for HCC. Methods: Whole-genome expression profiling was performed on HCC tumors collected from 40 patients following partial hepatectomy. Tumors underwent transcriptome-based categorization into 3 molecular sub-classes (S1, S2, and S3). Patient groups based on molecular sub-class and AFP level were then compared with regards to clinical features and survival. Differences associated with AFP level and other clinical parameters were also examined at the gene signature level by gene set enrichment analysis. Results: Statistically confident (false discovery rate < 0.05) sub-classifications were made in 98% (39/40) of tumors. Patient sub-groups differed significantly with regards to serum AFP level, with significantly lower levels in the S3 sub-group as compared to S1 (P = 0.048) and S2 (P = 0.010). Serum AFP > 400 ng/mL predicted significant tumor enrichment for genes corresponding to MYC target activation, high cell proliferation, poor clinical prognosis, and the S2 sub-class. AFP > 400 ng/mL and non-S3 tumor classification were found to be significant predictors of overall survival. Conclusion: Distinct sub-classes of HCC associated with different molecular features and survival outcomes can be detected with statistical confidence in a Pacific Island cohort. Molecular classification signatures and other predictive markers for HCC that are valid for all patient populations are needed to support multi-center efforts to develop targeted therapies for HCC.展开更多
Mutations involving CTNNB1,the gene encoding beta-catenin,and other molecular alterations that affect the Wnt/beta-catenin signaling pathway are exceptionally common in hepatocellular carcinoma.Several of these altera...Mutations involving CTNNB1,the gene encoding beta-catenin,and other molecular alterations that affect the Wnt/beta-catenin signaling pathway are exceptionally common in hepatocellular carcinoma.Several of these alterations have also been associated with scarcity of immune cells in the tumor microenvironment and poor clinical response to immune checkpoint inhibitor therapy.In light of these associations,tumor biomarkers of betacatenin status could have the potential to serve as clinical predictors of immunotherapy outcome.This editorial review article summarizes recent pre-clinical and clinical research pertaining to associations between beta-catenin activation and diminished anti-tumor immunity.Potential non-invasive biomarkers that may provide a window into this oncogenic mechanism of immune evasion are also presented and discussed.展开更多
文摘Aim: Increased serum alpha-fetoprotein (AFP) levels are associated with specific molecular subclasses of hepatocellular carcinoma (HCC), supporting AFP as a predictive or therapeutic biomarker for precision treatment of this disease. Considering recent efforts to validate HCC molecular classification systems across different populations, we applied existing signature-based classification templates to Hawaii cohorts and examined whether associations between HCC molecular sub-class, AFP levels, and clinical features found elsewhere can also be found in Hawaii, a region with a unique demographic and risk factor profile for HCC. Methods: Whole-genome expression profiling was performed on HCC tumors collected from 40 patients following partial hepatectomy. Tumors underwent transcriptome-based categorization into 3 molecular sub-classes (S1, S2, and S3). Patient groups based on molecular sub-class and AFP level were then compared with regards to clinical features and survival. Differences associated with AFP level and other clinical parameters were also examined at the gene signature level by gene set enrichment analysis. Results: Statistically confident (false discovery rate < 0.05) sub-classifications were made in 98% (39/40) of tumors. Patient sub-groups differed significantly with regards to serum AFP level, with significantly lower levels in the S3 sub-group as compared to S1 (P = 0.048) and S2 (P = 0.010). Serum AFP > 400 ng/mL predicted significant tumor enrichment for genes corresponding to MYC target activation, high cell proliferation, poor clinical prognosis, and the S2 sub-class. AFP > 400 ng/mL and non-S3 tumor classification were found to be significant predictors of overall survival. Conclusion: Distinct sub-classes of HCC associated with different molecular features and survival outcomes can be detected with statistical confidence in a Pacific Island cohort. Molecular classification signatures and other predictive markers for HCC that are valid for all patient populations are needed to support multi-center efforts to develop targeted therapies for HCC.
基金supported by U.S.National Institutes of Health grants(R01CA161209-06,U54MD007584-07,5P30CA071789)Hawaii Legislative Act(265(19)HB654HD1SD1CD1).
文摘Mutations involving CTNNB1,the gene encoding beta-catenin,and other molecular alterations that affect the Wnt/beta-catenin signaling pathway are exceptionally common in hepatocellular carcinoma.Several of these alterations have also been associated with scarcity of immune cells in the tumor microenvironment and poor clinical response to immune checkpoint inhibitor therapy.In light of these associations,tumor biomarkers of betacatenin status could have the potential to serve as clinical predictors of immunotherapy outcome.This editorial review article summarizes recent pre-clinical and clinical research pertaining to associations between beta-catenin activation and diminished anti-tumor immunity.Potential non-invasive biomarkers that may provide a window into this oncogenic mechanism of immune evasion are also presented and discussed.
