Lipika Goyal | Search PubMed

PubMed2026

Promises and Pitfalls of ctDNA testing in the Management of Cholangiocarcinoma.

Diagnosis and treatment of cholangiocarcinoma is often limited by the availability of tissue biopsies for genomic analysis. Liquid biopsies using blood circulating tumor DNA (ctDNA) have emerged as a valuable and non-invasive alternative to conventional testing. ctDNA analysis has advanced the treatment paradigm for cholangiocarcinoma (CCA) by identifying targetable mutations and molecular mechanisms of treatment resistance. Additionally, it has shown preliminary promise in stratifying patients for adjuvant systemic therapy and enabling earlier detection of relapse. However, current ctDNA platforms face biological and technical challenges that limit their sensitivity for certain mutation types (i.e. gene fusions and amplifications), which are commonly found in CCA. To overcome these hurdles, new sequencing techniques and analytic methods involving artificial intelligence, epigenetic profiling, and diverse reference genomes are being developed. These advanced technologies underscore the promise of ctDNA testing as an indispensable tool in the management and study of CCAs.

Cholangiocarcinoma↗

PubMed2026

Plasma cell-CD8+ T cell co-enrichment distinguishes immunotherapy-responsive hepatocellular carcinoma subtypes.

BACKGROUND: Hepatocellular carcinoma (HCC) is characterised by significant racial disparities in incidence and outcomes, yet whether these reflect distinct tumour biology or differential distribution of molecular subtypes among immunotherapy patients remains unclear. METHODS: We characterised molecular heterogeneity among 46 patients with HCC of differing background population from the NCI-CLARITY cohort receiving immune checkpoint inhibitor therapy, using transcriptomic and genomic profiling, with validation across multiple independent cohorts. RESULTS: Differential expression analysis comparing African American versus non-African American patients identified 126 genes, of which 55 demonstrated tumour-specific expression across independent validation cohorts with paired tumour-normal samples. Consensus clustering revealed two molecular subtypes with no significant race association, indicating these clusters capture tumour-intrinsic biology rather than ancestry. The genomic landscape showed minimal differences between subtypes. A prognostic signature derived from these expression profiles demonstrated significant risk stratification in the NCI-CLARITY cohort and TCGA-LIHC, but not in Asian cohorts, suggesting population-specific applicability. Immune deconvolution revealed that the two subtypes represent distinct immune microenvironments: one subtype exhibited markedly elevated plasma cell infiltration with strong plasma cell-CD8+T cell correlation suggesting coordinated adaptive immunity, along with elevated tertiary lymphoid structure signatures. The other subtype showed regulatory T cell-macrophage correlation and enrichment for immune-excluded phenotypes. The immune-enriched subtype trended towards higher immunotherapy response rates. CONCLUSIONS: Molecular heterogeneity in HCC reveals distinct tumour-immune ecosystems that transcend racial classification. Tumour immune heterogeneity in HCC reflects distinct molecular patterns, with immune hot tumours characterised by elevated tertiary lymphoid structure signatures and enriched plasma cell and CD8+T cells. These patterns may serve as prognostic biomarkers for immunotherapy patient stratification and demonstrate the value of diverse cohort representation in identifying clinically relevant therapeutic targets.

Gastrointestinal Cancer↗