GENETIC PREDISPOSITION AND HEREDITARY FACTORS

Familial ICC and Potential Hereditary Syndromes

Although the majority of iCCA cases are sporadic, familial iCCA and its correlation with certain genetic disorders are gaining recognition. Genetic predisposition contributes to a minority of instances, frequently associated with hereditary mutations that increase susceptibility to cancer growth. Hereditary cancer syndromes, including Lynch syndrome [related to mutations in mismatch repair (MMR) genes] and Li-Fraumeni syndrome (connected to TP53 mutations), may elevate the chance of developing iCCA. Furthermore, hereditary mutations in BRCA1/2, typically linked to breast and ovarian cancers, have been connected with certain instances of cholangiocarcinoma, indicating a wider involvement in cancer susceptibility. Other familial disorders, including hereditary hemochromatosis and primary sclerosing cholangitis (PSC), may elevate the risk of iCCA due to persistent inflammation and hepatic injury [95]. Comprehending these hereditary connections is essential for early identification, genetic counseling, and customized monitoring measures in high-risk families. Recent genetic data, particularly from the multi-omics study, have yielded essential insights into the invasive characteristics of ICC, particularly CA19-9-positive tumors [108]. The work integrated data from various clinical cohorts, synthesizing findings from whole-exome sequencing, transcriptomics, proteomics, single-cell RNA sequencing, and spatial transcriptomics to provide a comprehensive understanding of intrahepatic cholangiocarcinoma biology. The results indicated that CA19-9-positive ICCs exhibit significantly greater aggressiveness, with substantially reduced overall survival (median 24.1 months) and recurrence-free survival (median 11.7 months) in comparison to CA19-9-negative cases. Genetically, CA19-9-positive tumors demonstrated an increased incidence of KRAS mutations, whereas IDH1/2 mutations were more common in the CA19-9-negative cohort. Transcriptomic profiling indicated an increase in glycolysis-related pathways, implying a metabolic change that facilitates tumor development. Single-cell analysis revealed different cellular subpopulations, Epi_SLC2A1, CAF_VEGFA, and Mph_SPP1, linked to hypoxia-induced metabolic reprogramming. These subclusters established interactive cellular communities that facilitated epithelial-mesenchymal transition (EMT) and angiogenesis, both of which are critical characteristics of tumor invasiveness. The study discovered six possible therapeutic molecules through drug sensitivity analysis, presenting potential options for focused treatment. This integrative approach may enhance our comprehension of ICC heterogeneity and emphasize the clinical significance of CA19-9 as a prognostic biomarker. The results can facilitate the development of more tailored and efficacious treatment approaches for this challenging cancer.

Role of Environment-Genetic Interactions

Environment-genetic interactions significantly influence the development of iCCA. Environmental variables, including chronic liver inflammation, parasite infections (e.g., Opisthorchis viverrini), hepatitis B and C infections, and exposure to chemicals, such as thorotrast or dioxins, can induce genetic changes that facilitate carcinogenesis [96]. Individuals possessing predisposing genetic variants, such as those in TP53, IDH1/2, or FGFR2, may exhibit increased susceptibility to certain environmental triggers. Moreover, persistent inflammation cultivates a mutagenic milieu, heightening the probability of DNA damage and epigenetic modifications. Comprehending these connections is crucial for risk evaluation, early identification, and preventive measures in iCCA.

Impact of Liver Diseases (e.g., Cirrhosis, Viral Hepatitis) on Genetic Mutation Susceptibility

Chronic liver illnesses, including cirrhosis and viral hepatitis (HBV, HCV), markedly elevate the risk of genetic alterations that promote the development of iCCA [97]. Chronic liver inflammation and fibrosis establish a pro-mutagenic milieu by producing oxidative stress, causing DNA damage, and hindering DNA repair processes. This facilitates mutations in critical oncogenes and tumor suppressor genes, such as TP53, KRAS, and IDH1/2. The hepatitis B virus (HBV) can incorporate its DNA into the host genome, immediately inducing genetic instability, whereas the hepatitis C virus (HCV) instigates chronic inflammation. These hepatic disorders not only heighten sensitivity to mutations, but also facilitate tumor advancement and therapeutic resistance.