# Impact of differential detection of TM6SF2 rs58542926 mutation in circulating tumor DNA versus peripheral blood cells on hepatocellular carcinoma patients

## TL;DR

This study shows that the TM6SF2 rs58542926 gene variant behaves differently in tumor DNA and blood cells, and is linked to liver cancer risk in hepatitis C patients.

## Contribution

The study reveals how TM6SF2 rs58542926 genotype differences in ctDNA and PBMC correlate with HCC progression and risk factors in HCV-infected patients.

## Key findings

- The CT genotype of TM6SF2 rs58542926 is associated with higher bilirubin, leucocyte count, and hemoglobin in HCC patients.
- Circulating DNA with the CT genotype correlates with worse liver function and higher HCC risk factors like smoking and alcohol intake.
- TM6SF2 genotype differences in ctDNA and PBMC provide real-time insights into liver disease progression and HCC risk.

## Abstract

This study aimed to investigate the differential distribution of the genotypes of the TM6SF2 rs58542926 polymorphism in circulating tumor DNA (ctDNA) versus peripheral blood cells (PBMC) and its association with the development of hepatocellular carcinoma (HCC) in patients infected with the hepatitis C virus (HCV) in Egypt. A total of 147 HCC patients were enrolled in the study, and their genomic and ctDNA were analyzed for the TM6SF2 rs58542926 genotype. The CC genotype was identified as the most common among patients with HCC in Egypt, while the CT genotype was associated with higher serum direct bilirubin, total leucocyte count, and hemoglobin levels than those with the CC genotype. Circulating samples from patients with the CT genotype had significantly higher serum direct bilirubin, ALT, and prothrombin time than those with the CC genotype, as well as a significantly higher percentage of smokers, alcohol intake, and HCV PCR-positive patients. Our findings suggest that lifestyle factors such as smoking and alcohol intake may contribute to the development of HCC in patients with the CT genotype. Both genomic and ctDNA for the TM6SF2 rs58542926 genotype complemented and correlated with parameters of chronic liver disease and underlying risk factors for HCC. Circulating DNA for gene polymorphism provided additional real-time information and more value in correlation with the worsening of liver condition and the presence of HCC risk factors.

The online version contains supplementary material available at 10.1007/s12672-025-02812-9.

Our study provides evidence for the differential distribution of genotypes of TM6SF2 rs58542926 gene polymorphism in PBMC versus ctDNA and both correlate with the development of HCC in patients with HCV infection. Alteration in TM6SF2 rs58542926 genotypes in ctDNA correlated with worsening of liver condition indicating its impact on disease progression monitoring.Our findings suggest that smoking and alcohol intake may contribute to the development of HCC in patients with the CT genotype of TM6SF2 rs58542926.Our results may help to inform future research and clinical practice in the diagnosis and treatment of HCC in patients with HCV infection.

Our study provides evidence for the differential distribution of genotypes of TM6SF2 rs58542926 gene polymorphism in PBMC versus ctDNA and both correlate with the development of HCC in patients with HCV infection.

Alteration in TM6SF2 rs58542926 genotypes in ctDNA correlated with worsening of liver condition indicating its impact on disease progression monitoring.

Our findings suggest that smoking and alcohol intake may contribute to the development of HCC in patients with the CT genotype of TM6SF2 rs58542926.

Our results may help to inform future research and clinical practice in the diagnosis and treatment of HCC in patients with HCV infection.

The online version contains supplementary material available at 10.1007/s12672-025-02812-9.