Different Mutation Processes Affect HBV Genome In Peruvian Patients With Hepatocellular Carcinoma

Pascal PINEAU, Institut Pasteur, France
MARCHIO A. 1 , BERTANI S. 2 , CERAPIO J. 1 , ROJAS ROJAS T. 3 , DOIMI F. 4 , TERRIS B. 5 , DEHARO E. 2 , RUIZ E. 6

1 Unité d'Organisation Nucléaire et Oncogenèse, Institut Pasteur, INSERM U993, Paris, France
2 UMR152 PHARMADEV, Université de Toulouse, IRD, UPS, Toulouse, France
3 UMR912 SESSTIM, Aix Marseille Université, Marseille, France
4 Departamento de Patología, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru
5 Service d'Anatomie et Cytologie Pathologiques, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France
6 Departamento de Cijuría en Abdomen, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru

Purpose
In Peru, Hepatocellular carcinoma (HCC) is characterized by an unusual bimodal distribution for age with a first peak of incidence around 20-25 yo. Although, some hitherto unidentified risk factors are suspected to be involved in the patho-physiology of the disease, hepatitis B virus (HBV), found in almost 80% of cases, is known to play here a prominent role.

Methods
We characterized HBV at the molecular level in 64 pairs of HCC and matching non-tumor liver tissues from Peruvian patients.

Results
All viral strains were belonging to F1b subtype, endemic to this region of South America. A striking feature was the extremely low viral loads observed both in tumor and non-tumor tissues (1 viral copy for 100 cell genomes), a situation in contradiction with most observations that consider high HBV loads as the key-risk factor for early HCC. The comparison of HBV DNA mutation spectra in young (n=34) and older (n=19) patients was performed on different region of HBV genome (PreS-S, HBx, HBe-HBc, ≈1500 nucleotides/isolate) and revealed significant differences. Whereas HBV from young patients were mostly mutated on HBe-HBc gene (mean=24 vs. 12%, P=0.004), those from older ones were altered mostly in HBx. Furthermore, HBV DNA in young patients was displaying significantly higher rates of mutation at TT di-nucleotides (27 vs. 15% of total mutation number, p=0.002).

Conclusion
This situation suggests that liver tissue in young patients is the siege of a specific mutational process that contributes to virus restriction. Whether it is contributing or not in liver tumorigenesis is currently under investigation.

Funding sources
This work was funded by the French National Alliance for Life Sciences and Health (Aviesan), the Peruvian National Council of Science and Technology (CONCyTEC), the Peruvian Fund for Innovation, Science, and Technology (FINCyT), and the Institut de Recherche pour le Développement (IRD).