A peculiar mutation spectrum emerging from young peruvian patients with hepatocellular carcinoma.

Agnès Marchio,Franco Doimi,Stéphane Bertani,Eric Deharo,Teresa Rojas Rojas,Eloy Ruiz,Anne Dejean,Pascal Pineau,Benoît Terris,Isabelle A Chemin

doi:10.1371/journal.pone.0114912

Abstract

Hepatocellular carcinoma usually afflicts individuals in their later years following longstanding liver disease. In Peru, hepatocellular carcinoma exists in a unique clinical presentation, which affects patients around age 25 with a normal, healthy liver. In order to deepen our understanding of the molecular processes ongoing in Peruvian liver tumors, mutation spectrum analysis was carried out on hepatocellular carcinomas from 80 Peruvian patients. Sequencing analysis focused on nine genes typically altered during liver carcinogenesis, i.e. ARID2, AXIN1, BRAF, CTNNB1, NFE2L2, H/K/N-RAS, and TP53. We also assessed the transcription level of factors involved in the control of the alpha-fetoprotein expression and the Hippo signaling pathway that controls contact inhibition in metazoans. The mutation spectrum of Peruvian patients was unique with a major class of alterations represented by Insertions/Deletions. There were no changes at hepatocellular carcinoma-associated mutation hotspots in more than half of the specimens analyzed. Furthermore, our findings support the theory of a consistent collapse in the Hippo axis, as well as an expression of the stemness factor NANOG in high alpha-fetoprotein-expressing hepatocellular carcinomas. These results confirm the specificity of Peruvian hepatocellular carcinoma at the molecular genetic level. The present study emphasizes the necessity to widen cancer research to include historically neglected patients from South America, and more broadly the Global South, where cancer genetics and tumor presentation are divergent from canonical neoplasms.

Highlights

Hepatocellular carcinoma (HCC), the major form of primary liver cancer, is a leading cause of death from malignancy, ranking at the third position worldwide [1]
HCC is a malignant tumor resulting from exposition to a plethora of different risk factors acting frequently in concomitance, but not evenly distributed globally [29]
HCC displays a remarkable heterogeneity in terms of patient demographical features, clinical presentation, rates of underlying cirrhosis, tumor pathology, or molecular epidemiology [30]

Summary

Introduction

Hepatocellular carcinoma (HCC), the major form of primary liver cancer, is a leading cause of death from malignancy, ranking at the third position worldwide [1]. HCC incidence is known to vary widely throughout the world depending on region with areas of high incidence, such as Eastern Asia and sub-Saharan Africa, and areas of low incidence, like Northern Europe and North America [2]. High incidence areas of HCC correspond grossly to zones with distribution of two major risk factors, i.e. chronic infection with hepatitis B virus (HBV) and aflatoxin B1 (AFB1) intoxication [3]. Chronic infection with hepatitis C virus (HCV), excessive alcohol use, or dysmetabolic conditions dominate HCC epidemiology, neighboring sometime with additional endemic risk factors, such as hemochromatosis in Western Europe or alpha-1 antitrypsin deficiency in Scandinavia. Large geographic areas, such as Eastern Europe, Northern and Central Asia, Latin America, and the Caribbean, have not been fairly scrutinized regarding prevalent risk factors and common liver cancer clinical presentation. The issues raised here represent a serious matter for global public health

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