The higher body mass index is associated with a lower somatic mutation dependency in hepatocellular carcinoma

Abstract

Background: Reaching a certain somatic mutation threshold is a prerequisite of neoplastic initiation. High Body Mass Indexes (BMI) have been introduced as an independent risk factor for cancer development. However, there is evidence for lower mutational dependency in obese individuals in some types of cancers. In this study, we conducted a differential mutation analysis among patients with hepatocellular carcinoma (HCC) with different BMI. Methods: Mutation annotation files of 158 normal-weights, 112 overweight and 76 obese HCC patients were retrieved from the TCGA-LIHC project using the TCGAbiolinks library [3]. The Ensembl Variant Effect Predictor (VEP) tool was used to further annotate the identified common and exclusive mutations in both BMI categories. The pathway enrichment of the characterized pathogenic mutations in different BMI categories was performed using the KEGG database. Result: HCC patients with normal BMIs showed a significantly higher frequency of pathogenic mutations compared with higher BMI groups. Pathogenic mutations in HCC-associated genes, namely TP53, CTTNB1, ARID2, ARID1A, AXIN1, and NFE2L2 were observed in the three BMI categories. However, they were more frequently targeted in normal-weights. Accordingly, a significantly larger number of mutated genes involved in cancer-associated signaling pathways, including Hepatocellular Carcinoma, PI3K-Akt, MAPK, and p53 were observed in patients with normal body weights compared with the higher BMI groups. In addition to the common targeted pathways among the three BMI groups, cAMP, Wnt, Hippo, and JAK-STAT signaling pathways were shared between normal-weight and overweight patients with HCC., Ras and mTOR signaling pathways were also exclusively targeted in the normal-weight group. Conclusion: Obese and overweight patients with HCC represent lower mutation dependency to develop HCC. More investigations considering central obesity measures will help to specify the molecular alterations caused by the presence of central fat that may promote tumor progression regardless of BMI.

Keywords

• Hepatocellular carcinoma
• Obesity
• Mutation dependency