Conference 2021 Pre-Recorded Video

 

Project title

Whole exome sequencing based somatic mutation profiling to match patients with targeted therapy in hepatocellular cancer

 

Authors and Affiliations

Wendy Andrea D’Souza1, Naresh Pradhan1, Radha Mishra1, Ashwini Nargund2, Malathi M2, Arun Kumar1

1. Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science (IISc), Bengaluru 560012, Karnataka, India
2. Department of Pathology, Kidwai Memorial Institute of Oncology, Bengaluru 560029, Karnataka, India

 

Abstract

Background

Hepatocellular carcinoma (HCC) is molecularly and clinically a heterogeneous disease. With the dawn of next-generation sequencing (NGS) technologies, new opportunities have surfaced in whole exome analysis in HCC. This study was designed to further explore the molecular landscape of HCC and therapeutic implications in HCC, in the process we uncovered major cancer driver genes and associated oncogenic pathways.

Methods

Matched tumor/normal DNA from 37 patients with HCC were analyzed using the xGen Exome Research Panel v1.0 kit (Integrated DNA Technologies, Inc, Coralville, Iowa). Potential actionable variants, prioritization and filtration was performed at IISc (Bengaluru, India).

Results

In total, whole exome sequencing (WES) was obtained for 37 patients with HCC. Of these 37 patients, 28 (75.68%) were men, 9 (24.32%) women, 14 (37.83%) had hepatitis B or C-related HCC. WES revealed at least 1 molecular abnormality in 33 patients (mean 3.41 + 3.18, range 1‑12). A total of 126 variants were identified in 21 genes, with 29.36% of these variants not previously reported in the COSMIC database. The identified common hotspot somatic missense variants were present in tumor protein 53 (TP53, 24.32%) and β‑catenin 1 (CTNNB1, 10.81%). In addition, somatic mutations in genes encoding MAP2K3 (43.24%), AR (21.62%), SMARCA2 (21.62%), ARID1A (16.21%), DRD4 (13.51%), SLC9A5 (10.81%), ALB (8.11%), APC (5.41%), AXIN1 (5.41%), MSH3 (5.41%), APOB (5.41%), KEAP1 (5.41%), RB1 (5.41%), TUBA3D (5.41%), ZNRF3 (5.41%), ACVR2A (2.71%), ATR (2.71%), CDKN2A (2.71%), and TSC1 (2.71%) were also identified. Of all the patients, 43.24% exhibited variants in the target of BRAF and MEK inhibitors, 32.43% in the targets of CDK inhibitors, 27.02% in the targets of FZD inhibitors and 13.51% in the targets of mTOR inhibitors, and other drugs that have been FDA approved to treat other types of cancer.

Conclusions

This diverse molecular spectrum of HCC provides a unique molecular signature with clinical implications in novel molecular therapies and treatment response. NGS as a companion diagnostic test to first-line clinical care has the potential to stratify patients likely to benefit from standard-of-care therapy or tailored genome-directed therapies.