Journal Article

Genome sequencing analysis of blood cells identifies germline haplotypes strongly associated with drug resistance in osteosarcoma patients

Gusev, Yuriy, Deeken, John, Madhavan, Subha, Iyer, Ramaswamy, Harris, Michael, Vilboux, Thierry, Bhuvaneshwar, Krithika, Yang, Elizabeth, Shankar, Sadhna

2019

Overview

Background Osteosarcoma is the most common malignant bone tumor in children. Survival remains poor among histologically poor responders, and there is a need to identify them at diagnosis to avoid delivering ineffective therapy. Genetic variation contributes to a wide range of response and toxicity related to chemotherapy. The aim of this study is to use sequencing of blood cells to identify germline haplotypes strongly associated with drug resistance in osteosarcoma patients. Methods We used sequencing data from two patient datasets, from Inova Hospital and the NCI TARGET. We explored the effect of mutation hotspots, in the form of haplotypes, associated with relapse outcome. We then mapped the single nucleotide polymorphisms (SNPs) in these haplotypes to genes and pathways. We also performed a targeted analysis of mutations in Drug Metabolizing Enzymes and Transporter (DMET) genes associated with tumor necrosis and survival. Results We found intronic and intergenic hotspot regions from 26 genes common to both the TARGET and INOVA datasets significantly associated with relapse outcome. Among significant results were mutations in genes belonging to AKR enzyme family, cell-cell adhesion biological process and the PI3K pathways; as well as variants in SLC22 family associated with both tumor necrosis and overall survival. The SNPs from our results were confirmed using Sanger sequencing. Our results included known as well as novel SNPs and haplotypes in genes associated with drug resistance. Conclusion We show that combining next generation sequencing data from multiple datasets and defined clinical data can better identify relevant pathway associations and clinically actionable variants, as well as provide insights into drug response mechanisms.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: 1-Phosphatidylinositol 3-kinase / Alleles / Biomarkers, Tumor / Biomedical and Life Sciences / Biomedicine / Blood cells / Blood Cells - metabolism / Bone cancer / Bone Neoplasms - genetics / Bone Neoplasms - mortality / Bone tumors / Breast cancer / Cancer / Cancer Research / Cancer therapies / Cell adhesion / Chemotherapy / Childhood cancer / Childhood cancers / Chromosomes / Datasets / DNA sequencing / Drug dosages / Drug resistance / Drug Resistance, Neoplasm - genetics / Drug therapy / Enzymes / Gene expression / Gene Frequency / Genes / Genetic aspects / Genetic diversity / Genetic polymorphisms / Genetic research / Genetics / Genomes / Genomics / Genomics - methods / genomics and epigenetics / Genotype / Germ-Line Mutation / Haplotypes / Health Promotion and Disease Prevention / High-Throughput Nucleotide Sequencing / Humans / Kaplan-Meier Estimate / Medicine/Public Health / Metastasis / Mutation / Mutation hot spots / Necrosis / Next-generation sequencing / Novels / Oncology / Osteosarcoma / Osteosarcoma - genetics / Osteosarcoma - mortality / Pediatrics / Pharmacogenomics / Polymorphism / Polymorphism, Single Nucleotide / Prognosis / Proteins / Research Article / Sarcoma / Single nucleotide polymorphisms / Single-nucleotide polymorphism / Studies / Surgical Oncology / Toxicity / Tumors / Whole genome sequencing