Clinical application of genomic profiling to find druggable targets for adolescent and young adult (AYA) cancer patients with metastasis

BMC Cancer. 2016 Feb 29;16:170. doi: 10.1186/s12885-016-2209-1.

Abstract

Background: Although adolescent and young adult (AYA) cancers are characterized by biological features and clinical outcomes distinct from those of other age groups, the molecular profile of AYA cancers has not been well defined. In this study, we analyzed cancer genomes from rare types of metastatic AYA cancers to identify driving and/or druggable genetic alterations.

Methods: Prospectively collected AYA tumor samples from seven different patients were analyzed using three different genomics platforms (whole-exome sequencing, whole-transcriptome sequencing or OncoScan™). Using well-known bioinformatics tools (bwa, Picard, GATK, MuTect, and Somatic Indel Detector) and our annotation approach with open access databases (DAVID and DGIdb), we processed sequencing data and identified driving genetic alterations and their druggability.

Results: The mutation frequencies of AYA cancers were lower than those of other adult cancers (median = 0.56), except for a germ cell tumor with hypermutation. We identified patient-specific genetic alterations in candidate driving genes: RASA2 and NF1 (prostate cancer), TP53 and CDKN2C (olfactory neuroblastoma), FAT1, NOTCH1, and SMAD4 (head and neck cancer), KRAS (urachal carcinoma), EML4-ALK (lung cancer), and MDM2 and PTEN (liposarcoma). We then suggested potential drugs for each patient according to his or her altered genes and related pathways. By comparing candidate driving genes between AYA cancers and those from all age groups for the same type of cancer, we identified different driving genes in prostate cancer and a germ cell tumor in AYAs compared with all age groups, whereas three common alterations (TP53, FAT1, and NOTCH1) in head and neck cancer were identified in both groups.

Conclusion: We identified the patient-specific genetic alterations and druggability of seven rare types of AYA cancers using three genomics platforms. Additionally, genetic alterations in cancers from AYA and those from all age groups varied by cancer type.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Chromosomal Instability
  • Computational Biology / methods
  • Cyclin-Dependent Kinase Inhibitor p18 / genetics
  • Cyclin-Dependent Kinase Inhibitor p18 / metabolism
  • Drug Discovery*
  • Exome
  • Female
  • Gene Expression Profiling*
  • Genomics* / methods
  • High-Throughput Nucleotide Sequencing
  • Humans
  • INDEL Mutation
  • Male
  • Molecular Targeted Therapy
  • Mutation Rate
  • Neoplasms / drug therapy
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism
  • Polymorphism, Single Nucleotide
  • Receptors, Notch / metabolism
  • Signal Transduction / drug effects
  • Wnt Signaling Pathway
  • Young Adult
  • ras Proteins / genetics
  • ras Proteins / metabolism

Substances

  • Antineoplastic Agents
  • Cyclin-Dependent Kinase Inhibitor p18
  • EML4-ALK fusion protein, human
  • Oncogene Proteins, Fusion
  • Receptors, Notch
  • ras Proteins