title: Clinical application of genomic profiling to find druggable targets for adolescent and young adult (AYA) cancer patients with metastasis.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. soojincha36@gmail.com.
authors.forename: Soojin
authors.initials: S
authors.lastname: Cha
authors.affiliation: Interdisciplinary Program for Bioengineering of Graduate School, Seoul National University, Seoul, Republic of Korea. jeleedict@gmail.com.
authors.forename: Jeongeun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Genomic Medicine Institute, Seoul National University, Seoul, Republic of Korea. jongyeon.anna@gmail.com.
authors.forename: Jong-Yeon
authors.initials: JY
authors.lastname: Shin
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea. medijiyeon@gmail.com.
authors.forename: Ji-Yeon
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea. cantusprote@gmail.com.
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Sim
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. bhumsuk@snu.ac.kr.|Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea. bhumsuk@snu.ac.kr.
authors.forename: Bhumsuk
authors.initials: B
authors.lastname: Keam
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. gabriel9@snu.ac.kr.|Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea. gabriel9@snu.ac.kr.
authors.forename: Tae Min
authors.initials: TM
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. kimdw@snu.ac.kr.|Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea. kimdw@snu.ac.kr.
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. heo1013@snu.ac.kr.|Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea. heo1013@snu.ac.kr.
authors.forename: Dae Seog
authors.initials: DS
authors.lastname: Heo
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. sehoon.lee119@gmail.com.|Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea. sehoon.lee119@gmail.com.|Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. sehoon.lee119@gmail.com.|Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea. sehoon.lee119@gmail.com.
authors.forename: Se-Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. jongil@snu.ac.kr.|Genomic Medicine Institute, Seoul National University, Seoul, Republic of Korea. jongil@snu.ac.kr.|Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea. jongil@snu.ac.kr.|Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea. jongil@snu.ac.kr.
authors.forename: Jong-Il
authors.initials: JI
authors.lastname: Kim
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D043171:Chromosomal Instability; D019295:Computational Biology / Q000379:methods; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics / Q000378:metabolism; D055808:Drug Discovery; D059472:Exome; D005260:Female; D020869:Gene Expression Profiling; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D054643:INDEL Mutation; D008297:Male; D058990:Molecular Targeted Therapy; D059645:Mutation Rate; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D060449:Wnt Signaling Pathway; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D050763:Cyclin-Dependent Kinase Inhibitor p18; C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion; D051880:Receptors, Notch; D018631:ras Proteins