title: Identification of a novel TP53 cancer susceptibility mutation through whole-genome sequencing of a patient with therapy-related AML.
abstract: BACKGROUND
  The identification of patients with inherited cancer susceptibility syndromes facilitates early diagnosis, prevention, and treatment. However, in many cases of suspected cancer susceptibility, the family history is unclear and genetic testing of common cancer susceptibility genes is unrevealing.
  
  
  OBJECTIVE
  To apply whole-genome sequencing to a patient without any significant family history of cancer but with suspected increased cancer susceptibility because of multiple primary tumors to identify rare or novel germline variants in cancer susceptibility genes. DESIGN, SETTING, AND PARTICIPANT: Skin (normal) and bone marrow (leukemia) DNA were obtained from a patient with early-onset breast and ovarian cancer (negative for BRCA1 and BRCA2 mutations) and therapy-related acute myeloid leukemia (t-AML) and analyzed with the following: whole-genome sequencing using paired-end reads, single-nucleotide polymorphism (SNP) genotyping, RNA expression profiling, and spectral karyotyping.
  
  
  METHODS
  Structural variants, copy number alterations, single-nucleotide variants, and small insertions and deletions (indels) were detected and validated using the described platforms. RESULTS; Whole-genome sequencing revealed a novel, heterozygous 3-kilobase deletion removing exons 7-9 of TP53 in the patient's normal skin DNA, which was homozygous in the leukemia DNA as a result of uniparental disomy. In addition, a total of 28 validated somatic single-nucleotide variations or indels in coding genes, 8 somatic structural variants, and 12 somatic copy number alterations were detected in the patient's leukemia genome.
  
  
  CONCLUSIONS
  Whole-genome sequencing can identify novel, cryptic variants in cancer susceptibility genes in addition to providing unbiased information on the spectrum of mutations in a cancer genome.
authors.affiliation: Department of Medicine, Siteman Cancer Center, Washington University, St Louis, Missouri, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
authors.forename: Laura G
authors.initials: LG
authors.lastname: Schuettpelz
authors.forename: Dong
authors.initials: D
authors.lastname: Shen
authors.forename: Jinling
authors.initials: J
authors.lastname: Wang
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Walter
authors.forename: Shashikant
authors.initials: S
authors.lastname: Kulkarni
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: Payton
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ivanovich
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Goodfellow
authors.forename: Michelle
authors.initials: M
authors.lastname: Le Beau
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Koboldt
authors.forename: David J
authors.initials: DJ
authors.lastname: Dooling
authors.forename: Robert S
authors.initials: RS
authors.lastname: Fulton
authors.forename: R Hugh F
authors.initials: RH
authors.lastname: Bender
authors.forename: Lucinda L
authors.initials: LL
authors.lastname: Fulton
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Delehaunty
authors.forename: Catrina C
authors.initials: CC
authors.lastname: Fronick
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Appelbaum
authors.forename: Heather
authors.initials: H
authors.lastname: Schmidt
authors.forename: Rachel
authors.initials: R
authors.lastname: Abbott
authors.forename: Michelle
authors.initials: M
authors.lastname: O'Laughlin
authors.forename: Ken
authors.initials: K
authors.lastname: Chen
authors.forename: Michael D
authors.initials: MD
authors.lastname: McLellan
authors.forename: Nobish
authors.initials: N
authors.lastname: Varghese
authors.forename: Rakesh
authors.initials: R
authors.lastname: Nagarajan
authors.forename: Sharon
authors.initials: S
authors.lastname: Heath
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Graubert
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ley
authors.forename: Gerard P
authors.initials: GP
authors.lastname: Zambetti
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
mesh_terms: D000328:Adult; D017668:Age of Onset; D001943:Breast Neoplasms / Q000628:therapy; D018284:Cystadenocarcinoma, Serous / Q000628:therapy; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000628:therapy; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; D016159:Tumor Suppressor Protein p53