title: Design and validation of an oligonucleotide microarray for the detection of genomic rearrangements associated with common hereditary cancer syndromes.
abstract: BACKGROUND
  Conventional Sanger sequencing reliably detects the majority of genetic mutations associated with hereditary cancers, such as single-base changes and small insertions or deletions. However, detection of genomic rearrangements, such as large deletions and duplications, requires special technologies. Microarray analysis has been successfully used to detect large rearrangements (LRs) in genetic disorders.
  
  
  METHODS
  We designed and validated a high-density oligonucleotide microarray for the detection of gene-level genomic rearrangements associated with hereditary breast and ovarian cancer (HBOC), Lynch, and polyposis syndromes. The microarray consisted of probes corresponding to the exons and flanking introns of BRCA1 and BRCA2 (≈1,700) and Lynch syndrome/polyposis genes MLH1, MSH2, MSH6, APC, MUTYH, and EPCAM (≈2,200). We validated the microarray with 990 samples previously tested for LR status in BRCA1, BRCA2, MLH1, MSH2, MSH6, APC, MUTYH, or EPCAM. Microarray results were 100% concordant with previous results in the validation studies. Subsequently, clinical microarray analysis was performed on samples from patients with a high likelihood of HBOC mutations (13,124), Lynch syndrome mutations (18,498), and polyposis syndrome mutations (2,739) to determine the proportion of LRs.
  
  
  RESULTS
  Our results demonstrate that LRs constitute a substantial proportion of genetic mutations found in patients referred for hereditary cancer genetic testing.
  
  
  CONCLUSIONS
  The use of microarray comparative genomic hybridization (CGH) for the detection of LRs is well-suited as an adjunct technology for both single syndrome (by Sanger sequencing analysis) and extended gene panel testing by next generation sequencing analysis. Genetic testing strategies using microarray analysis will help identify additional patients carrying LRs, who are predisposed to various hereditary cancers.
authors.forename: Debora
authors.initials: D
authors.lastname: Mancini-DiNardo
authors.forename: Thaddeus
authors.initials: T
authors.lastname: Judkins
authors.forename: Nick
authors.initials: N
authors.lastname: Woolstenhulme
authors.forename: Collin
authors.initials: C
authors.lastname: Burton
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schoenberger
authors.forename: Matthew
authors.initials: M
authors.lastname: Ryder
authors.forename: Adam
authors.initials: A
authors.lastname: Murray
authors.forename: Natalia
authors.initials: N
authors.lastname: Gutin
authors.forename: Aaron
authors.initials: A
authors.lastname: Theisen
authors.forename: Jayson
authors.initials: J
authors.lastname: Holladay
authors.forename: Jonathan
authors.initials: J
authors.lastname: Craft
authors.forename: Christopher
authors.initials: C
authors.lastname: Arnell
authors.forename: Kelsey
authors.initials: K
authors.lastname: Moyes
authors.forename: Benjamin
authors.initials: B
authors.lastname: Roa
mesh_terms: D005091:Exons; D023281:Genomics / Q000379:methods; D006801:Humans; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary / Q000175:diagnosis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D015203:Reproducibility of Results; D014178:Translocation, Genetic
chemical_list: D051718:MutS Homolog 2 Protein