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Åke Borg

Åke Borg

Principal investigator

Åke Borg

Detection and precise mapping of germline rearrangements in BRCA1, BRCA2, MSH2, and MLH1 using zoom-in array comparative genomic hybridization (aCGH).

Author

  • Johan Staaf
  • Therese Törngren
  • Eva Rambech
  • Ulla Johansson
  • Camilla Olsson
  • Gunilla Sellberg
  • Lina Tellhed
  • Mef Nilbert
  • Åke Borg

Summary, in English

Disease-predisposing germline mutations in cancer susceptibility genes may consist of large genomic rearrangements that are challenging to detect and characterize using standard PCR-based mutation screening methods. Here, we describe a custom-made zoom-in microarray comparative genomic hybridization (CGH) platform of 60mer oligonucleotides. The 4 x 44 K array format provides high-resolution coverage (200-300 bp) of 400-700 kb genomic regions surrounding six cancer susceptibility genes. We evaluate its performance to accurately detect and precisely map earlier described or novel large germline deletions or duplications occurring in BRCA1 (n=11), BRCA2 (n=2), MSH2 (n=7), or MLH1 (n=9). Additionally, we demonstrate its applicability for uncovering complex somatic rearrangements, exemplified by zoom-in analysis of the PTEN and CDKN2A loci in breast cancer cells. The sizes of rearrangements ranged from several 100 kb, including large flanking regions, to <500-bp deletions, including parts of single exons that would be missed by standard multiplex ligation-dependent probe amplification (MLPA) methods. Zoom-in CGH arrays accurately defined the borders of rearrangements, allowing convenient design of primers for sequence determination of the breakpoints. The array platform can be streamlined for a particular application, e.g., focusing on breast cancer susceptibility genes, with increased capacity using multiformat design, and represents a valuable new tool and complement for genetic screening in clinical diagnostics.

Department/s

  • Breastcancer-genetics
  • Familial Breast Cancer

Publishing year

2008

Language

English

Pages

555-564

Publication/Series

Human Mutation

Volume

29

Issue

4

Document type

Journal article

Publisher

John Wiley & Sons Inc.

Topic

  • Medical Genetics

Status

Published

Research group

  • Familial Breast Cancer

ISBN/ISSN/Other

  • ISSN: 1059-7794