High-resolution detection of chromosomal rearrangements in leukemias through mate pair whole genome sequencing

PLoS One. 2018 Mar 12;13(3):e0193928. doi: 10.1371/journal.pone.0193928. eCollection 2018.

Abstract

The detection of recurrent somatic chromosomal rearrangements is standard of care for most leukemia types. Even though karyotype analysis-a low-resolution genome-wide chromosome analysis-is still the gold standard, it often needs to be complemented with other methods to increase resolution. To evaluate the feasibility and applicability of mate pair whole genome sequencing (MP-WGS) to detect structural chromosomal rearrangements in the diagnostic setting, we sequenced ten bone marrow samples from leukemia patients with recurrent rearrangements. Samples were selected based on cytogenetic and FISH results at leukemia diagnosis to include common rearrangements of prognostic relevance. Using MP-WGS and in-house bioinformatic analysis all sought rearrangements were successfully detected. In addition, unexpected complexity or additional, previously undetected rearrangements was unraveled in three samples. Finally, the MP-WGS analysis pinpointed the location of chromosome junctions at high resolution and we were able to identify the exact exons involved in the resulting fusion genes in all samples and the specific junction at the nucleotide level in half of the samples. The results show that our approach combines the screening character from karyotype analysis with the specificity and resolution of cytogenetic and molecular methods. As a result of the straightforward analysis and high-resolution detection of clinically relevant rearrangements, we conclude that MP-WGS is a feasible method for routine leukemia diagnostics of structural chromosomal rearrangements.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Marrow
  • Chromosome Aberrations*
  • Computational Biology
  • Early Detection of Cancer
  • Exons
  • Feasibility Studies
  • Humans
  • In Situ Hybridization, Fluorescence
  • Leukemia / genetics*
  • Leukemia / pathology
  • Whole Genome Sequencing / methods*

Grants and funding

This work was supported by Barncancerfonden Sweden TJ 2015-0047 GB, PR 2014-0020 GB, Cancerfonden CAN 2013-700 GB, Stockholms County Council grant 2015-0065 MN.