Quantification of subclonal distributions of recurrent genomic aberrations in paired pre-treatment and relapse samples from patients with B-cell chronic lymphocytic leukemia

Research output: Contribution to journalArticlepeer-review

Authors

  • S J L Knight
  • C Yau
  • R Clifford
  • A T Timbs
  • E Sadighi Akha
  • H M Dréau
  • A Burns
  • C Ciria
  • D G Oscier
  • A R Pettitt
  • S Dutton
  • C C Holmes
  • J Taylor
  • A Schuh

Colleges, School and Institutes

Abstract

Genome-wide array approaches and sequencing analyses are powerful tools for identifying genetic aberrations in cancers, including leukemias and lymphomas. However, the clinical and biological significance of such aberrations and their subclonal distribution are poorly understood. Here, we present the first genome-wide array based study of pre-treatment and relapse samples from patients with B-cell chronic lymphocytic leukemia (B-CLL) that uses the computational statistical tool OncoSNP. We show that quantification of the proportion of copy number alterations (CNAs) and copy neutral loss of heterozygosity regions (cnLOHs) in each sample is feasible. Furthermore, we (i) reveal complex changes in the subclonal architecture of paired samples at relapse compared with pre-treatment, (ii) provide evidence supporting an association between increased genomic complexity and poor clinical outcome (iii) report previously undefined, recurrent CNA/cnLOH regions that expand or newly occur at relapse and therefore might harbor candidate driver genes of relapse and/or chemotherapy resistance. Our findings are likely to impact on future therapeutic strategies aimed towards selecting effective and individually tailored targeted therapies.

Details

Original languageEnglish
Pages (from-to)1564-75
Number of pages12
JournalLeukemia
Volume26
Issue number7
Publication statusPublished - Jul 2012

Keywords

  • Adult, Aged, Aged, 80 and over, Chromosome Aberrations, Clone Cells, Female, Gene Dosage, Genome, Human, Genomics, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Loss of Heterozygosity, Male, Middle Aged, Neoplasm Recurrence, Local, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Prognosis, Tumor Markers, Biological