title: Quantification of subclonal distributions of recurrent genomic aberrations in paired pre-treatment and relapse samples from patients with B-cell chronic lymphocytic leukemia.
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.
authors.affiliation: NIHR Biomedical Research Centre, Oxford, UK.
authors.forename: S J L
authors.initials: SJ
authors.lastname: Knight
authors.forename: C
authors.initials: C
authors.lastname: Yau
authors.forename: R
authors.initials: R
authors.lastname: Clifford
authors.forename: A T
authors.initials: AT
authors.lastname: Timbs
authors.forename: E
authors.initials: E
authors.lastname: Sadighi Akha
authors.forename: H M
authors.initials: HM
authors.lastname: Dréau
authors.forename: A
authors.initials: A
authors.lastname: Burns
authors.forename: C
authors.initials: C
authors.lastname: Ciria
authors.forename: D G
authors.initials: DG
authors.lastname: Oscier
authors.forename: A R
authors.initials: AR
authors.lastname: Pettitt
authors.forename: S
authors.initials: S
authors.lastname: Dutton
authors.forename: C C
authors.initials: CC
authors.lastname: Holmes
authors.forename: J
authors.initials: J
authors.lastname: Taylor
authors.forename: J-B
authors.initials: JB
authors.lastname: Cazier
authors.forename: A
authors.initials: A
authors.lastname: Schuh
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D002869:Chromosome Aberrations; D002999:Clone Cells / Q000473:pathology*; D005260:Female; D018628:Gene Dosage; D015894:Genome, Human; D023281:Genomics; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000628:therapy; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000628:therapy; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor