Array based genetic profiling of chronic lymphocytic leukemia

Research output: ThesisDoctoral Thesis (compilation)

Standard

Array based genetic profiling of chronic lymphocytic leukemia. / Gunnarsson, Rebeqa.

Department of Laboratory Medicine, Lund University, 2010. 99 p.

Research output: ThesisDoctoral Thesis (compilation)

Harvard

APA

Gunnarsson, R. (2010). Array based genetic profiling of chronic lymphocytic leukemia. Department of Laboratory Medicine, Lund University.

CBE

Gunnarsson R. 2010. Array based genetic profiling of chronic lymphocytic leukemia. Department of Laboratory Medicine, Lund University. 99 p.

MLA

Gunnarsson, Rebeqa Array based genetic profiling of chronic lymphocytic leukemia Department of Laboratory Medicine, Lund University. 2010.

Vancouver

Gunnarsson R. Array based genetic profiling of chronic lymphocytic leukemia. Department of Laboratory Medicine, Lund University, 2010. 99 p. (Lund University Faculty of Medicine Doctoral Dissertation Series ).

Author

Gunnarsson, Rebeqa. / Array based genetic profiling of chronic lymphocytic leukemia. Department of Laboratory Medicine, Lund University, 2010. 99 p.

RIS

TY - THES

T1 - Array based genetic profiling of chronic lymphocytic leukemia

AU - Gunnarsson, Rebeqa

N1 - Defence details Date: 2010-02-12 Time: 13:00 Place: Segerfalk lecture hall, BMC, Lund External reviewer(s) Name: Klein, Ulf Title: Assistant Professor Affiliation: Columbia University, New York, US --- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Hematology/Transplantation (013022014)

PY - 2010

Y1 - 2010

N2 - Although no common genetic defect has been described in chronic lymphocytic leukemia (CLL), recurrent genomic aberrations (i.e. deletions of chromosome 11q, 13q, 17p and trisomy 12) are important for prognostication. Deletion of 13q as single aberration is associated with the best prognosis, whereas del(11q) and del(17p) predict a poor outcome. Recent development of high-resolution genomic techniques, i.e. microarrays, provides effective detection of the known recurrent aberrations and simultaneous exploration of the whole genome. Hence, this thesis aimed to map genomic aberrations in CLL through application of high-resolution microarrays. In paper I, we investigated the pros and cons of four differently designed microarray platforms. All platforms readily detected the known recurrent aberrations in CLL as well as other large copy-number aberrations (CNAs). The difference in technical performance and discrepancies in detection of small CNAs were influenced by differential platform density, different reference sets, and platform-specific analysis. In paper II and IV, 250K single nucleotide polymorphism (SNP)-array screening of 203 and 370 samples, respectively, detected CNAs in >90% and the known recurrent aberrations in >70% of patients. Moreover, novel recurrent gains of chromosome 2p in combination with 11q deletion and copy-number neutral loss of heterozygosity on chromosome 13q were revealed. Furthermore, a high genomic complexity was correlated to worse survival, but also closely linked to poor-prognostic markers. In addition, study IV also included follow-up samples (n=43) to investigate clonal evolution, which showed that patients with unmutated immunoglobulin heavy chain variable (IGHV) genes and treated patients with mutated IGHV genes often gained novel aberrations. In paper III, high-density screening revealed a different spectrum of genomic aberrations in CLL patients with ‘stereotyped’ IGHV3-21 (poor-prognostic) versus IGHV4-34 (good-prognostic) B-cell receptors. IGHV3-21 subset #2 (n=29) showed a high frequency of samples carrying genomic aberrations, and a particularly high prevalence of del(13q) and del(11q), which may correspond to the adverse survival reported for these patients. In contrast, IGHV4-34 subset #4 (n=17) showed a lower frequency and complexity of CNAs, which may reflect an inherent low-proliferative disease, preventing accumulation of genomic alterations. In summary, the studies included in this thesis provided a greater insight of genomic aberrations in newly diagnosed patients, at follow-up and in different subgroups of CLL.

AB - Although no common genetic defect has been described in chronic lymphocytic leukemia (CLL), recurrent genomic aberrations (i.e. deletions of chromosome 11q, 13q, 17p and trisomy 12) are important for prognostication. Deletion of 13q as single aberration is associated with the best prognosis, whereas del(11q) and del(17p) predict a poor outcome. Recent development of high-resolution genomic techniques, i.e. microarrays, provides effective detection of the known recurrent aberrations and simultaneous exploration of the whole genome. Hence, this thesis aimed to map genomic aberrations in CLL through application of high-resolution microarrays. In paper I, we investigated the pros and cons of four differently designed microarray platforms. All platforms readily detected the known recurrent aberrations in CLL as well as other large copy-number aberrations (CNAs). The difference in technical performance and discrepancies in detection of small CNAs were influenced by differential platform density, different reference sets, and platform-specific analysis. In paper II and IV, 250K single nucleotide polymorphism (SNP)-array screening of 203 and 370 samples, respectively, detected CNAs in >90% and the known recurrent aberrations in >70% of patients. Moreover, novel recurrent gains of chromosome 2p in combination with 11q deletion and copy-number neutral loss of heterozygosity on chromosome 13q were revealed. Furthermore, a high genomic complexity was correlated to worse survival, but also closely linked to poor-prognostic markers. In addition, study IV also included follow-up samples (n=43) to investigate clonal evolution, which showed that patients with unmutated immunoglobulin heavy chain variable (IGHV) genes and treated patients with mutated IGHV genes often gained novel aberrations. In paper III, high-density screening revealed a different spectrum of genomic aberrations in CLL patients with ‘stereotyped’ IGHV3-21 (poor-prognostic) versus IGHV4-34 (good-prognostic) B-cell receptors. IGHV3-21 subset #2 (n=29) showed a high frequency of samples carrying genomic aberrations, and a particularly high prevalence of del(13q) and del(11q), which may correspond to the adverse survival reported for these patients. In contrast, IGHV4-34 subset #4 (n=17) showed a lower frequency and complexity of CNAs, which may reflect an inherent low-proliferative disease, preventing accumulation of genomic alterations. In summary, the studies included in this thesis provided a greater insight of genomic aberrations in newly diagnosed patients, at follow-up and in different subgroups of CLL.

KW - prognostic markers

KW - copy-number neutral loss of heterozygosity

KW - copy-number aberrations

KW - chronic lymphocytic leukemia

KW - genomic microarrays

KW - clonal evolution

KW - stereotyped B-cell receptors

M3 - Doctoral Thesis (compilation)

SN - 978-91-86443-22-1

T3 - Lund University Faculty of Medicine Doctoral Dissertation Series

PB - Department of Laboratory Medicine, Lund University

ER -