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Telomere length as a prognostic parameter in chronic lymphocytic leukemia with special reference to VH gene mutation status
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
Vise andre og tillknytning
2005 (engelsk)Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 105, nr 12, s. 4807-4812Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

B-cell chronic lymphocytic leukemia (CLL) consists of 2 prognostic entities where cases with mutated immunoglobulin VH genes have better outcome than unmutated cases. VH-mutated CLLs display longer telomeres compared with unmutated cases and telomere length has been indicated to predict outcome, although the prognostic value of telomere length has not been fully established in CLL. We analyzed telomere length, VH gene mutation status, and clinical parameters in a large series of CLL. Telomere length was assessed by quantitative polymerase chain reaction (PCR), giving a very good correlation to telomere length estimated by Southern blotting (P < .001). The prognostic information given by mutation status (n = 282) and telomere length (n = 246) was significant (P < .001, respectively). Telomere length was a prognostic factor for stage A (P = .021) and stage B/C (P = .018) patients, whereas mutation status predicted outcome only in stage A patients (P < .001). Furthermore, mutated CLLs were subdivided by telomere length into 2 groups with different prognoses (P = .003), a subdivision not seen for unmutated cases (P = .232). Interestingly, the VH-mutated group with short telomeres had an overall survival close to that of the unmutated cases. Thus, by combining VH mutation status and telomere length, an improved subclassification of CLL was achieved identifying previously unrecognized patient groups with different outcomes.

sted, utgiver, år, opplag, sider
2005. Vol. 105, nr 12, s. 4807-4812
Emneord [en]
Adult, Aged, Aged; 80 and over, Blotting; Southern, Female, Genes; Immunoglobulin, Humans, Immunoglobulin Heavy Chains/*genetics, Immunophenotyping, In Situ Hybridization; Fluorescence, Leukemia; Lymphocytic; Chronic/*diagnosis/*genetics, Lymph Nodes/pathology, Male, Middle Aged, Models; Statistical, Mutation, Polymerase Chain Reaction, Prognosis, Reverse Transcriptase Polymerase Chain Reaction, Telomere/*ultrastructure, Time Factors, Treatment Outcome
HSV kategori
Forskningsprogram
patologi
Identifikatorer
URN: urn:nbn:se:umu:diva-15407DOI: 10.1182/blood-2004-11-4394PubMedID: 15746080OAI: oai:DiVA.org:umu-15407DiVA, id: diva2:155079
Tilgjengelig fra: 2008-01-11 Laget: 2008-01-11 Sist oppdatert: 2018-06-09bibliografisk kontrollert
Inngår i avhandling
1. Telomere length as prognostic parameter in chronic lymphocytic leukemia
Åpne denne publikasjonen i ny fane eller vindu >>Telomere length as prognostic parameter in chronic lymphocytic leukemia
2011 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia among the adult population in western countries and accounts for 30-40% of all leukemias. With survival time ranging from months to decades, the clinical course of individual CLL patients is highly variable. This heterogeneity and in the end the need for means to identify the patients with less favorable disease has encouraged the search for biomarkers that can predict the prognosis.

Telomeres are repetitive structures protecting the chromosomal endings and shorten at each cell division. Telomere length (TL) has been indicated as a prognostic factor both in hematological malignancies and solid tumors. In B-CLL, TL is associated with mutation status of the immunoglobulin heavy chain variable (IGHV) gene and with clinical course. In the present thesis the main aim was to evaluate TL as a biomarker in B-CLL using a quantitative PCR-based method for TL determination.

In paper I, TL was shown to be a prognostic factor for stage A and stage B/C patients, whereas IGHV mutation status predicted outcome only in stage A patients. Moreover, IGHV mutated CLL cases were subdivided by TL into two groups with different prognosis, a subdivision not seen for unmutated cases. Interestingly, the IGHV-mutated group with short telomeres had en overall survival close to that of the unmutated cases. Thus, a combination of IGHV mutation status and telomere length gave an improved subclassification of CLL identifying previously unrecognized patient groups with different outcomes.

TL correlates with cellular origin of B-cell malignancies in relation to the germinal center (GC). In paper II different B-cell lymphoma/leukemia subtypes were analyzed. Shortest telomeres were found in IGHV unmutated CLLs, differing significantly from IGHV mutated cases. Contrary to this, mantle cell lymphomas (MCL) demonstrated similar TL regardless of IGHV mutation status. TL differed significantly between GC-like and non-GC-like diffuse large B-cell lymphomas (DLBCL) and follicular lymphomas (FL) had shorter telomeres than GC-like DLBCL. Hairy cell leukemias, which display Ig gene intraclonal heterogeneity, had longer telomeres than FLs and non-GC-DLBCL, but shorter than GC-DLBCL. In conclusion, TL seemed not to simply correlate with GC origin.

Paper III presents a B-CLL cohort assessed for TL, genomic aberrations, IGHV mutation status, CD38 and ZAP-70 expression. An inverse correlation existed between TL and IGHV homology, CD38 and ZAP-70 expression. The presence of genomic aberrations was similar among patients regardless of TL. In contrast, 13q deletion, a favorable biomarker, was more frequent in patients with long telomeres, while 11q and 17p deletions (markers of less favorable outcome) were more frequent in the subgroup with short telomeres.

In paper IV a large group of mainly indolent CLL cases from a population based cohort was studied again showing an association between TL and prognosis, especially in “good” prognosis cases as defined by other biomarkers. Multivariate analysis indicated a strong connection between IGHV mutation status, lipoprotein lipase (LPL) expression and TL. A comparison of TL in diagnostic and follow up samples demonstrated a significant correlation, and also in the follow samples TL constituted a significant biomarker for survival.

sted, utgiver, år, opplag, sider
Umeå: Umeå University, 2011. s. 60
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1399
Emneord
telomere length, chronic lymphocytic leukemia, prognosis, longitudinal sampling, genomic aberrations, IGHV, CD38, ZAP70, prognostic factors
HSV kategori
Forskningsprogram
patologi
Identifikatorer
urn:nbn:se:umu:diva-39463 (URN)978-91-7459-138-5 (ISBN)
Disputas
2011-02-18, E04, Norrlands Universitetssjukhus, Byggnad 6E, Umeå, 23:06 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2011-02-01 Laget: 2011-01-27 Sist oppdatert: 2018-06-08bibliografisk kontrollert

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