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Prepublished online as a Blood First Edition Paper on August 1, 2002; DOI 10.1182/blood-2002-04-1078.
Submitted April 8, 2002
Accepted July 17, 2002
CHK2-decreased protein expression and infrequent genetic alterations mainly occur in aggressive types of non-Hodgkin's lymphomas
Frederic Tort, Silvia Hernandez, Silvia Bea, Antonio Martinez, Manel Esteller, James G Herman, Xavier Puig, Emma Camacho, Luis Hernandez, Montse Sanchez, Iracema Nayach, Armando Lopez-Guillermo, Pedro L Fernandez, Dolors Colomer, and Elias Campo*
Laboratory of Pathology, Hospital Clinic, Barcelona, Spain
Cancer Epigenetics Laboratory, Spanish National Cancer Research Center, Madrid, Spain
Johns Hopkins Oncology Center, Baltimore, MD, USA
Department of Health and Social Security, Information and Studies Service, Barcelona, Spain
Department of Haematology, Hospital Clinic, Barcelona, Spain
* Corresponding author; email: campo{at}medicina.ub.es.
CHK2 gene codifies for a serine/threonine kinase that plays a central role in DNA damage response pathways. To determine the potential role of CHK2 alterations in the pathogenesis of lymphoid neoplasms we have examined the gene status, protein, and mRNA expression in a series of tumors and non-neoplastic lymphoid samples. A heterozygous I157T substitution, also present in the germ-line of the patient, was detected in a blastoid mantle cell lymphoma (MCL). CHK2 protein and mRNA expression levels were similar in all types of lymphomas and reactive samples, and these levels were independent of the proliferative activity of the tumors. However, five tumors, one typical MCL, two blastoid MCL, and two large cell lymphomas, showed marked loss of protein expression, including two samples with complete absence of CHK2 protein. These two lymphomas showed the highest number of chromosomal imbalances detected by comparative genomic hybridization in the whole series of cases. However, no mutations, deletions, or hypermethylation of the promoter region were identified in any of these tumors. mRNA levels were similar in cases with low and normal protein expression, suggesting a post-transcriptional regulation of the protein in these tumors. CHK2 gene and protein alterations were not related to p53 and ATM gene status. In conclusion, CHK2 alterations are uncommon in malignant lymphomas but occur in a subset of aggressive tumors independently of p53 or ATM alterations. The high number of chromosomal imbalances in tumors with complete absence of CHK2 protein suggests a role of this gene in chromosomal instability in human lymphomas.
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