title: CHK2-decreased protein expression and infrequent genetic alterations mainly occur in aggressive types of non-Hodgkin lymphomas.
abstract: The 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 nonneoplastic lymphoid samples. A heterozygous Ile157Thr 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, 5 tumors, one typical MCL, 2 blastoid MCLs, and 2 large cell lymphomas, showed marked loss of protein expression, including 2 samples with complete absence of CHK2 protein. These 2 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 posttranscriptional 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.
authors.affiliation: Laboratory of Pathology, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Spain.
authors.forename: Frederic
authors.initials: F
authors.lastname: Tort
authors.forename: Silvia
authors.initials: S
authors.lastname: Hernàndez
authors.forename: Silvia
authors.initials: S
authors.lastname: Beà
authors.forename: Antonio
authors.initials: A
authors.lastname: Martínez
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
authors.forename: Xavier
authors.initials: X
authors.lastname: Puig
authors.forename: Emma
authors.initials: E
authors.lastname: Camacho
authors.forename: Montse
authors.initials: M
authors.lastname: Sánchez
authors.forename: Iracema
authors.initials: I
authors.lastname: Nayach
authors.forename: Armando
authors.initials: A
authors.lastname: Lopez-Guillermo
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Fernández
authors.forename: Dolors
authors.initials: D
authors.lastname: Colomer
authors.forename: Luis
authors.initials: L
authors.lastname: Hernàndez
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
mesh_terms: D019943:Amino Acid Substitution; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002455:Cell Division; D064447:Checkpoint Kinase 2; D002869:Chromosome Aberrations; D019175:DNA Methylation; D004268:DNA-Binding Proteins; D004790:Enzyme Induction; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology* / Q000235:genetics; D008221:Lymphoid Tissue / Q000201:enzymology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000201:enzymology / Q000235:genetics; D020522:Lymphoma, Mantle-Cell / Q000201:enzymology / Q000235:genetics; D008228:Lymphoma, Non-Hodgkin / Q000201:enzymology* / Q000235:genetics; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000032:analysis*; D018807:Polymorphism, Single-Stranded Conformational; D011494:Protein Kinases / Q000032:analysis*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases