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Blood, Vol. 94 No. 2 (July 15), 1999:
pp. 748-753
Somatic ATM Mutations Indicate a Pathogenic Role of ATM in
B-Cell Chronic Lymphocytic Leukemia
Claudia Schaffner,
Stephan Stilgenbauer,
Gudrun A. Rappold,
Hartmut Döhner, and
Peter Lichter
From Abteilung "Organisation komplexer Genome", Deutsches
Krebsforschungszentrum, Heidelberg; Medizinische Klinik und Poliklinik
V, University of Heidelberg, Heidelberg; and the Institut für
Humangenetik, University of Heidelberg, Heidelberg, Germany.
Deletion in chromosome bands 11q22-q23 is one of the most common
chromosome aberrations in B-cell chronic lymphocytic leukemia (B-CLL).
It is associated with extensive lymph node involvement and poor
survival. The minimal consensus deletion comprises a segment, which
contains the ATM gene presenting an interesting candidate gene, as
mutations in ATM predispose A-T patients to lymphoid
malignancies. To investigate a potential pathogenic role of ATM in
B-cell tumorigenesis, we performed mutation analysis of ATM in
29 malignant lymphomas of B-cell origin (B-CLL = 27; mantle cell
lymphoma, [MCL] = 2). Twenty-three of these carried an 11q22-q23
deletion. In five B-CLLs and one MCL with deletion of one ATM
allele, a point mutation in the remaining allele was detected, which
resulted in aberrant transcript splicing, alteration, or truncation of
the protein. In addition, mutation analysis identified point mutations
in three cases without 11q deletion: two B-CLLs with one altered allele
and one MCL with both alleles mutated. In four cases analyzed, the
ATM alterations were not present in the germ line indicating a
somatic origin of the mutations. Our study demonstrates somatic
disruption of both alleles of the ATM gene by deletion or point
mutation and thus its pathogenic role in sporadic B-cell lineage tumors.
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