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Prepublished online as a Blood First Edition Paper on April 30, 2002; DOI 10.1182/blood-2002-02-0382.
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Blood, 15 August 2002, Vol. 100, No. 4, pp. 1430-1437
NEOPLASIA
ATM mutations are associated with inactivation of the
ARF-TP53 tumor suppressor pathway in diffuse
large B-cell lymphoma
Kirsten Grønbæk,
Jesper Worm,
Elisabeth Ralfkiaer,
Vibeke Ahrenkiel,
Peter Hokland, and
Per Guldberg
From the Institute of Cancer Biology, Danish Cancer
Society; Department of Pathology, Rigshospitalet; and Department of
Pathology, Herlev University Hospital, Copenhagen, Denmark, and
Department of Hematology, Aarhus University Hospital, Aarhus, Denmark.
The ATM serine-threonine kinase plays a central role in the
cellular response to DNA damage. Germ-line mutations in the
ATM gene cause ataxia-telangiectasia (A-T), a multisystem
disorder associated with predisposition to lymphoma and acute leukemia. Moreover, somatic ATM mutations have been identified in
T-cell prolymphocytic leukemia, mantle cell lymphoma, and B-cell
chronic lymphocytic leukemia. In this study, the entire ATM
coding sequence was examined in genomic DNA from 120 lymphoid
neoplasms. Novel mutations and mutations implicated in cancer and/or
A-T were found in 9 of 45 diffuse large B-cell lymphomas (DLBCLs), 2 of
24 follicular lymphomas, and 1 of 27 adult acute lymphoblastic
leukemias, whereas no such mutations were detected among 24 peripheral
T-cell lymphomas. The mutational spectrum consisted of 2 nonsense
mutations, 1 mutation affecting RNA splicing, and 10 missense variants.
Most of these mutations were associated with loss or mutation of the
paired ATM allele, consistent with biallelic inactivation
of ATM. Of the 9 DLBCLs with ATM mutations, 7 also carried TP53 mutations and/or deletions of the
INK4a/ARF locus (P = .003). The
ATM 735C>T substitution previously considered a rare
normal variant was found to be 5.6 times more frequent in individuals
with DLBCL than in random individuals (P = .026),
suggesting that it may predispose to B-cell lymphoma. Our data suggest
that ATM mutations contribute to the development of
DLBCL, and that ATM and the ARF-p53 tumor suppressor pathway may
cooperate in the pathogenesis of this malignancy.
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