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Blood, 1 January 2002, Vol. 99, No. 1, pp. 238-244
NEOPLASIA
ATM gene inactivation in mantle cell
lymphoma mainly occurs by truncating mutations and missense mutations
involving the phosphatidylinositol-3 kinase domain and is associated
with increasing numbers of chromosomal imbalances
Emma Camacho,
Luis Hernández,
Silvia Hernández,
Frederic Tort,
Beatriz Bellosillo,
Silvia Beà,
Francesc Bosch,
Emili Montserrat,
Antonio Cardesa,
Pedro L. Fernández, and
Elias Campo
From the Departments of Anatomic Pathology and
Hematology, Hospital Clinic, Institut d'Investigacions
Biomèdiques August Pi i Sunyer, University of Barcelona, Spain;
and Centro de Investigación del Cáncer, CSIC-University of
Salamanca, Spain.
The ataxia-telangiectasia mutated (ATM) gene
codifies for a protein critically involved in the cellular response to
DNA damage. ATM alterations have been observed in some sporadic
lymphoproliferative disorders. The recurrent 11q22-23 deletions found
in mantle cell lymphoma (MCL) suggest that ATM could be inactivated in
these lymphomas. In this study, ATM gene alterations and
protein expression were examined in 20 and 17 MCL tumor specimens,
respectively. Previously, these patients had been examined for
p53 and p14ARF gene status and
analyzed by comparative genomic hybridization. Nine patients had
11q22-23 losses. Eight ATM gene mutations were detected in
7 patients. These alterations were 3 missense mutations in the
phosphatidylinositol-3 kinase (PI-3K) domain and 5 truncating mutations, including 3 frameshifts, a nonsense mutation, and a substitution of the initial methionine. All truncating mutations were
associated with lack of protein expression. Somatic origin was
demonstrated in 3 mutations, whereas one mutation was carried heterozygously in the patient germ line. Chromosomal imbalances were
significantly higher in typical MCL with ATM inactivation (7.8 ± 1.3) than in tumors with the wild-type gene
(3 ± 1.1) (P = .001). Moreover, tumors with bi-allelic
ATM alteration were associated with 3q gains (P = .015)
and frequent extranodal involvement (P = .049).
ATM gene alterations were not related to the histologic variant of the tumors, p53/p14ARF gene status,
survival, or other clinicopathologic features of the patients. These
findings indicate that ATM gene mutations in MCL are mainly
truncating or missense mutations involving the PI-3K domain, and that
may play a role in the pathogenesis of a subset of these tumors with
increased numbers of chromosomal imbalances.
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