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ATM mutations are associated with inactivation of the ARF-TP53 tumor suppressor pathway in diffuse large B-cell
Kirsten Grønbaek1, Jesper Worm, Elisabeth Ralfkiaer
1Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark.
Abstract:
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.
Insights
ATM gene mutations are implicated in lymphoid cancers like diffuse large B-cell lymphoma (DLBCL). This study found ATM mutations in DLBCL, suggesting a role in its development and potential cooperation with the ARF-p53 pathway.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- The ATM serine-threonine kinase is crucial for DNA damage response.
- Germline ATM mutations cause ataxia-telangiectasia (A-T), increasing lymphoma and leukemia risk.
- Somatic ATM mutations are found in various lymphoid malignancies.
Purpose of the Study:
- To investigate the role of ATM gene mutations in lymphoid neoplasms.
- To identify novel ATM mutations and their association with cancer and A-T.
- To explore the potential cooperative mechanisms between ATM and the ARF-p53 pathway in DLBCL pathogenesis.
Main Methods:
- Sequencing of the entire ATM coding sequence in genomic DNA from 120 lymphoid neoplasms.
- Analysis of mutation spectrum, including nonsense, splicing, and missense variants.
- Assessment of ATM allele status (loss or mutation) and correlation with TP53 mutations and INK4a/ARF locus deletions.
Main Results:
- ATM mutations were identified in 9/45 diffuse large B-cell lymphomas (DLBCLs), 2/24 follicular lymphomas, and 1/27 adult acute lymphoblastic leukemias.
- No ATM mutations were detected in 24 peripheral T-cell lymphomas.
- Most ATM mutations were associated with biallelic inactivation; 7/9 DLBCLs with ATM mutations also had TP53 mutations and/or INK4a/ARF deletions.
- The ATM 735C>T variant was significantly more frequent in DLBCL patients, suggesting a predisposition.
Conclusions:
- ATM mutations contribute to the development of DLBCL.
- ATM and the ARF-p53 tumor suppressor pathway may cooperate in DLBCL pathogenesis.
- The ATM 735C>T variant may predispose individuals to B-cell lymphoma.