Lymphoid tumours and breast cancer in ataxia telangiectasia: substantial protective effect of residual ATM kinase activity against childhood tumours

A Reiman, V Srinivasan, G Barone, J I Last, L L Wootton, E G Davies, M M Verhagen, M A Willemsen, C M Weemaes, P J Byrd, L Izatt, D F Easton, D J Thompson, A M Taylor

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Immunodeficiency in ataxia telangiectasia (A-T) is less severe in patients expressing some mutant or normal ATM kinase activity. We, therefore, determined whether expression of residual ATM kinase activity also protected against tumour development in A-T.

METHODS: From a total of 296 consecutive genetically confirmed A-T patients from the British Isles and the Netherlands, we identified 66 patients who developed a malignant tumour; 47 lymphoid tumours and 19 non-lymphoid tumours were diagnosed. We determined their ATM mutations, and whether cells from these patients expressed any ATM with residual ATM kinase activity.

RESULTS: In childhood, total absence of ATM kinase activity was associated, almost exclusively, with development of lymphoid tumours. There was an overwhelming preponderance of tumours in patients <16 years without kinase activity compared with those with some residual activity, consistent with a substantial protective effect of residual ATM kinase activity against tumour development in childhood. In addition, the presence of eight breast cancers in A-T patients, a 30-fold increased risk, establishes breast cancer as part of the A-T phenotype.

CONCLUSION: Overall, a spectrum of tumour types is associated with A-T, consistent with involvement of ATM in different mechanisms of tumour formation. Tumour type was influenced by ATM allelic heterogeneity, residual ATM kinase activity and age.

Original languageEnglish
Pages (from-to)586-591
Number of pages6
JournalBritish Journal of Cancer
Volume105
Issue number4
DOIs
Publication statusPublished - 9 Aug 2011

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Ataxia Telangiectasia
Phosphotransferases
Breast Neoplasms
Neoplasms
Netherlands
Phenotype

Keywords

  • Adolescent
  • Adult
  • Ataxia Telangiectasia
  • Ataxia Telangiectasia Mutated Proteins
  • Brain Neoplasms
  • Breast Neoplasms
  • Cell Cycle Proteins
  • Child
  • DNA-Binding Proteins
  • Female
  • Humans
  • Immunoblotting
  • Kaplan-Meier Estimate
  • Lymphoma
  • Male
  • Mutation
  • Neoplasms
  • Netherlands
  • Protein-Serine-Threonine Kinases
  • Tumor Suppressor Proteins
  • United Kingdom
  • Young Adult
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Lymphoid tumours and breast cancer in ataxia telangiectasia : substantial protective effect of residual ATM kinase activity against childhood tumours. / Reiman, A; Srinivasan, V; Barone, G; Last, J I; Wootton, L L; Davies, E G; Verhagen, M M; Willemsen, M A; Weemaes, C M; Byrd, P J; Izatt, L; Easton, D F; Thompson, D J; Taylor, A M.

In: British Journal of Cancer, Vol. 105, No. 4, 09.08.2011, p. 586-591.

Research output: Contribution to journalArticle

Reiman, A, Srinivasan, V, Barone, G, Last, JI, Wootton, LL, Davies, EG, Verhagen, MM, Willemsen, MA, Weemaes, CM, Byrd, PJ, Izatt, L, Easton, DF, Thompson, DJ & Taylor, AM 2011, 'Lymphoid tumours and breast cancer in ataxia telangiectasia: substantial protective effect of residual ATM kinase activity against childhood tumours' British Journal of Cancer, vol. 105, no. 4, pp. 586-591. https://doi.org/10.1038/bjc.2011.266
Reiman, A ; Srinivasan, V ; Barone, G ; Last, J I ; Wootton, L L ; Davies, E G ; Verhagen, M M ; Willemsen, M A ; Weemaes, C M ; Byrd, P J ; Izatt, L ; Easton, D F ; Thompson, D J ; Taylor, A M. / Lymphoid tumours and breast cancer in ataxia telangiectasia : substantial protective effect of residual ATM kinase activity against childhood tumours. In: British Journal of Cancer. 2011 ; Vol. 105, No. 4. pp. 586-591.
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abstract = "BACKGROUND: Immunodeficiency in ataxia telangiectasia (A-T) is less severe in patients expressing some mutant or normal ATM kinase activity. We, therefore, determined whether expression of residual ATM kinase activity also protected against tumour development in A-T.METHODS: From a total of 296 consecutive genetically confirmed A-T patients from the British Isles and the Netherlands, we identified 66 patients who developed a malignant tumour; 47 lymphoid tumours and 19 non-lymphoid tumours were diagnosed. We determined their ATM mutations, and whether cells from these patients expressed any ATM with residual ATM kinase activity.RESULTS: In childhood, total absence of ATM kinase activity was associated, almost exclusively, with development of lymphoid tumours. There was an overwhelming preponderance of tumours in patients <16 years without kinase activity compared with those with some residual activity, consistent with a substantial protective effect of residual ATM kinase activity against tumour development in childhood. In addition, the presence of eight breast cancers in A-T patients, a 30-fold increased risk, establishes breast cancer as part of the A-T phenotype.CONCLUSION: Overall, a spectrum of tumour types is associated with A-T, consistent with involvement of ATM in different mechanisms of tumour formation. Tumour type was influenced by ATM allelic heterogeneity, residual ATM kinase activity and age.",
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T1 - Lymphoid tumours and breast cancer in ataxia telangiectasia

T2 - substantial protective effect of residual ATM kinase activity against childhood tumours

AU - Reiman, A

AU - Srinivasan, V

AU - Barone, G

AU - Last, J I

AU - Wootton, L L

AU - Davies, E G

AU - Verhagen, M M

AU - Willemsen, M A

AU - Weemaes, C M

AU - Byrd, P J

AU - Izatt, L

AU - Easton, D F

AU - Thompson, D J

AU - Taylor, A M

PY - 2011/8/9

Y1 - 2011/8/9

N2 - BACKGROUND: Immunodeficiency in ataxia telangiectasia (A-T) is less severe in patients expressing some mutant or normal ATM kinase activity. We, therefore, determined whether expression of residual ATM kinase activity also protected against tumour development in A-T.METHODS: From a total of 296 consecutive genetically confirmed A-T patients from the British Isles and the Netherlands, we identified 66 patients who developed a malignant tumour; 47 lymphoid tumours and 19 non-lymphoid tumours were diagnosed. We determined their ATM mutations, and whether cells from these patients expressed any ATM with residual ATM kinase activity.RESULTS: In childhood, total absence of ATM kinase activity was associated, almost exclusively, with development of lymphoid tumours. There was an overwhelming preponderance of tumours in patients <16 years without kinase activity compared with those with some residual activity, consistent with a substantial protective effect of residual ATM kinase activity against tumour development in childhood. In addition, the presence of eight breast cancers in A-T patients, a 30-fold increased risk, establishes breast cancer as part of the A-T phenotype.CONCLUSION: Overall, a spectrum of tumour types is associated with A-T, consistent with involvement of ATM in different mechanisms of tumour formation. Tumour type was influenced by ATM allelic heterogeneity, residual ATM kinase activity and age.

AB - BACKGROUND: Immunodeficiency in ataxia telangiectasia (A-T) is less severe in patients expressing some mutant or normal ATM kinase activity. We, therefore, determined whether expression of residual ATM kinase activity also protected against tumour development in A-T.METHODS: From a total of 296 consecutive genetically confirmed A-T patients from the British Isles and the Netherlands, we identified 66 patients who developed a malignant tumour; 47 lymphoid tumours and 19 non-lymphoid tumours were diagnosed. We determined their ATM mutations, and whether cells from these patients expressed any ATM with residual ATM kinase activity.RESULTS: In childhood, total absence of ATM kinase activity was associated, almost exclusively, with development of lymphoid tumours. There was an overwhelming preponderance of tumours in patients <16 years without kinase activity compared with those with some residual activity, consistent with a substantial protective effect of residual ATM kinase activity against tumour development in childhood. In addition, the presence of eight breast cancers in A-T patients, a 30-fold increased risk, establishes breast cancer as part of the A-T phenotype.CONCLUSION: Overall, a spectrum of tumour types is associated with A-T, consistent with involvement of ATM in different mechanisms of tumour formation. Tumour type was influenced by ATM allelic heterogeneity, residual ATM kinase activity and age.

KW - Adolescent

KW - Adult

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KW - Ataxia Telangiectasia Mutated Proteins

KW - Brain Neoplasms

KW - Breast Neoplasms

KW - Cell Cycle Proteins

KW - Child

KW - DNA-Binding Proteins

KW - Female

KW - Humans

KW - Immunoblotting

KW - Kaplan-Meier Estimate

KW - Lymphoma

KW - Male

KW - Mutation

KW - Neoplasms

KW - Netherlands

KW - Protein-Serine-Threonine Kinases

KW - Tumor Suppressor Proteins

KW - United Kingdom

KW - Young Adult

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/bjc.2011.266

DO - 10.1038/bjc.2011.266

M3 - Article

VL - 105

SP - 586

EP - 591

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 4

ER -