Pathogenic ATM mutations occur rarely in a subset of multiple myeloma patients.
Ataxia Telangiectasia (A-T) patients have biallelic inactivation of the ATM gene and exhibit a 200-fold-increased frequency of lymphoid tumours. ATM mutations have been found in a number of adult lymphoid malignancies but there is no data on the occurrence of ATM mutations in multiple myeloma tumours. The purpose of our work was to investigate the occurrence of ATM mutations in multiple myeloma and to this end we screened 45 sporadic cases for ATM mutations using denaturing high-performance liquid chromatography analysis and DNA sequencing. Pathogenic ATM mutations were identified in 2/45 of the myelomas compared with a published estimate of ATM mutant allele frequency in the UK population of 2/521 (P = 0.033). One was the missense mutation 7181C>T which was then modelled in an expression system and the S2394L protein shown to have no ATM kinase activity. The second myeloma had the pathogenic ATM splice site mutation IVS40-1G>C leading to loss of exon 41. We also report a 48-year-old ataxia telangiectasia patient who developed multiple myeloma. Taken together our study suggests that ATM mutation may play a role in the pathogenesis of a subset of multiple myelomas.
Austen
Belinda
B
CRUK Institute for Cancer Studies, University of Birmingham, Birmingham, UK.
Barone
Giancarlo
G
Reiman
Anne
A
Byrd
Philip J
PJ
Baker
Claire
C
Starczynski
Jane
J
Nobbs
Michael C
MC
Murphy
Raymond P
RP
Enright
Helen
H
Chaila
Elijah
E
Quinn
John
J
Stankovic
Tatjana
T
Pratt
Guy
G
Taylor
A Malcolm R
AM
D000368:Aged; D000369:Aged, 80 and over; D001260:Ataxia Telangiectasia / Q000150:complications; D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western / Q000379:methods; D018797:Cell Cycle Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D009101:Multiple Myeloma / Q000209:etiology / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012189:Retrospective Studies; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases