High incidence of cancer in a family segregating a mutation of the ATM gene: possible role of ATM heterozygosity in cancer.
ATM mutations predispose cells to malignancy by promoting chromosomal instability. We have identified a family with multiple cancers that segregates a mutant allele of ATM, IVS61+2insTA, which causes skipping of exon 61 in the mRNA, as well as a previously undescribed polymorphism, IVS61+104C(54):T(46). The mutation was inherited by two sisters, one who developed breast cancer at age 39 and the second at age 44, from their mother, who developed kidney cancer at age 67. Molecular studies were undertaken to determine the role of the ATM gene in the development of cancer in this family. Studies of irradiated lymphocytes from both sisters revealed elevated numbers of chromatid breaks, typical of A-T heterozygotes. Studies on lymphoblastoid cell lines established from these individuals revealed abnormal p53 induction and apoptosis after DNA damage. Loss of heterozygosity (LOH) in the ATM region of chromosome 11q23.1 showed that the normal ATM allele was lost in the breast tumor of the older sister. LOH was not seen at the BRCA1 or BRCA2 loci. BRCA2 is not likely to be a cancer-predisposing gene in this family because each sister inherited different chromosomes 13 from each parent. The sisters share their maternal BRCA1 allele, although no mutation in this gene was detected in the family. Our findings suggest that haploinsufficiency at ATM may promote tumorigenesis, even though LOH at the locus supports a more classic two-hit tumor suppressor gene model.
Bay
J O
JO
Laboratoire d'Oncologie Moléculaire, Centre régional de lutte contre le cancer Jean Perrin, Clermont-Ferrand, France.
Uhrhammer
N
N
Pernin
D
D
Presneau
N
N
Tchirkov
A
A
Vuillaume
M
M
Laplace
V
V
Grancho
M
M
Verrelle
P
P
Hall
J
J
Bignon
Y J
YJ
D000328:Adult; D000368:Aged; D001260:Ataxia Telangiectasia / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics; D018797:Cell Cycle Proteins; D004247:DNA / Q000235:genetics; D004249:DNA Damage; D004268:DNA-Binding Proteins; D005091:Exons; D005260:Female; D019398:Genes, BRCA1; D006579:Heterozygote; D006801:Humans; D007438:Introns; D007680:Kidney Neoplasms / Q000235:genetics; D019656:Loss of Heterozygosity; D008214:Lymphocytes / Q000528:radiation effects; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D004247:DNA; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases