Cancer risks and mortality in heterozygous ATM mutation carriers.
BACKGROUND
Homozygous or compound heterozygous mutations in the ATM gene are the principal cause of ataxia telangiectasia (A-T). Several studies have suggested that heterozygous carriers of ATM mutations are at increased risk of breast cancer and perhaps of other cancers, but the precise risk is uncertain.


METHODS
Cancer incidence and mortality information for 1160 relatives of 169 UK A-T patients (including 247 obligate carriers) was obtained through the National Health Service Central Registry. Relative risks (RRs) of cancer in carriers, allowing for genotype uncertainty, were estimated with a maximum-likelihood approach that used the EM algorithm. Maximum-likelihood estimates of cancer risks associated with three groups of mutations were calculated using the pedigree analysis program MENDEL. All statistical tests were two-sided.


RESULTS
The overall relative risk of breast cancer in carriers was 2.23 (95% confidence interval [CI] = 1.16 to 4.28) compared with the general population but was 4.94 (95% CI = 1.90 to 12.9) in those younger than age 50 years. The relative risk for all cancers other than breast cancer was 2.05 (95% CI = 1.09 to 3.84) in female carriers and 1.23 (95% CI = 0.76 to 2.00) in male carriers. Breast cancer was the only site for which a clear risk increase was seen, although there was some evidence of excess risks of colorectal cancer (RR = 2.54, 95% CI = 1.06 to 6.09) and stomach cancer (RR = 3.39, 95% CI = 0.86 to 13.4). Carriers of mutations predicted to encode a full-length ATM protein had cancer risks similar to those of people carrying truncating mutations.


CONCLUSIONS
These results confirm a moderate risk of breast cancer in A-T heterozygotes and give some evidence of an excess risk of other cancers but provide no support for large mutation-specific differences in risk.
Thompson
Deborah
D
CR-UK Genetic Epidemiology Unit, University of Cambridge, Cambridge, UK.
Duedal
Silvia
S
Kirner
Jennifer
J
McGuffog
Lesley
L
Last
James
J
Reiman
Anne
A
Byrd
Philip
P
Taylor
Malcolm
M
Easton
Douglas F
DF
D000328:Adult; D000368:Aged; D000465:Algorithms; D001260:Ataxia Telangiectasia / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D016001:Confidence Intervals; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000453:epidemiology* / Q000235:genetics* / Q000401:mortality; D010375:Pedigree; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D006113:United Kingdom / Q000453:epidemiology
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases