Polymorphisms in apoptosis- and proliferation-related genes, ionizing radiation exposure, and risk of breast cancer among U.S. Radiologic Technologists.
BACKGROUND
Although genes involved in apoptosis pathways and DNA repair pathways are both essential for maintaining genomic integrity, genetic variants in DNA repair have been thought to increase susceptibility to radiation carcinogenesis, but similar hypotheses have not generally been raised about apoptosis genes. For this reason, potential modification of the relationship between ionizing radiation exposure and breast cancer risk by polymorphic apoptosis gene variants have not been investigated among radiation-exposed women.


METHODS
In a case-control study of 859 cases and 1,083 controls within the U.S. Radiologic Technologists cohort, we assessed breast cancer risk with respect to 16 candidate variants in eight genes involved in apoptosis, inflammation, and proliferation. Using carefully reconstructed cumulative breast dose estimates from occupational and personal diagnostic ionizing radiation, we also investigated the joint effects of these polymorphisms on the risk of breast cancer.


RESULTS
In multivariate analyses, we observed a significantly decreased risk of breast cancer associated with the homozygous minor allele of CASP8 D302H [rs1045485, odds ratio (OR), 0.3; 95% confidence interval (95% CI), 0.1-0.8]. We found a significantly increased breast cancer risk with increasing minor alleles for IL1A A114S (rs17561); heterozygote OR 1.2 (95% CI, 1.0-1.4) and homozygote OR 1.5 (95% CI, 1.1-2.0), P(trend) = 0.008. Assuming a dominant genetic model, IL1A A114S significantly modified the dose-response relationship between cumulative personal diagnostic radiation and breast cancer risk, adjusted for occupational dose (P(interaction) = 0.004).


CONCLUSIONS
The U.S. Radiologic Technologists breast cancer study provided a unique opportunity to examine the joint effects of common genetic variation and ionizing radiation exposure to the breast using detailed occupational and personal diagnostic dose data. We found evidence of effect modification of the radiation and breast cancer dose-response relationship that should be confirmed in studies with more cases and controls and quantified radiation breast doses in the low-to-moderate range.
Sigurdson
Alice J
AJ
Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, 6120 Executive Boulevard, EPS 7092, MSC 7238, Bethesda, MD 20892-7238, USA. sigurdsa@mail.nih.gov
Bhatti
Parveen
P
Doody
Michele M
MM
Hauptmann
Michael
M
Bowen
Laura
L
Simon
Steven L
SL
Weinstock
Robert M
RM
Linet
Martha S
MS
Rosenstein
Marvin
M
Stovall
Marilyn
M
Alexander
Bruce H
BH
Preston
Dale L
DL
Struewing
Jeffrey P
JP
Rajaraman
Preetha
P
D000369:Aged, 80 and over; D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000528:radiation effects; D001943:Breast Neoplasms / Q000235:genetics*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics; D016022:Case-Control Studies; D002455:Cell Division / Q000235:genetics* / Q000528:radiation effects; D015331:Cohort Studies; D004307:Dose-Response Relationship, Radiation; D005260:Female; D015870:Gene Expression / Q000528:radiation effects; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D053582:Interleukin-1alpha / Q000235:genetics; D008875:Middle Aged; D009381:Neoplasms, Radiation-Induced / Q000235:genetics* / Q000473:pathology; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018570:Risk Assessment; D013679:Technology, Radiologic
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C508584:IL1A protein, human; D053582:Interleukin-1alpha