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Articles by R. A Gatti
Total Records ( 2 ) for R. A Gatti
  J. L Bernstein , R. W Haile , M Stovall , J. D Boice , R. E Shore , B Langholz , D. C Thomas , L Bernstein , C. F Lynch , J. H Olsen , K. E Malone , L Mellemkjaer , A. L Borresen Dale , B. S Rosenstein , S. N Teraoka , A. T Diep , S. A Smith , M Capanu , A. S Reiner , X Liang , R. A Gatti , P Concannon and and the WECARE Study Collaborative Group
  Background

Ionizing radiation is a known mutagen and an established breast carcinogen. The ATM gene is a key regulator of cellular responses to the DNA damage induced by ionizing radiation. We investigated whether genetic variants in ATM play a clinically significant role in radiation-induced contralateral breast cancer in women.

Methods

The Women's Environmental, Cancer, and Radiation Epidemiology Study is an international population-based case–control study nested within a cohort of 52 536 survivors of unilateral breast cancer diagnosed between 1985 and 2000. The 708 case subjects were women with contralateral breast cancer, and the 1397 control subjects were women with unilateral breast cancer matched to the case subjects on age, follow-up time, registry reporting region, and race and/or ethnicity. All women were interviewed and underwent full mutation screening of the entire ATM gene. Complete medical treatment history information was collected, and for all women who received radiotherapy, the radiation dose to the contralateral breast was reconstructed using radiotherapy records and radiation measurements. Rate ratios (RRs) and corresponding 95% confidence intervals (CIs) were estimated by using multivariable conditional logistic regression. All P values are two-sided.

Results

Among women who carried a rare ATM missense variant (ie, one carried by <1% of the study participants) that was predicted to be deleterious, those who were exposed to radiation (mean radiation exposure = 1.2 Gy, SD = 0.7) had a statistically significantly higher risk of contralateral breast cancer compared with unexposed women who carried the wild-type genotype (0.01–0.99 Gy: RR = 2.8, 95% CI = 1.2 to 6.5; ≥1.0 Gy: RR = 3.3, 95% CI = 1.4 to 8.0) or compared with unexposed women who carried the same predicted deleterious missense variant (0.01–0.99 Gy: RR = 5.3, 95% CI = 1.6 to 17.3; ≥1.0 Gy: RR = 5.8, 95% CI = 1.8 to 19.0; Ptrend = .044).

Conclusions

Women who carry rare deleterious ATM missense variants and who are treated with radiation may have an elevated risk of developing contralateral breast cancer. However, the rarity of these deleterious missense variants in human populations implies that ATM mutations could account for only a small portion of second primary breast cancers.

  S Zha , C. H Bassing , T Sanda , J. W Brush , H Patel , P. H Goff , M. M Murphy , S Tepsuporn , R. A Gatti , A. T Look and F. W. Alt
 

Ataxia telangiectasia mutated (ATM) deficiency predisposes humans and mice to T lineage lymphomas with recurrent chromosome 14 translocations involving the T cell receptor / (Tcra/d) locus. Such translocations have been thought to result from aberrant repair of DNA double-strand breaks (DSBs) during Tcra locus V(D)J recombination, and to require the Tcra enhancer (E) for Tcra rearrangement or expression of the translocated oncogene. We now show that, in addition to the known chromosome 14 translocation, ATM-deficient mouse thymic lymphomas routinely contain a centromeric fragment of chromosome 14 that spans up to the 5' boundary of the Tcra/d locus, at which position a 500-kb or larger region centromeric to Tcra/d is routinely amplified. In addition, they routinely contain a large deletion of the telomeric end of one copy of chromosome 12. In contrast to prior expectations, the recurrent translocations and amplifications involve V(D)J recombination–initiated breaks in the Tcrd locus, as opposed to the Tcra locus, and arise independently of the E. Overall, our studies reveal previously unexpected mechanisms that contribute to the oncogenic transformation of ATM-deficient T lineage cells.

 
 
 
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