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Variants in Activators and Downstream Targets of ATM, Radiation Exposure, and Contralateral Breast Cancer Risk in the WECARE Study

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Variants in Activators and Downstream Targets of ATM, Radiation Exposure, and Contralateral Breast Cancer Risk in the WECARE Study RESEARCH ARTICLE OFFICIAL JOURNAL Variants in Activators and Downstream Targets of ATM, Radiation Exposure, and Contralateral Breast Cancer Risk www.hgvs.org in the WECARE Study Jennifer D. Brooks,1∗ Sharon N. Teraoka,2 Anne S. Reiner,1 Jaya M. Satagopan,1 Leslie Bernstein,3 Duncan C. Thomas,4 Marinela Capanu,1 Marilyn Stovall,5 Susan A. Smith,5 Shan Wei,6 Roy E. Shore,7,8 John D. Boice, Jr.,9,10 Charles F. Lynch,11 Lene Mellemkjær,12 Kathleen E. Malone,13 Xiaolin Liang,1 the WECARE Study Collaborative Group,14 Robert W. Haile,4 Patrick Concannon,2 and Jonine L. Bernstein1 1Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York; 2Center for Public Health Genomics and the Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia; 3Division of Cancer Etiology, Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, California; 4Department of Preventive Medicine, University of Southern California, Los Angeles, California; 5Department of Radiation Physics, M.D. Anderson Cancer Center, University of Texas, Houston, Texas; 6Benaroya Research Institute at Virginia Mason, Seattle, Washington; 7Department of Environmental Medicine, New York University, New York, New York; 8Radiation Effects Research Foundation, Hiroshima, Japan; 9International Epidemiology Institute, Rockville, Maryland; 10Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt School of Medicine, Nashville, Tennessee; 11Department of Epidemiology, University of Iowa, Iowa City, Iowa; 12Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark; 13Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington; 14WECARE Study Collaborative Group members are listed in the Acknowledgments Communicated by Peter J. Oefner Received 3 November 2010; accepted revised manuscript 25 August 2011. Published online 6 September 2011 in Wiley Online Library (www.wiley.com/humanmutation).DOI: 10.1002/humu.21604 ABSTRACT: Ionizing radiation (IR) is a breast carcino- haplotype may be susceptible to the DNA-damaging gen that induces DNA double-strand breaks (DSBs), effects of radiation therapy associated with radiation- and variation in genes involved in the DNA DSB re- induced breast cancer. sponse has been implicated in radiation-induced breast Hum Mutat 00:1–7, 2011. C 2011 Wiley Periodicals, Inc. cancer. The Women’s Environmental, Cancer, and Ra- KEY WORDS: DNA repair; haplotypes; polymorphisms; diation Epidemiology (WECARE) study is a population- radiation; contralateral breast cancer based study of cases with contralateral breast cancer (CBC) and matched controls with unilateral breast cancer. The location-specific radiation dose received by the con- tralateral breast was estimated from radiotherapy records Introduction and mathematical models. One hundred fifty-two SNPs in six genes (CHEK2, MRE11A, MDC1, NBN, RAD50, Many of the genes known to be associated with increased sus- TP53BP1) involved in the DNA DSBs response were ceptibility to breast cancer function within a common biochemical genotyped. No variants or haplotypes were associated with pathway involved in signaling the presence of, and coordinating the CBC risk (649 cases and 1,284 controls) and no vari- response to, DNA double-strand breaks (DSBs) (i.e., BRCA1 [MIM# ants were found to interact with radiation dose. Carriers 113705], BRCA2 [MIM# 600185], CHEK2 [MIM# 604373], ATM of a RAD50 haplotype exposed to ≥1gray(Gy)hadan [MIM# 607585]) [Thompson and Easton, 2004]. Ionizing radiation increased risk of CBC compared with unexposed carri- (IR) is a known breast carcinogen [Boice Jr, 2001; Boice Jr et al., ers (Rate ratios [RR] = 4.31 [95% confidence intervals 1992; Hooning et al., 2008; Land et al., 2003; Preston et al., 2002; [CI] 1.93–9.62]); with an excess relative risk (ERR) per Stovall et al., 2008] and induces multiple types of DNA damage, Gy = 2.13 [95% CI 0.61–5.33]). Although the results most notably DSBs, that activate this signaling pathway. of this study were largely null, carriers of a haplotype The cellular response to the presence of DSBs begins with the in RAD50 treated with radiation had a greater CBC risk recognition of damage sites. A major component of DNA DSB sens- than unexposed carriers. This suggests that carriers of this ing is the MRE11A-RAD50-NBN (MRN) complex that acts to stabi- lize the broken strands of DNA at the break and carry out initial pro- cessing of the free DNA ends [Dzikiewicz-Krawczyk, 2008; Jazayeri et al., 2008; Lee and Paull, 2005]. The MRN complex recruits ATM, Additional Supporting Information may be found in the online version of this article. a large serine-threonine kinase to the site of damage and facilitates ∗ Correspondence to: Jennifer D. Brooks, Department of Epidemiology and Biostatis- its activation. Once activated, ATM phosphorylates a number of tics, Memorial Sloan-Kettering Cancer Center, 307 E 63rd Street, 3rd floor, New York, downstream targets including CHEK2, NBN, MDC1, and TP53BP1 NY 10065. E-mail: [email protected] [Dzikiewicz-Krawczyk, 2008; Lee et al., 2010; Lee and Paull, 2005], Contract grant sponsor: National Cancer Institute (R01CA114236, R01CA097397, amplifying the damage signal by stabilizing the presence of proteins U01CA083178, and R01CA137420 [to JS]). at the DSB site, such as the MRN, and recruiting others, such as C 2011 WILEY PERIODICALS, INC. MDC1 and TP53BP1. Ultimately, multiple signaling cascades are Materials and Methods activated by this process invoking cell-cycle checkpoint arrest, DNA repair, and apoptosis [Lavin, 2008]. Given the importance of DNA Study Population damage both in initiating carcinogenesis and in treating existing cancers, the key molecules in the pathway that signal the presence The Women’s Environmental, Cancer, and Radiation Epidemi- of DNA DSBs have become candidate risk factors for a variety of ology (WECARE) study is a multicenter, population-based, case– cancers, including breast cancer. control study where cases are women with asynchronous CBC Treatments received for a first breast cancer can influence a and controls are women with unilateral breast cancer (UBC) woman’s risk of developing a second primary breast cancer in the [Bernstein et al., 2004]. Participants were identified, recruited, and contralateral breast (CBC) especially among long-term survivors interviewed through four population-based cancer registries in the treated with radiation (RT) at an early age [Boice Jr et al., 1992; United States that are part of the National Cancer Institute’s Surveil- Hooning et al., 2008; Stovall et al., 2008]. Chemotherapy and ta- lance, Epidemiology, and End Results program: the Los Angeles moxifen both can reduce CBC risk [Bertelsen et al., 2008; Chen et al., County Cancer Surveillance Program; Cancer Surveillance System 1999]. Additionally, mutations in ATM, MRE11A (MIM# 600814), of the Fred Hutchinson Cancer Research Center (Seattle); State RAD50 (MIM# 604040), and NBN (MIM# 602667) lead to the syn- Health Registry of Iowa; and Cancer Surveillance Program of Or- dromes ataxia-telangiectasia (MIM# 208900), ataxia-telangiectasia- ange County/San Diego-Imperial Organization for Cancer Con- like disorder (MIM# 604391), RAD50 deficiency (MIM# 613078), trol (Orange County/San Diego). The fifth registry from which and Nijmegen breakage syndrome (MIM# 251260), respectively, participants were recruited was the Danish Breast Cancer Coop- that are associated with increased cellular sensitivity to IR [Helleday erative Group Registry and the Danish Cancer Registry [Bernstein et al., 2008]. et al., 2004]. Previously, we showed that CBC was not significantly associated Eligible women with CBC (cases) (n = 708) were selected from a with RT dose to the contralateral breast (Rate ratios, [RR] = 1.1 [95% cohort of 52,536 women with histologically confirmed breast can- confidence intervals, CI 0.9–1.3] overall, but that women under age cer reported to one of the five population-based cancer registries 40 exposed to >1 gray (Gy) had higher risk of CBC than unexposed who met the following criteria: (1) diagnosed between 1 January, women, RR = 2.5 [95% CI 1.4–4.5]) [Stovall et al., 2008]. We also 1985 and 31 December, 2000 with UBC followed by a second pri- showed that there are genetic variants that influence a woman’s mary, in situ or invasive, breast cancer in the contralateral breast, susceptibility to this radiation exposure. For example, rare vari- diagnosed at least 1 year later (i.e., between 1 January, 1986 and ants in ATM, predicted in silico to be deleterious, were associated 31 December, 2000); (2) resided in the same study reporting area with a nonsignificant increase in CBC risk in this study population for both diagnoses; (3) had no previous or intervening cancer di- [Concannon et al., 2008]. Conversely, some of the common ATM agnosis; (4) were under age 55 years at the time of diagnosis of variants were found to be associated with a reduction in CBC risk the first primary breast cancer; (5) were alive at the time of con- [Concannon et al., 2008]. When missense variants in ATM (minor tact; and (6) provided informed consent, completed an interview, allele frequency [MAF] < 1%), predicted to be deleterious, were ex- and provided a blood sample. The time between cases’ two diag- amined in the presence of RT, a statistically significant increase in noses defined the “at-risk interval.” A 1-year interval between first CBC risk was seen among carriers exposed to ≥1Gytothecontralat- and second breast cancer diagnosis was used to rule out synchronous eral breast compared radiation-unexposed women with wild-type disease. genotype (RR = 2.0 [95% CI 1.1–3.9]). Additionally, an increased WECARE study controls (n = 1,399) were selected from the risk was seen among carriers exposed to RT compared with unex- same five population-based cancer registries and met the follow- posed carriers with an excess relative risk (ERR) per Gy of 2.6 (95% ing criteria: (1) diagnosed between 1 January, 1985 and 31 De- CI 0.0–10.6), P for trend = 0.04 [Bernstein et al., 2010].
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