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Risk of Cancer by ATM Missense Mutations in the General Population

Sarah Louise Dombernowsky, Maren Weischer, Kristine Højgaard Allin, Stig Egil Bojesen, Anne Tybjjrg-Hansen, Børge Grønne Nordestgaard

From the Department of Clinical Biochemistry, Herlev University Hospital, Herlev; the Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, and the Copenhagen City Heart Study, Bispebjerg University Hospital, University of Copenhagen, Denmark

Corresponding author: Børge G. Nordestgaard, MD, DMSc, Department of Clinical Biochemistry, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark; e-mail: brno{at}heh.regionh.dk

	ABSTRACT

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Purpose Truncating and missense mutations in the ATM gene, which cause insufficient DNA damage surveillance, allow damaged cells to proceed into mitosis, which eventually results in increased cancer susceptibility. We tested the hypotheses that ATM Ser49Cys and ATM Ser707Pro heterozygosity increase the risk of cancer overall, of breast cancer, and of 26 other cancer subtypes in the general population.

Patients and Methods We genotyped 10,324 individuals from the Danish general population who were observed prospectively for 36 years, during which 2,056 developed cancer.

Results Multifactorially adjusted hazard ratios for ATM Ser49Cys heterozygotes versus noncarriers were 1.2 (95% CI, 0.9 to 1.5) for cancer overall, 0.8 (95% CI, 0.3 to 2.0) for breast cancer, 4.8 (95% CI, 2.2 to 11) for melanoma, 2.3 (95% CI, 1.1 to 5.0) for prostate cancer, and 3.4 (95% CI, 1.1 to 11) for cancer of the oral cavity/pharynx. Multifactorially adjusted hazard ratios for ATM Ser707Pro heterozygotes versus noncarriers were 0.8 (95% CI, 0.6 to 1.2) for cancer overall, 0.6 (95% CI, 0.2 to 1.6) for breast cancer, 10 (95% CI, 1.1 to 93) for thyroid/other endocrine tumors, and 2.7 (95% CI, 1.0 to 7.6) for cancer of corpus uteri.

Conclusion ATM missense mutations do not increase the risk of cancer overall or of breast cancer in the general population; however, we observed in exploratory analyses that ATM missense mutations may be associated with an increased risk of other cancer subtypes. As we did multiple comparisons, some of these findings could represent chance findings rather than real phenomena.

	INTRODUCTION

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ATM encodes the ataxia telangiectasia mutated protein, which is activated in response to DNA double-strand breakage that is caused by especially ionizing radiation.¹ When activated, ATM phosphorylates a variety of downstream substrates, including p53, CHEK2 and BRCA1, thereby mediating cell cycle arrest, DNA repair, or apoptosis.² Insufficient DNA damage surveillance by cell cycle checkpoints allows damaged cells to proceed into mitosis, which eventually results in increased cancer susceptibility.

ATM dysfunction caused by homozygosity of truncating and missense ATM mutations results in the clinical condition called ataxia telangiectasia, in which patients suffer neurologic symptoms and increased cancer susceptibility.³ Relatives of patients with ataxia telangiectasia obligate heterozygous for a broad range of truncating and missense ATM mutations also have increased cancer susceptibility.^4,5 It is, therefore, possible that ATM missense mutations could increase the risk of sporadic cancer in the general population.³

So far, various missense mutations in ATM have been associated with breast, lung, and prostate cancer in case-control studies.^6-8 Among these, ATM Ser49Cys and ATM Ser707Pro have been previously associated with two- to five-fold increased risks of breast cancer in some,^8-10 but not all, studies.^11,12 ATM Ser49Cys is located in a region involved in binding chromatin and p53,^13,14 and, therefore, could alter the targeting of ATM to sites of DNA damage. Furthermore, the introduction of cysteine could possibly interfere with the formation of disulfide bridges. ATM Ser707Pro also is likely to interfere with secondary and tertiary protein structure, as the exchange of proline for serine introduces a much bulkier side chain and removes a hydroxyl group that possibly participates in hydrogen bonding. Therefore, ATM Ser49Cys and ATM Ser707Pro carriers could have impaired ATM function and, thereby, have increased susceptibility to cancer.

We tested the hypotheses that ATM Ser49Cys and ATM Ser707Pro heterozygosity increase the risk of cancer overall, of breast cancer, and of 26 other cancer subtypes in the general population; although the two former were primary hypotheses, the latter represents an exploratory analysis. For this purpose, we genotyped 10,324 individuals from the Danish general population who were observed prospectively for 36 years, during which 2,056 developed a first cancer. Homozygotes for these two mutations were too rare to reliably test these hypotheses; however, we still report some results on homozygotes for completion.

	PATIENTS AND METHODS

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Participants
We performed a population-based study of 10,324 individuals from the Danish general population who were participating in the Copenhagen City Heart Study, a prospective study. Participants were selected at random after age and sex stratification on the basis of their unique Danish central person registration numbers and were invited for a free health examination. Participants were interviewed in 1976 to 1978, 1981 to 1983, 1991 to 1994, and 2001 to 2003 regarding alcohol consumption, smoking habits, and reproductive history (women only). Before each examination, participants filled out a questionnaire, which was validated by an examiner at the day of attendance. At each examination, height and weight were measured for a calculation of body mass index (BMI). At the 1991 to 1994 and the 2001 to 2003 examinations, blood samples for DNA extraction were drawn. Of the 17,600 individuals invited to these two examinations, 10,324 (59%) participated and were genotyped for the present study. Roughly 99% of the participants were white and of Danish descent. Diagnoses of invasive cancer (according to the WHO International Classification of Diseases, seventh edition¹⁵) for the whole cohort from 1947 through March 11, 2004, were obtained from the Danish Cancer Registry, which identifies 98% of all cancers in Denmark.^16,17

According to WHO criteria, cancer diagnoses were divided in 27 subgroups¹⁵: oral cavity/pharynx (n = 35), esophagus (n = 23), stomach (n = 29), colon/rectum/anus (n = 225), liver/biliary tract (n = 36), pancreas (n = 50), larynx (n = 30), lung (n = 247), melanoma (n = 66), breast (n = 294), cervix uteri (n = 39), corpus uteri (n = 80), ovary (n = 53), prostate (n = 123), testis (n = 10), bladder/excretory urinary tract (n = 158), kidney (n = 33), brain/nervous tissue (n = 40), thyroid/other endocrine tumors (n = 5), non-Hodgkin's lymphoma (n = 39), Hodgkin's disease (n = 4), multiple myeloma (n = 20), leukemia (n = 53), nonmelanoma skin (n = 509), sarcoma/other mesodermal tumors (n = 19), other tumors (n = 34), and metastases (n = 39). Among study participants, 2,056 had a first cancer during follow-up. In total, we detected 2,293 cancers, of which 237 occurred in participants who had previously had another cancer.

Follow-up time for each participant began at the establishment of the Danish Civil Register System (April 1, 1968) or on the participant's 20th birthday, whichever came last. Follow-up ended at death, at event, at emigration, or on March 11, 2004, whichever came first. Participants with cancer before their 20th birthday or April 1, 1968, were excluded (n = 70). Only participants successfully genotyped for both ATM Ser49Cys and ATM Ser707Pro were included. Maximum and median follow-up periods were 36 and 27 years, respectively. Follow-up was 100% complete.

Genotyping
Genotyping of ATM Ser49Cys and ATM Ser707Pro was done on isolated leukocyte DNA using TaqMan assays (Applied Biosystems, Foster City, CA). Primers and probes are available from the authors on request. In each 384-well plate, two known heterozygotes and one known homozygote were run as positive controls, and water was run as a negative control. To reduce the number of no-calls to a minimum, two rounds of reruns were performed.

Ethics
All participants gave written informed consent. Herlev University Hospital and the Danish ethical committee for Copenhagen and Frederiksberg approved the study (No. 100.2039/91).

Statistical Analyses
We used the statistical software STATA (STATA Corp, College Station, TX). Two-sided P < .05 was regarded as significant. Statistical tests used were the Mann-Whitney U test, the Pearson ² test, the log-rank test, and Cox regression with delayed entry and age as the underlying time variable; thus, analysis is automatically adjusted for age. Multifactorially adjusted models included time-dependent covariates from the 1976 to 1978, 1981 to 1983, 1991 to 1994, and 2001 to 2003 examinations. This implies that, initially, baseline covariate values were used for the following years until that person was examined again, after which the new value was used in the analyses. If only baseline values were available, these were used for adjustment during the entire follow-up period. To analyze the overall cancer risk, multifactorial adjustment included age, sex, BMI ( 25 kg/m² v > 25 kg/m² to 30 kg/m² v > 30 kg/m²), weekly alcohol intake (0 g/wk v 1 to 168 g/wk v > 168 g/wk for women, and 0 g/wk v 1 to 252 g/wk v > 252 g/wk for men), present smoking status (yes v no), smoking history (ever v never), and—additionally for women—parity (number of children), nulliparity (yes v no), use of oral contraceptive drugs at the time of examination (yes v no), menopausal status (premenopausal v postmenopausal), and use of hormonal replacement therapy at the time of examination (yes v no). The proportional hazard assumption for Cox regression was tested graphically by plotting ln(–ln[survival probability]) versus ln(analysis time) for all comparisons; no violations were observed. Two-factor interaction terms between each of the two genotypes and each of the covariates listed above were tested for interaction in the Cox regression. Population attributable risk was estimated as (f[HR – 1]) ÷ (1 + f[HR – 1]), in which f is the frequency of ATM Ser49Cys or ATM Ser707Pro in the population and HR is the corresponding hazard ratio for cancer.¹⁸

	RESULTS

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We were able to genotype for both ATM Ser49Cys and ATM Ser707Pro in 10,317 of 10,324 included participants, which corresponds to a call rate of 99.9%. Of those genotyped, 0.02% were homozygotes, 2.5% were heterozygotes, and 97.5% were noncarriers of ATM Ser49Cys; 0.01% were homozygotes, 2.1% were heterozygotes, and 97.9% were noncarriers of ATM Ser707Pro. Both distributions were in Hardy-Weinberg equilibrium (ATM Ser49Cys, P = .77; ATM Ser707Pro, P = .87 by ² test). Because of the small number of homozygotes, we only calculated hazard ratios for heterozygotes versus noncarriers. There were two ATM Ser49Cys homozygotes: both were female, and one of these developed breast cancer. There was one ATM Ser707Pro homozygote: this participant was male and did not develop any cancer. Table 1 lists characteristics of participants at study entry. We detected 2,056 participants with a first cancer during the 36 years of follow-up.

Risk of Any Cancer by ATM Ser707Pro
Cancer incidence for the combined sexes was 67 per 10,000 person-years for both noncarriers and heterozygotes (Table 2). The multifactorially adjusted hazard ratio for heterozygotes versus noncarriers was 0.8 (95% CI, 0.6 to 1.2) for sexes combined, 0.8 (95% CI, 0.5 to 1.3) for women, and 0.8 (95% CI, 0.5 to 1.3) for men. None of the covariates listed in Table 1 interacted with the ATM Ser707Pro genotype on the risk of cancer.

Risk of Breast Cancer and Other Cancer Subtypes by ATM Ser707Pro
The incidence of breast cancer in women per 10,000 person-years was 17 and 10 for noncarriers and heterozygotes, respectively (Table 3). The multifactorially adjusted hazard ratio of developing breast cancer in women who were ATM Ser707Pro heterozygotes versus noncarriers was 0.6 (95% CI, 0.2 to 1.6).

In exploratory analyses among 26 other cancer subtypes, we found ATM Ser707Pro heterozygosity to be associated with thyroid/other endocrine tumors and cancer of corpus uteri (Table 3). The multifactorially adjusted hazard ratio in ATM Ser707Pro heterozygotes versus noncarriers was 10 (95% CI, 1.1 to 93) for thyroid/other endocrine tumors, and 2.7 (95% CI, 1.0 to 7.6) for cancer of corpus uteri. However, these risk estimates were based on only one heterozygote with thyroid/other endocrine tumors and five heterozygotes with cancer of corpus uteri.

	DISCUSSION

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An association between ATM mutation heterozygosity and an increased risk of cancer was first suspected when several studies reported an increased risk of cancer, particularly breast cancer, in relatives of patients with ataxia telangiectasia.^4,5 Since then, a multitude of studies have evaluated numerous ATM mutations, most often in the setting of small, case-control studies, with varying results.^6-12,19 The present paper is the first to examine ATM missense mutation heterozygosity in a prospective study of the general population with respect to the risk of cancer.

Our findings in the general population of no increased overall risk of cancer in ATM Ser49Cys and ATM Ser707Pro heterozygotes compared with noncarriers could seem to contrast with the increased risk of cancer overall observed in obligate heterozygous ataxia telangiectasia relatives in some studies.^4,5 However, to the best of our knowledge, the ATM Ser49Cys and ATM Ser707Pro missense mutations do not cause ataxia telangiectasia in homozygotes,¹⁹ so are likely not as detrimental to the function of the ATM protein as those truncating and missense ATM mutations that cause ataxia telangiectasia in the homozygous state. Thus, although truncating and missense mutations severe enough to cause ataxia telangiectasia might elevate the risk of cancer substantially in the heterozygous state, it is likely that less detrimental missense mutations found relatively often in the general population, such as ATM Ser49Cys and ATM Ser707Pro, do not increase the risk of cancer to the same extent. Furthermore, it is also possible that the increased cancer risk of relatives of patients with ataxia telangiectasia is polygenic and stems from a cluster of unknown common mutations that are segregated in ataxia telangiectasia families, unlike in individuals from the general population, such as those included in our study.

We could not confirm the two- to five-fold risk of breast cancer associated with ATM Ser49Cys or ATM Ser707Pro heterozygosity observed by others.^8-10 Studies that originally demonstrated an increased risk of breast cancer in ATM Ser49Cys heterozygotes were small,^8,9 and a recent report by the Breast Cancer Association Consortium also failed to show an association between ATM Ser49Cys heterozygosity and an increased risk of breast cancer.¹¹ Likewise, the study that originally demonstrated an association between ATM Ser707Pro heterozygosity and an increased risk of breast cancer was a case-control study with a much smaller study population than ours.¹⁰ Our results are also in accordance with a study by Spurdle et al¹² that showed ATM Ser707Pro heterozygosity to be unassociated with breast cancer risk. Originally, an association between ATM mutations and breast cancer was suspected, because relatives of patients with ataxia telangiectasia had an increased risk of breast cancer.^4,5 However, a recent study by Renwick et al¹⁹ has shown that only ATM mutations that are known to cause ataxia telangiectasia in the homozygous state predispose to breast cancer in heterozygotes. This finding agrees with our result that neither ATM Ser49Cys nor ATM Ser707Pro heterozygosity predispose to breast cancer.

ATM Ser49Cys appears to predispose to several other cancer subtypes. In accordance with this, other mutations in cell cycle regulatory genes (eg, CHEK2*1100delC²⁰) are known to predispose to certain cancer subtypes, although they do not increase the overall risk of cancer. It is becoming increasingly clear that there is a high degree of communication between ATM and ATM- and rad3-related kinase (ATR) and that there is some overlap in DNA repair pathways controlled by these two.²¹ The contribution of ATR to these DNA repair pathways may be greater in some tissues than others. An impairment of ATM caused by ATM Ser49Cys might, therefore, have a greater impact on some cell types than others, which would result in an increased susceptibility to certain cancer subtypes without an overall elevation of the risk of cancer. Our observed association of ATM Ser49Cys heterozygosity with an increased risk of melanoma is biologically plausible, as recent studies have shown ATM to be important for DNA repair in response to UV light.^22,23 Furthermore, even when we correct this finding for 26 different comparisons by using the Bonferroni method (P = .05 ÷ 26 = .002), this finding remains highly significant. This association is interesting, because relatively few melanoma-predisposing genes have been discovered so far. Given that 2.5% of the Danish population are heterozygous for ATM Ser49Cys and that we estimated a hazard ratio for melanoma of 4.8, the corresponding population attributable fraction is 9%. This means that the incidence of melanoma in Denmark would decrease by 9% if ATM Ser49Cys was not present in the Danish population. However, our findings were based on only seven heterozygotes with melanoma; therefore, our estimated hazard ratio and population attributable fraction could be overinflated by chance alone. In support of a role for ATM Ser49Cys heterozygosity in prostate cancer, ATM P1054R heterozygosity also was associated with this disease.⁶

This study also shows that ATM Ser49Cys is associated with cancer of the oral cavity/pharynx and that ATM Ser707Pro is associated with thyroid/other endocrine tumors and cancer of corpus uteri. At this point there is little or no additional evidence to support an association with these cancer subtypes. Therefore, these findings either could be accidental findings, caused in part to the low incidence of cancer of the oral cavity/pharynx, thyroid/other endocrine tumors, and cancer of corpus uteri in our study, or could represent real associations observed for the first time.

There are some limitations to our study. First, as we performed multiple comparisons, some of our findings could represent chance findings rather than real phenomena. In exploratory analyses, we tested two ATM mutations for the risk of 26 different cancer subtypes and would therefore expect two to three associations to be significant because of chance alone. However, we detected three significant associations for ATM Ser49Cys heterozygosity and two significant associations for ATM Ser707Pro heterozygosity, so two to three of these associations could represent real phenomena. We also found that ATM Ser707Pro heterozygosity was associated with an increased risk of other cancers, but we did not report this, because we believe this is a highly unlikely finding. Second, both ATM Ser49Cys and ATM Ser707Pro heterozygosity are relatively rare, so increased or decreased risk is hard to detect, particularly for rare cancer subtypes, which suggests that we easily could have overlooked other associations. Third, our knowledge of some cancer risk factors was limited. Most important, our knowledge of melanoma risk factors was incomplete. Although we did adjust for the most relevant cancer risk factors, we cannot completely exclude the possibility of confounding by other risk factors on some of the observed associations. Fourth, participants were genotyped only if they attended the 1991 to 1994 or 2001 to 2003 examinations of the Copenhagen City Heart Study. A selection bias may have occurred if death or morbidity prevented certain individuals from attending these examinations. However, two observations make substantial selection bias against genotype less likely: 1) age percentiles for noncarriers and heterozygotes display a linear relationship, as would be expected if no selection occurred against heterozygotes; and 2) both genotype distributions are in Hardy-Weinberg equilibrium. Thus, we do not consider selection bias against heterozygosity likely. Fifth, we investigated only two of numerous reported ATM missense mutations. Therefore, we cannot exclude that other mutations in this gene may influence the risk of cancer in the general population. Finally, misclassification of cancer end points may have occurred. This is not likely, however, because we had 100% follow-up on participants and because complete records of hospital admissions and deaths exist. Furthermore, the Danish National Cancer Registry identifies 98% of all cancers in Denmark.²⁴

In conclusion, ATM missense mutations do not increase the risk of cancer overall or of breast cancer in the general population; however, we observed in exploratory analyses that ATM missense mutations may be associated with an increased risk of other cancer subtypes. As we did multiple comparisons, some of these findings could represent chance findings rather than real phenomena.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Sarah Louise Dombernowsky, Maren Weischer, Kristine Højgaard Allin, Stig Egil Bojesen, Anne Tybjjrg-Hansen, Børge Nordestgaard

Financial support: Anne Tybjjrg-Hansen, Børge Nordestgaard

Administrative support: Børge Nordestgaard

Provision of study materials or patients: Stig Egil Bojesen, Anne Tybjjrg-Hansen, Børge Nordestgaard

Collection and assembly of data: Sarah Louise Dombernowsky, Maren Weischer, Kristine Højgaard Allin, Stig Egil Bojesen, Anne Tybjjrg-Hansen, Børge Nordestgaard

Data analysis and interpretation: Sarah Louise Dombernowsky, Maren Weischer, Stig Egil Bojesen, Anne Tybjjrg-Hansen, Børge Nordestgaard

Manuscript writing: Sarah Louise Dombernowsky, Maren Weischer, Børge Nordestgaard

Final approval of manuscript: Sarah Louise Dombernowsky, Maren Weischer, Kristine Højgaard Allin, Stig Egil Bojesen, Anne Tybjjrg-Hansen, Børge Nordestgaard

	NOTES

 
B.G.N. was supported by the Danish Medical Research Council, the Copenhagen County Foundation, and the Danish Heart Foundation.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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3. Gatti RA, Tward A, Concannon P: Cancer risk in ATM heterozygotes: A model of phenotypic and mechanistic differences between missense and truncating mutations. Mol Genet Metab 68:419-423, 1999[CrossRef][Medline]

4. Swift M, Morrell D, Massey RB, et al: Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med 325:1831-1836, 1991[Abstract]

5. Thompson D, Duedal S, Kirner JFR, et al: Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst 97:813-822, 2005[Abstract/Free Full Text]

6. Angèle S, Falconer A, Edwards SM, et al: ATM polymorphisms as risk factors for prostate cancer development. Br J Cancer 91:783-787, 2004[Medline]

7. Kim JH, Kim H, Lee KY, et al: Genetic polymorphisms of ataxia telangiectasia mutated affect lung cancer risk. Hum Mol Genet 15:1181-1186, 2006[Abstract/Free Full Text]

8. Stredrick DL, Garcia-Closas M, Pineda MA, et al: The ATM missense mutation p.Ser49Cys (c. 146C > G) and the risk of breast cancer. Hum Mutat 27:538-544, 2006[CrossRef][Medline]

9. Buchholz TA, Weil MM, Ashorn CL, et al: A Ser49Cys variant in the ataxia telangiectasia, mutated, gene that is more common in patients with breast carcinoma compared with population controls. Cancer 100:1345-1351, 2004[CrossRef][Medline]

10. Dörk T, Bendix R, Bremer M, et al: Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients. Cancer Res 61:7608-7615, 2001[Abstract/Free Full Text]

11. Cox A, Dunning AM, Garcia-Closas M, et al: A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet 39:352-358, 2007[CrossRef][Medline]

12. Spurdle AB, Hopper JL, Chen X, et al: No evidence for association of ataxia-telangiectasia mutated gene T2119C and C3161G amino acid substitution variants with risk of breast cancer. Breast Cancer Res 4:R15, 2002[CrossRef][Medline]

13. Khanna KK, Keating KE, Kozlov S, et al: ATM associates with and phosphorylates p53: Mapping the region of interaction. Nat Genet 20:398-400, 1998[CrossRef][Medline]

14. Young DB, Jonnalagadda J, Gatei M, et al: Identification of domains of ataxia-telangiectasia mutated required for nuclear localization and chromatin association. J Biol Chem 280:27587-27594, 2005[Abstract/Free Full Text]

15. Bojesen SE, Tybjjrg-Hansen A, Nordestgaard BG: Integrin beta3 Leu33Pro homozygosity and risk of cancer. J Natl Cancer Inst 95:1150-1157, 2003[Abstract/Free Full Text]

16. Storm HH: The Danish Cancer Registry, a self-reporting national cancer registration system with elements of active data collection. IARC Sci Publ:220-236, 1991

17. Storm HH, Michelsen EV, Clemmensen IH, et al: The Danish Cancer Registry: History, content, quality and use. Dan Med Bull 44:535-539, 1997[Medline]

18. Khoury MJ, Beaty TH, Cohen BH: Fundamentals of Genetic Epidemiology. New York, NY, Oxford University Press, 1993

19. Renwick A, Thompson D, Seal S, et al: ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet 38:873-875, 2006[CrossRef][Medline]

20. Weischer M, Bojesen SE, Tybjjrg-Hansen A, et al: Increased risk of breast cancer associated with CHEK2*1100delC. J Clin Oncol 25:57-63, 2007[Abstract/Free Full Text]

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22. Hannan MA, Hellani A, Al-Khodairy FM, et al: Deficiency in the repair of UV-induced DNA damage in human skin fibroblasts compromised for the ATM gene. Carcinogenesis 23:1617-1624, 2002[Abstract/Free Full Text]

23. Oakley GG, Loberg LI, Yao JQ, et al: UV-induced hyperphosphorylation of replication protein a depends on DNA replication and expression of ATM protein. Mol Biol Cell 12:1199-1213, 2001[Abstract/Free Full Text]

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Submitted September 28, 2007; accepted March 11, 2008.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dombernowsky, S. L. Articles by Nordestgaard, B. G. Search for Related Content PubMed PubMed Citation Articles by Dombernowsky, S. L. Articles by Nordestgaard, B. G. Social Bookmarking                            What's this?