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Originally published as JCO Early Release 10.1200/JCO.2005.05.5160 on July 31 2006 © 2007 American Society of Clinical Oncology. Increased Risk of Breast Cancer Associated With CHEK2*1100delC
From the Department of Clinical Biochemistry, Herlev University Hospital; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital; The Copenhagen City Heart Study, Bispebjerg University Hospital; and Department of Breast Surgery, Herlev University Hospital, University of Copenhagen, Copenhagen, Denmark Address reprint requests to Børge G. Nordestgaard, Professor and Chief Physician, Department of Clinical Biochemistry, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark; e-mail: brno{at}herlevhosp.kbhamt.dk
Purpose CHEK2*1100delC heterozygosity has been associated with increased risk of breast, prostate, and colorectal cancer in case-control studies. We tested the hypothesis that CHEK2*1100delC heterozygosity in the general population increases the risk of cancer in general, and breast, prostate, and colorectal cancer in particular. Patients and Methods We performed a prospective study of 9,231 individuals from the Danish general population, who were observed for 34 years, and we performed a case-control study including 1,101 cases of breast cancer and 4,665 controls. Results Of the general population, 0.5% were heterozygotes and 99.5% were noncarriers. In the prospective study, multifactorially adjusted hazard ratios by CHEK2*1100delC heterozygosity versus noncarriers were 1.2 (95% CI, 0.7 to 2.1) for all cancers, 3.2 (95% CI, 1.0 to 9.9) for breast cancer, 2.3 (95% CI, 0.6 to 9.5) for prostate cancer, and 1.6 (95% CI, 0.4 to 6.5) for colorectal cancer. In the case-control study, age-matched odds ratio for breast cancer by CHEK2*1100delC heterozygosity versus noncarriers was 2.6 (95% CI, 1.3 to 5.4). The absolute 10-year risk of breast cancer in CHEK2*1100delC heterozygotes amounted to 24% in women older than 60 years undergoing hormone replacement therapy, with a body mass index of 25 kg/m2 or higher. Conclusion CHEK2*1100delC heterozygosity is associated with a three-fold risk of breast cancer in women in the general population.
In most countries, women with breast cancer and a familial predisposition to this disease are offered screening for mutations in all of the BRCA1 and BRCA2 genes. However, in fewer than a quarter of the women screened, a causative mutation is found in either of these two genes. Besides mutations in the BRCA1 and BRCA2 genes, the common CHEK2*1100delC mutation is the most likely candidate to explain genetic risk of breast cancer.1-9 CHEK2 (OMIM 604373) is a key checkpoint kinase that acts as a tumor suppressor in response to DNA double-strand breakage.1 DNA damage results in activation of cell-cycle checkpoints that block cell proliferation and initiate DNA repair.1 Impaired function of such checkpoints can lead to genomic instability and susceptibility to cancer. Through its ability to phosphorylate p53, Cdc25c, and BRCA1, CHEK2 leads to cell cycle arrest or apoptosis. The first evidence suggesting the implication of CHEK2 in cancer development was the germline mutation CHEK2*1100delC found in several Li-Fraumeni and Li-Fraumeni–like families.2,3 The CHEK2*1100delC variant is caused by a deletion of a single cytosine at position 1100, resulting in the introduction of a stop codon after aminoacid 380,2 and in complete loss of CHEK2 kinase activity. Apart from the association with the Li-Fraumeni syndromes, CHEK2*1100delC heterozygosity has also been associated with breast,4-9 prostate,10,11 and colorectal cancer7,12; CHEK2*1100delC heterozygosity are found in 1.1% to 1.4% of white people in Northern Europe.6,9 These studies4-12 were all case-control studies and the effect of CHEK2*1100delC heterozygosity in the general population has never previously been examined. We tested the hypothesis that CHEK2*1100delC heterozygosity in the general population increases the risk of cancer in general, and breast, prostate, and colorectal cancer in particular. For this purpose, we genotyped 9,231 individuals from the Danish general population who were observed for 34 years, and the risk of 24 other cancer subtypes were examined in exploratory analyses. Furthermore, we also genotyped 1,101 consecutively collected female breast cancer patients from a large surgical department and compared them with 4,665 female controls from the general population.
Study Populations For the prospective study, we examined 9,231 individuals (randomly selected after age and sex stratification) from the Danish general population who participated in the 1991 to 1994 Copenhagen City Heart Study13-15 (56% of those invited participated in our study). Participants were interviewed and examined in the years 1976 to 1978, 1981 to 1983 and 1991 to 1994, and participants' medical history, family history of disease, alcohol consumption, smoking habits, and reproductive history (women only) were noted. Height and weight were measured at every examination. Blood samples for DNA extraction were drawn at the 1991 to 1994 examination. More than 99% of the participants were white and of Danish descent. Diagnoses of invasive cancer (diagnoses were made using WHO International Classification of Diseases, seventh edition; ICD-714) for the whole cohort from 1947 until December 31, 2002, were obtained from the Danish Cancer Registry,16,17 which identifies 98% of all cancers in Denmark.18 Cancer diagnoses were divided in 27 subgroups according to WHO criteria.19 ICD-7 codes 170.0 to 170.5, 470.0 to 470.1, and 970.0 to 970.1 were classified as breast cancer; 177.0, 477.0, and 977.0 were classified as prostate cancer; 91.0, 153.0 to 153.4, 154. 0, 154.9, 253.0 to 253.4, 453.0 to 453.5, 453.8, 454.0, 554.0, 953.0 to 953.4, and 954.0 were classified as colorectal cancer; 93.1, 93.3 to 93.7, 193.1 to 193.2, 195.4, 293.0 to 293.2, 393.1, 493.0, 493.2 to 493.3, 493.5 to 493.7, and 993.0 to 993.1 were classified as brain/nerve tissue cancers; 204.0 to 204.4, 214.0 to 214.1, 404.0, 503.0, 504.4, 904.4, and 914.1 were classified as leukemia; and 180.0, 180.3, 980.0, and 980.3 were classified as kidney cancer. Follow-up time for each participant began at the establishment of the Danish Civil Register System April 1, 1968, or the participant's 20th birthday, whichever came later, and ended at death, event, emigration, or on December 31st, 2002, whichever came earlier. Participants with disease before or after follow-up were excluded. This included 141 events of any cancer, 17 of breast cancer, six of prostate cancer, 12 of colorectal cancer, three of brain/nerve tissue cancers, two of leukemia, and none of kidney cancer. The maximum and median follow-up periods were 34.7 and 33.8 years, respectively. Follow-up was 100% complete. Death due to intercurrent disease was treated as censoring. The case-control study included 1,101 women with invasive breast cancer consecutively recruited at Herlev University Hospital (Herlev, Denmark) between February 2001 and August 2004 (98% of those invited participated in our study). Participants gave blood and filled out questionnaires regarding medical history, family history of breast cancer, alcohol consumption, use of oral contraceptives, use of hormonal replacement therapy, reproductive history, height, and weight. More than 97% of the participants were white and of Danish descent. Information on tumor characteristics and dissemination was obtained from The Danish Breast Cancer Group.20 Controls were 4,665 women from the general population (The Copenhagen City Heart Study) within the same age range as the patients, who had no history of breast cancer before the end of 2002.
Ethics
Genotyping
Statistical Analyses
In the prospective study, we used Cox regression with delayed entry and used age as the underlying time variable; we thus automatically adjusted for age. Multifactorially adjusted models also included time-dependent covariates from the 1976 to 1978, 1981 to 1983 and 1991 to 1994 examinations. Multifactorial adjustment for breast cancer included age, body mass index (< 25 v The case-control study was matched with a 1-year age strata to perform conditional logistic regression. This resulted in 64 strata with a mean of 4.2 controls per patient. A two-factor interaction term tested for interaction in the logistic regression model. Population attributable risk was estimated as [f(HR–1)]/[1+f(HR–1)], where f is the frequency of CHEK2*1100delC in the population and HR is the hazard ratio for breast cancer.21
Absolute risks for breast cancer by CHEK2*1100delC heterozygosity were estimated by using the regression coefficients from a Poisson regression model with the following covariates: body mass index in two groups (< 25 kg/m2 v
Role of the Funding Organizations
Prospective Study Of the general population, 0.5% were CHEK2*1100delC heterozygotes and 99.5% were noncarriers. No homozygotes were identified. This distribution was in Hardy-Weinberg equilibrium (  2 test, P = .81). Characteristics of the participants are listed in Table 1. There were no significant differences between heterozygotes and noncarriers for any of these established risk factors for cancer in either study (data not shown).
Hypotheses Testing During the 34 years of follow-up, we detected 1,914 participants with a first incidence of cancer (Table 1). Cancer incidences for noncarriers and heterozygotes, for both sexes combined, were 70 and 114 per 10,000 person-years, respectively. Equivalent values were 68 and 66 in women, respectively, and 71 and 180 in men, respectively. The age-adjusted hazard ratios for heterozygotes versus noncarriers were 1.4 (95% CI, 0.9 to 2.4) for men and women combined, 1.0 (95% CI, 0.4 to 2.3) for women alone, and 1.8 (95% CI, 1.0 to 3.4) for men alone. After multifactorial adjustment for the covariates that have been listed in Table 1, the equivalent hazard ratios were 1.2 (95% CI, 0.7 to 2.1) for men and women combined, 1.1 (95% CI, 0.4 to 2.6) for women alone, and 1.5 (95% CI, 0.7 to 2.9) for men alone. Genotype and sex did not interact with the risk of all cancer (P = .20). Among women, incidences of breast cancer in noncarriers and CHEK2*1100delC heterozygotes were 17 and 39 per 10,000 person-years, respectively (Table 2). The age-adjusted hazard ratio of breast cancer for heterozygotes versus noncarriers was 2.5 (95% CI, 0.8 to 7.7), which increased to 3.2 (95% CI, 1.0 to 9.9) after multifactorial adjustment. Among men, incidences of prostate cancer in noncarriers versus heterozygotes were 9 and 31 per 10,000 person-years, respectively. The age-adjusted hazard ratio of prostate cancer for heterozygotes versus noncarriers was 2.3 (95% CI, 0.6 to 9.5). In women and men combined, incidences of colorectal cancer in noncarriers versus heterozygotes were 7 and 14 per 10,000 person-years, respectively. Age-adjusted and multifactorially adjusted hazard ratios of colorectal cancer in heterozygotes versus noncarriers were 1.7 (95% CI, 0.4 to 6.7) and 1.6 (95% CI, 0.4 to 6.5).
Exploratory Analyses Incidences of brain/nerve tissue cancer in noncarriers versus heterozygotes were 1 and 14 per 10,000 person-years, respectively (Table 2). Age-adjusted and multifactorially adjusted hazard ratios for brain or nerve tissue cancers in heterozygotes versus noncarriers were 10.1 (95% CI, 2.4 to 41.9) and 9.9 (95% CI, 2.4 to 41.2). Incidences of leukemia in noncarriers versus heterozygotes were 2 and 14 per 10,000 person-years, respectively. Age-adjusted and multifactorially adjusted hazard ratios for leukemia in heterozygotes versus noncarriers were 6.7 (95% CI, 1.6 to 27.7) and 6.3 (95% CI, 1.5 to 26.1). Incidences of kidney cancer in noncarriers versus heterozygotes were 1 and 14 per 10,000 person-years, respectively. Age-adjusted and multifactorially adjusted hazard ratios of kidney cancer in heterozygotes versus noncarriers were 10.8 (95% CI, 2.6 to 45.7) and 9.8 (95% CI, 2.3 to 41.2). CHEK2*1100delC heterozygosity was not associated with increased risk of any of the remaining 21 site-specific cancers.
Case-Control Study
After stratification for histologic subtypes of breast cancer, the odds ratio was 2.3 (95% CI, 1.0 to 5.5) for ductal tumor; for other histologic subtypes, the odds ratios were nominally higher, but not statistically significant (Table 3). After stratification for tumor characteristics and dissemination at diagnosis, odds ratios for breast cancer in heterozygotes versus noncarriers were 5.3 (95% CI, 1.5 to 19.0) in those patients with tumor size  10 mm, 4.3 (95% CI, 1.2 to 15.3) and 3.0 (95% CI, 1.2 to 7.7) in those patients with grade 1 and unknown grades of malignancy in ductal carcinoma, 3.4 (95% CI, 1.6 to 7.5) in those patients with hormone-receptor–negative tumors, 5.3 (95% CI, 1.9 to 14.7) in those patients with tumor-positive lymph nodes without breakthrough of capsule, and 2.6 (95% CI, 1.2 to 5.8) in those patients with absent distant metastases (Table 4). In the other subgroups examined, the odds ratios were all higher than 1.0, but were not statistically significant.
Population-Attributable Risk of Breast Cancer Based on a frequency of 0.5% for CHEK2*1100delC in the general population and a hazard ratio of 3.2 for breast cancer in female heterozygotes versus noncarriers, the population-attributable risk of breast cancer in women for CHEK2*1100delC was 1.1%.
Absolute Risk of Breast Cancer
CHEK2 is part of a phylogenetically conserved pathway that is activated in response to DNA damage.1 This, together with the fact that a recent case-control study found an association between mutations in CHEK2 (IVS2+1G  A and 1100delC) and thyroid, breast, and prostate cancer, as well as between another variant (I157T) and breast, colon, kidney, prostate, and thyroid cancer,22 support the hypothesis that CHEK2 may be a general cancer susceptibility gene. However, our study in the Danish general population following 9,231 individuals for 34 years, during which 1,914 incident cancers developed, was not able to support this hypothesis. The contribution of hereditary factors to the causation of breast cancer is 27% (95% CI, 4% to 41%).23 BRCA1 and BRCA2 genes account for only 3% to 8% of all breast cancers in women.24 In our prospective study, we found a carrier frequency of CHEK2*1100delC of 0.5% in the general population, similar to that observed in controls from Germany.25 The 3.2-fold risk of breast cancer in CHEK2*1100delC heterozygotes found in the general population is similar to the 2.6-fold risk observed in our large case-control study, and to the 2.3-fold risk reported in a large multicenter case-control study by the CHEK2 Breast Cancer Consortium.4 The 3.2-fold risk and a frequency of 0.5% results in a population-attributable risk of breast cancer in women of 1.1% for CHEK2*1100delC, or slightly less than the total of 3% to 8%, accounted for by all mutations in BRCA1 and BRCA2.24 In populations with a CHEK2*1100delC heterozygosity frequency of 1.4%, like in Finland,9 a 3.2-fold risk of breast cancer would imply a 3.0% population-attributable risk of breast cancer in women. Our observation of positive odds ratios for breast cancer by CHEK2*1100delC heterozygosity in all strata, although some were not statistically significant, together with no evidence of statistical interaction between genotypes and context on breast cancer risk, support the interpretation that women heterozygous for CHEK2*1100delC have an increased risk of breast cancer regardless of age, body mass index, alcohol consumption, parity, use of oral contraceptives, menopausal status, and use of hormone replacement therapy. CHEK2*1100delC heterozygosity has been associated with an odds ratio of 1.7 to 2.1 in unselected Polish prostate cancer patients, increasing to 4.9 to 8.2 in Polish and Finnish heterozygotes with a positive family history of this disease.10,11,22 Our findings of a hazard ratio of 2.3 (95% CI, 0.6 to 9.5) for prostate cancer by CHEK2*1100delC heterozygosity, although not statistically significant, is in line with these results. Conflicting reports regarding the association between CHEK2*1100delC heterozygosity and colorectal cancer have been published previously; CHEK2*1100delC was first associated with colorectal cancer in Dutch families with hereditary breast and colorectal cancer,7 whereas case-control studies in the Finland, Poland, and the United Kingdom reported no such association.12,22,26 Although CHEK2*1100delC heterozygosity conferred a hazard ratio of 1.6 (95% CI, 0.4 to 6.5) for colorectal cancer in our study, this was not statistically significant. To the best of our knowledge, we are the first to report an association between CHEK2*1100delC heterozygosity and brain and/or nerve tissue cancers. Previously, only one study examined the association between CHEK2*1100delC heterozygosity and leukemia; Collado et al examined 107 Spanish leukemia patients and found no CHEK2*1100delC heterozygotes27; however, CHEK2*1100delC is nearly absent from the Spanish population, and this may explain their finding.27,28 Therefore, other studies are needed to confirm (or rebut) our findings of an association between CHEK2*1100delC and brain/nerve tissue cancers and leukemia. The association between CHEK2*1100delC and kidney cancer has been examined by Cybulski et al,22 who observed an insignificant odds ratio of 2.7 (P = .50). This is well below the hazard ratio of 9.8 that was observed in our prospective study; interestingly, however, that same article reported an odds ratio of 2.1 (P < .001) for kidney cancer by the CHEK2 I157T variant versus noncarriers.22 There are some limitations to our study, First, the number of CHEK2*1100delC heterozygotes is limited. Second, only participants attending the 1991 to 1994 examination of the Copenhagen City Heart Study were genotyped. A selection bias might have occurred if death or morbidity prevented certain participants from attending the 1991 to 1994 examination. However, two observations make substantial selection bias against any genotype less likely. (1) In the general population, the frequency of noncarriers and heterozygotes do not increase or decrease as a function of age. (2) The distribution between genotypes was in Hardy-Weinberg equilibrium. Third, misclassification of disease may have occurred. However, this is not very likely because we have 100% follow-up of participants, and because all hospital admissions and deaths are registered in the country. Furthermore, the Danish National Cancer Registry identifies 98% of all cancers in Denmark.18 A likely limitation of case-control studies is the selection of controls; however, we chose breast cancer–free female participants from the Danish general population as controls. Furthermore, cases and controls came from the same geographic area and were matched for age. Our participants could be affected by selection bias. However, this is less likely to have occurred because, (1) participants were consecutively collected, and (2) blood samples were drawn within 30 days of breast cancer diagnosis in more than 80% of the cases, practically excluding that CHEK2*1100delC heterozygotes died selectively compared with noncarriers. Women with CHEK2*1100delC may benefit from preventive examinations for breast cancer, preferably excluding ionizing radiation.29 In contrast with screening all BRCA1 and BRCA2 genes, CHEK2*1100delC testing is a single genotyping test that costs less than US$10, which detects 100% of carriers. Cost-effectiveness analyses should evaluate whether CHEK2*1100delC genotyping followed by preventive examinations should be offered to only women with high risk of familial breast cancer or sporadic breast cancer, and/or who have other risk factors (Fig 2), or if it should be offered to most women.
The authors indicated no potential conflicts of interest.
Conception and design: Maren Weischer, Stig E. Bojesen, Anne Tybjærg-Hansen, Børge G. Nordestgaard Financial support: Anne Tybjærg-Hansen, Børge G. Nordestgaard Administrative support: Børge G. Nordestgaard Provision of study materials or patients: Stig E. Bojesen, Anne Tybjærg-Hansen, Christen K. Axelsson, Børge G. Nordestgaard Collection and assembly of data: Maren Weischer, Stig E. Bojesen, Anne Tybjærg-Hansen, Christen K. Axelsson, Børge G. Nordestgaard Data analysis and interpretation: Maren Weischer, Stig E. Bojesen, Anne Tybjærg-Hansen, Børge G. Nordestgaard Manuscript writing: Maren Weischer, Stig E. Bojesen Final approval of manuscript: Stig E. Bojesen, Anne Tybjærg-Hansen, Christen K. Axelsson, Børge G. Nordestgaard
Nina Dahl Kjersgaard provided technical assistance.
published online ahead of print at www.jco.org on July 31, 2006. Supported by the Michaelsen Foundation, the Danish Heart Foundation, Chief Physician Johan Boserup and Lise Boserups Fund, the Danish Medical Research Council, the Research Fund at Rigshospitalet, Copenhagen University Hospital, and Copenhagen County. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Bartek J, Lukas J: Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 3:421-429, 2003[CrossRef][Medline] 2. Bell DW, Varley JM, Szydlo TE, et al: Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science 286:2528-2531, 1999 3. Vahteristo P, Tamminen A, Karvinen P, et al: p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: Further evidence of CHK2 in inherited cancer predisposition. Cancer Res 61:5718-5722, 2001 4. CHEK2 Breast Cancer Case-Control Consortium: CHEK2*1100delC and susceptibility to breast cancer: A collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies. Am J Hum Genet 74:1175-1182, 2004[CrossRef][Medline] 5. Kilpivaara O, Bartkova J, Eerola H, et al: Correlation of CHEK2 protein expression and c1100delC mutation status with tumor characteristics among unselected breast cancer patients. Int J Cancer 113:575-580, 2005[CrossRef][Medline] 6. Meijers-Heijboer H, van den OA, Klijn J, et al: Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31:55-59, 2002[CrossRef][Medline] 7. Meijers-Heijboer H, Wijnen J, Vasen H, et al: The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype. Am J Hum Genet 72:1308-1314, 2003[CrossRef][Medline] 8. Oldenburg RA, Kroeze-Jansema K, Kraan J, et al: The CHEK2*1100delC variant acts as a breast cancer risk modifier in non-BRCA1/BRCA2 multiple-case families. Cancer Res 63:8153-8157, 2003 9. Vahteristo P, Bartkova J, Eerola H, et al: A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet 71:432-438, 2002[CrossRef][Medline] 10. Cybulski C, Huzarski T, Gorski B, et al: A novel founder CHEK2 mutation is associated with increased prostate cancer risk. Cancer Res 64:2677-2679, 2004 11. Seppala EH, Ikonen T, Mononen N, et al: CHEK2 variants associate with hereditary prostate cancer. Br J Cancer 89:1966-1970, 2003[CrossRef][Medline] 12. Kilpivaara O, Laiho P, Aaltonen LA, et al: CHEK2 1100delC and colorectal cancer [letter]. J Med Genet 40:e110, 2003 (suppl 10) 13. Appleyard M, Hansen AT, Jensen G, et al: The Copenhagen City Heart Study: Østerbroundersøgelsen—A book of tables with data from the first examination (1976-78) and a five year follow-up (1981-1983). Scand J Soc Med Suppl 41:1-160, 1989[Medline] 14. Bojesen SE, Tybjærg-Hansen A, Nordestgaard BG: Integrin beta3 Leu33Pro homozygosity and risk of cancer. J Natl Cancer Inst 95:1150-1157, 2003 15. Schnohr P, Jensen G, Lange P, et al: The Copenhagen City Heart Study: Østerbroundersøgelsen—Tables with data from the third examination 1991-1994. Eur Heart J 3:H1-H83, 2001[CrossRef] 16. Storm HH: The Danish Cancer Registry, a self-reporting national cancer registration system with elements of active data collection. IARC Sci Publ 95:220-236, 1991[Medline] 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. Storm HH: Completeness of cancer registration in Denmark 1943-1966 and efficacy of record linkage procedures. Int J Epidemiol 17:44-49, 1988 19. Bray F, Sankila R, Ferlay J, et al: Estimates of cancer incidence and mortality in Europe in 1995. Eur J Cancer 38:99-166, 2002[CrossRef][Medline] 20. Danish Breast Cancer Cooperative Group: Structure and organisation of DBCG, subchapters 3.1-3.3. http://www.dbcg.dk 21. Khoury MJ, Beaty TH, Cohen BH: Fundamentals of Genetic Epidemiology. New York, NY, Oxford University Press, 1993, pp 77-79 22. Cybulski C, Gorski B, Huzarski T, et al: CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet 75:1131-1135, 2004[CrossRef][Medline] 23. Lichtenstein P, Holm NV, Verkasalo PK, et al: Environmental and heritable factors in the causation of cancer: Analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343:78-85, 2000 24. Brody LC, Biesecker BB: Breast cancer susceptibility genes: BRCA1 and BRCA2. Medicine (Baltimore) 77:208-226, 1998[CrossRef][Medline] 25. Dufault MR, Betz B, Wappenschmidt B, et al: Limited relevance of the CHEK2 gene in hereditary breast cancer. Int J Cancer 110:320-325, 2004[CrossRef][Medline] 26. Lipton L, Fleischmann C, Sieber OM, et al: Contribution of the CHEK2 1100delC variant to risk of multiple colorectal adenoma and carcinoma. Cancer Lett 200:149-152, 2003[CrossRef][Medline] 27. Collado M, Landt O, Barragan E, et al: Locked nucleic acid-enhanced detection of 1100delC*CHEK2 germ-line mutation in Spanish patients with hematologic malignancies. Clin Chem 50:2201-2204, 2004 28. Osorio A, Rodriguez-Lopez R, Diez O, et al: The breast cancer low-penetrance allele 1100delC in the CHEK2 gene is not present in Spanish familial breast cancer population. Int J Cancer 108:54-56, 2004[CrossRef][Medline] 29. Bernstein JL, Teraoka SN, John EM, et al: The CHEK2*1100delC allelic variant and risk of breast cancer: Screening results from the Breast Cancer Family Registry. Cancer Epidemiol Biomarkers Prev 15:348-352, 2006 Submitted December 27, 2005; accepted June 6, 2006.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
25 kg/m2), alcohol consumption (0 g/wk v > 0 g/wk), nulliparity (yes v no), current use of oral contraceptives (yes v no), menopausal status (pre- v postmenopausal), and current use of hormone replacement therapy (yes v no). Multifactorial adjustment for colorectal cancer included age, sex, body mass index (< 25 v 
