Skip Navigation


Carcinogenesis Advance Access originally published online on February 14, 2008
Carcinogenesis 2008 29(4):762-765; doi:10.1093/carcin/bgn044
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
29/4/762    most recent
bgn044v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (5)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Cybulski, C.
Right arrow Articles by Narod, S. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cybulski, C.
Right arrow Articles by Narod, S. A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Constitutional CHEK2 mutations are associated with a decreased risk of lung and laryngeal cancers

Cezary Cybulski*, Bartlomiej Masojc, Dorota Oszutowska, Ewa Jaworowska1, Tomasz Grodzki2, Piotr Waloszczyk2, Piotr Serwatowski2, Juliusz Pankowski2, Tomasz Huzarski, Tomasz Byrski, Bohdan Górski, Anna Jakubowska, Tadeusz Debniak, Dominika Wokolorczyk, Jacek Gronwald, Czeslawa Tarnowska1, Pablo Serrano-Fernández, Jan Lubinski and Steven A. Narod3

International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, ul. Polabska 4, 70-115 Szczecin, Poland
1 Department of Otolaryngology and Laryngological Oncology, Pomeranian Medical University, ul.Unii Lubelskiej, 71–252 Szczecin, Poland
2 Lung Diseases Hospital, ul. Sokolowskiego 11, 70–891 Szczecin, Poland
3 Women's College Research Institute, Toronto, Ontario M5G IN8, Canada

* To whom correspondence should be addressed. Tel: +48 91 466 1532; Fax: +48 91 466 1533; Email: cezarycy{at}sci.pam.szczecin.pl


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Mutations in the CHEK2 gene have been associated with increased risks of breast, prostate and colon cancer. In contrast, a previous report suggests that individuals with the I157T missense variant of the CHEK2 gene might be at decreased risk of lung cancer and upper aero-digestive cancers. To confirm this hypothesis, we genotyped 895 cases of lung cancer, 430 cases of laryngeal cancer and 6391 controls from Poland for four founder alleles in the CHEK2 gene, each of which has been associated with an increased risk of cancer at several sites. The presence of a CHEK2 mutation was protective against both lung cancer [odds ratio (OR) = 0.3; 95% confidence interval (CI) 0.2–0.5; P = 3 x 10–8] and laryngeal cancer (OR = 0.6; 95% CI 0.3–0.99; P = 0.05). The basis of the protective effect is unknown, but may relate to the reduced viability of lung cancer cells with a CHEK2 mutation. Lung cancers frequently possess other defects in genes in the DNA damage response pathway (e.g. p53 mutations) and have a high level of genotoxic DNA damage induced by tobacco smoke. We speculate that lung cancer cells with impaired CHEK2 function undergo increased rates of cell death.

Abbreviations: CI, confidence interval; OR, odds ratio; PCR, polymerase chain reaction


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Germ line mutations in CHEK2 have been associated with a range of cancer types, in particular of the breast and the prostate, but cancers of the kidney, thyroid and colon have also been implicated (1–12). In Poland, there are four known founder alleles of CHEK2; three alleles are protein truncating and the other is a missense variant (I157T). All four alleles have been associated with an increased risk of cancer (5,13). For breast and prostate cancers, the observed associations are stronger for the protein-truncating alleles than for the missense allele (13,14), but for colon cancer, only the missense allele appears to be pathogenic (15,16). It appears therefore that the risk of cancer associated with CHEK2 mutations varies, depending on the cancer site and the class of mutation studied.

In our 2004 study (5), we observed a low frequency of CHEK2 mutations in a sample of 272 unselected lung cancer patients, compared with 4000 controls in Poland (2.6% versus 5.5%). Following our initial results, Brennan et al. (17) found a highly significant protective effect of the I157T missense variant, both for lung cancer and for upper aero-digestive cancers, in a large case–control study conducted in Central and Eastern Europe. We wished to extend our initial findings and those of Brennan et al. We have extended our series of lung cancer cases from 272 to 895 and our control sample from 4000 to 6391. We have also identified a fourth deleterious CHEK2 allele (a large deletion of exons 9 and 10). Because smoking is the principal risk factor for lung cancer in Poland and elsewhere, we asked whether the protective effect of CHEK2 might extend to laryngeal cancer patients as well.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
We studied 895 unselected cases of lung cancer (226 women and 669 men) diagnosed in the Lung Diseases Hospital in Szczecin, Poland, between 2004 and 2006. We also ascertained 430 consecutive, unselected patients with squamous cell carcinoma of the larynx (70 women and 360 men) at Department of Otolaryngology and Laryngological Oncology of the Pomeranian Medical University, Szczecin, Poland, during the period 2001–2004. Patients were recruited from the oncology services of the contributing hospitals and were unselected for age or family history. Patients were approached by a member of the study team during an outpatient visit to the oncology clinic and were asked if they wished to participate. Patient acceptance rates exceeded 80% for both cancer sites. Patients provided written informed consent. A blood sample of 10 cc was then drawn for DNA extraction. Two hundred and seventy-two of the lung cancer patients have been included in our previous study (5). The mean age of diagnosis of the lung cancer patients was 61.4 years (range 29–88 years) and of the laryngeal cancer patients was 58.2 years (range 30–84). Patients completed a questionnaire about their smoking habits at the time of cancer diagnosis. Smoking histories were available for 818 of 895 (91%) lung cancer cases and for 387 of 430 (90%) laryngeal cancer cases. The study was approved by the Ethics Committee of the Pomeranian Medical University in Szczecin.

Unmatched analysis
In the unmatched analysis, four non-overlapping control groups were combined in order to maximize the number of controls.

The first control group of 1896 healthy adults, including 1079 women (age range 15–91, mean 58.3) and 817 men (age range 23–90, mean 59.4). These controls were selected at random from the computerized patient lists of five large family practices located in the region of Szczecin. These healthy adults were invited to participate by mail and participated in 2003 and 2004. Participation rates for this group exceeded 70%. During the interview, the goals of the study were explained, informed consent was obtained, genetic counselling was given and a blood sample was taken for DNA analysis. A detailed family history of cancer was taken (first- and second-degree relatives included). Probands were included regardless of their cancer family history status. Individuals affected with any malignancy were excluded from the study.

The second control group consisted of 1417 unselected young adults (705 women and 712 men; age range 18–35, mean 24.3) from Szczecin metropolitan region who submitted a blood sample for paternity testing between 1994 and 2001.

The third control group consisted of 2183 children from nine cities in Poland (Szczecin, Bialystok, Gorzow, Katowice, Wroclaw, Poznan, Opole, Lodz and Rzeszow) between 2003 and 2006. Seven hundred and ninety-nine infants were from Szczecin and 1384 were from other cities. Samples of cord blood from unselected infants were forwarded to the study centre in Szczecin.

The fourth group of control subjects consisted of 895 healthy adults (226 women and 669 men) with a negative family history of cancer from the region of Szczecin. These individuals were chosen for this study to be sex-matched, age-matched and geographically matched with the lung cancer cases. Age was matched within 2 years. The healthy adults were part of a population-based study of the 1.5 million residents of West Pomerania designed to identify familial aggregations of cancer by our centre. These subjects were invited for an interview in 2007. During the interview, the goals of the study were explained, informed consent was obtained and a blood sample was taken for DNA analysis. A detailed family history of cancer was taken (first- and second-degree relatives included) and a risk factor questionnaire was completed, including smoking history. Individuals affected with any malignancy or with any cancers diagnosed in a first-degree relative were excluded from this control group.

In total, there were 6391 controls. The allele frequencies for the various CHEK2 variants were similar in the younger and older individuals, and in males and females (shown in Table I). Also there was no observed difference between the allele frequencies among infants from Szczecin metropolitan region and from other cities; therefore, the four control groups were combined to generate the most precise estimates of the frequencies of the four CHEK2 mutations in the underlying Polish population.


View this table:
[in this window]
[in a new window]

  		Table I. Frequencies of CHEK2 variants in controls

 
Matched analysis
A matched analysis was also performed in order to investigate whether or not tobacco exposure is an important modifier of the possible association between CHEK2 mutations and lung and laryngeal cancer. In this analysis, two matched controls were selected for each case, selected on sex and year of birth. Age- and sex-matched controls were selected from the control set described above. We were able to identify 1692 suitable matched controls for the lung cancer cases. Smoking status was available for 1594 of these controls (94%). We also identified 860 age- and sex-matched controls for the laryngeal cancer cases (Table II).


View this table:
[in this window]
[in a new window]

  		Table II. Comparison of cases and controls: matched analysis

 
Genotyping
DNA was isolated from 5 to 10 ml peripheral blood. Two primers pairs were used for genotyping of the large deletion of exons 9 and 10 in a multiplex polymerase chain reaction (PCR) as described previously (13). The first primer pair flanked the breakpoint site in intron 8 and the second primer pair flanked the breakpoint site in intron 10. In mutation-negative cases, only two PCR fragments of 379 and 522 bp were amplified from the wild-type allele. In deletion-positive cases, the forward primer of the first pair and the reverse primer of the second pair amplified an additional PCR product of 450 bp. The other three mutations in CHEK2 (IVS2 + 1G>A, 1100delC and I157T) were genotyped as described previously (5). These variants are detected by Allele specific oligonucleotide or Restriction fragment length polymorphism–PCR analyses. In all reaction sets, positive and negative controls (without DNA) were used. All PCRs or enzymatic digestions were performed under a layer of mineral oil. Duplicate genotyping for quality control was performed for 462 randomly selected individuals, but no discrepancies with the initial results were found. As a further check, all mutation-positive cases were confirmed by sequencing, but again with no discrepancies.

There is evidence that all four CHEK2 alleles present in Poland are in the functional copy of CHEK2 gene at chromosome 22 (not in a pseudogene located elsewhere) (5,13,18).

Statistical analysis
The prevalence of each of the four CHEK2 alleles was compared in cases and in controls, singly and in combination. The three protein-truncating mutations were studied separately from the missense variant. Odds ratios (ORs) were generated from two-by-two tables and statistical significance was assessed using the Fisher exact test for the unmatched analysis. The ORs were generated separately for lung and laryngeal cancer patients. The analysis was conducted separately for the unmatched and matched analyses, for smokers and non-smokers.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
In total, 1325 cancer cases and 6391 controls were genotyped for the four CHEK2 variants. A CHEK2 mutation was found in 1.8% of the lung cancer cases, in 3.5% of the laryngeal cancer cases and in 5.8% of the controls. Both the truncating variants and the missense variants were observed more frequently in the controls than in the cases (Table III).


View this table:
[in this window]
[in a new window]

  		Table III. Prevalence of CHEK2 mutations in lung cancer and laryngeal cancer cases with corresponding ORs

 
A strong protective effect against lung cancer was seen for truncating and missense mutations combined [OR = 0.3; 95% confidence interval (CI) 0.2–0.5; P = 3 x 10–8]. The mean age of onset of lung cancer in carriers of a CHEK2 mutation was 3.5 years older than in non-carriers (65.1 years versus 61.6 years, respectively) but the difference was not significant (P = 0.1). Results by histologic subtype are given in Table IV. A very strong protective effect was observed for squamous cell cancer (OR = 0.2; 95% CI 0.1–0.5). Protective effects were also seen for small cell and adenocarcinoma subtypes, but these were not statistically significant. A stronger protective effect for lung cancer was seen for men (OR = 0.2; 95% CI 0.1–0.5) than for women (OR = 0.4; 95% CI 0.2–1.0).


View this table:
[in this window]
[in a new window]

  		Table IV. Effect of CHEK2 truncating and missense mutation on lung cancer risk, by histologic subtype

 
A modest effect of a CHEK2 mutation (all variants combined) was also seen for squamous cell carcinoma of the larynx (OR = 0.6; 95% CI 0.3–0.99; P = 0.05). Again, a stronger effect was seen for men (OR = 0.5; 95% CI 0.3–1.0) than for women (OR = 0.7; 95% CI 0.2–2.3). The mean ages of onset of laryngeal cancer in carriers and non-carriers were similar (56.1 years versus 58.3 years, respectively; P = 0.3).

In order to ensure that the observed effect was not due to incomparability of the cases and controls, a matched analysis was performed. Each case was matched to two controls for age, sex and geographical region (Table II). In this analysis, a protective effect of a similar size was seen for lung cancer (OR = 0.3; P = 0.000002) and laryngeal cancer (OR = 0.6; P = 0.06) (Table V). In this model, we were able to subdivide the subjects by smoking status. The majority of the cases (94%) and controls (61%) smoked (current or past). The protective effect of a CHEK2 mutation was stronger for smokers than for non-smokers, both for lung cancer (OR = 0.3 for smokers and OR = 0.6 for non-smokers) and for laryngeal cancer (OR = 0.6 for smokers and OR = 1.0 for non-smokers). However, for neither comparison was the test for heterogeneity statistically significant.


View this table:
[in this window]
[in a new window]

  		Table V. Effect of CHEK2 mutations on lung and laryngeal cancer risk; matched analysis

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
We have shown that the presence of an inherited CHEK2 mutation is associated with a decrease in the risk of two of the principal smoking-related cancers in Poland. These results are in agreement with those of Brennan et al. (17) who also investigated cases of Eastern European origin, but restricted the study to a single CHEK2 I157T mutation. In our study, both truncating and missense CHEK2 mutations appear to be protective against lung and laryngeal cancer. The ORs given the I157T in the two studies (this study, (17)) are remarkably similar and all are highly significant. In both studies, the strongest protective effect is seen for squamous subtype of lung cancer (OR = 0.2). Our paper also suggests a protective effect of three CHEK2 truncating alleles on lung and laryngeal cancer risks. These results contrast with our observations that both truncating and missense alleles are associated with increased risks of prostate and breast cancers in Poland (13,14).

The strengths of our study include large number of cases and controls, and the sampling of incident cases, unselected for age or family history. Cases and controls are all ethnic Poles. There is no reason to believe that our findings could be the result of inappropriate selection of controls. Allele frequencies were similar in controls of different ages and sex (Table I). The frequency of I157T in our controls (4.8%) is similar to that reported later by Brennan et al. (17) in a non-overlapping series of 790 controls from Poland (5.6%). The frequency of the 1100delC in both series is almost identical (0.2%). Using the same control population, we previously reported that CHEK2 mutations increase the risk of cancer in several different sites including the breast, prostate, thyroid, colon and kidney (5). Furthermore, in a subanalysis in which the cases and controls were matched for age and sex, the ORs were almost identical to those of the larger, unmatched analysis.

CHK2 is a versatile and multifunctional kinase that regulates the cellular response to DNA damage by phosphorylating a number of cellular substrates. As such, it might prevent tumour progression by averting genomic instability through DNA repair or by causing the cell to senesce or to die. CHK2 regulates DNA repair through phosphorylation of BRCA1, which functions within the error-free homologous recombination repair pathway. CHK2 is implicated in activating p53-mediated cell-cycle arrest and apoptosis. CHK2 can also promote apoptosis through a p53-independent mechanism. CHK2 is required for the release of survivin from mitochondria, which is thought to inhibit apoptosis in cancer cells. This interpretation of CHK2 function correlates with several human studies, which show that CHEK2 is a multiorgan tumour susceptibility gene (5,19).

It is of interest that CHEK2 mutations appear to increase the risk of cancer at some sites (e.g. breast, prostate) and protect against others (lung, larynx). This may relate to the smoking-dependent etiology of lung and laryngeal cancer and the typical mutational profile of these cancer cells. Several lines of evidence suggest that pharmacological inhibition of CHK2 in combination with DNA-damaging agents (ionizing radiation and chemotherapeutics) might trigger cell death in tumours that already possess defects in other genes in the DNA-damage response, in particular p53 (19). By analogy, germ line mutations in CHEK2 might also promote the death of cancer cells which are p53 deficient and which are exposed to a high level of DNA damage. Interestingly, both p53 somatic inactivation and a high level of DNA damage induced by smoking exposure are characteristics of lung cancer (20). The frequency of somatic mutations in p53 in lung cancer is higher (~70% in smokers) than in breast or prostate cancers (~20%), and the p53 mutational patterns are different between these cancers (21–23). These differences may in part explain the different effects of CHEK2 mutation on lung, breast and prostate cancer risks.

It has been suggested that CHK2 inhibitors might be useful in cancer treatment, and the success to this type of therapy is likely to depend on the mutational profile of the targeted cancer cell, in particular its p53 status (24). The expression of normal CHK2 protein may be essential to the viability of lung cancer cells. In particular, CHK2 might be a target of interest in the treatment of patients with lung cancer. It is also possible that the protective effect of mutant CHEK2 alleles is related to a function of CHEK2 that is not yet known. Studies of the role of CHEK2 in lung cancer cells could clarify this.


   Acknowledgments
 
Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

  1. Bogdanova N, et al. Association of two mutations in the CHEK2 gene with breast cancer. Int. J. Cancer (2005) 116:263–266.[CrossRef][Web of Science][Medline]
  2. Chaturvedi P, et al. Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway. Oncogene (1999) 18:4047–4054.[CrossRef][Web of Science][Medline]
  3. CHEK2 Breast Cancer Consortium. Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat. Genet. (2002) 31:55–59.[CrossRef][Web of Science][Medline]
  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. (2004) 74:1175–1182.[CrossRef][Web of Science][Medline]
  5. Cybulski C, et al. CHEK2 is a multiorgan cancer susceptibility gene. Am. J. Hum. Genet. (2004) 75:1131–1135.[CrossRef][Web of Science][Medline]
  6. Dong X, et al. Mutations in CHEK2 associated with prostate cancer risk. Am. J. Hum. Genet. (2003) 72:270–280.[CrossRef][Web of Science][Medline]
  7. Kilpivaara O, et al. CHEK2 variant I157T may be associated with increased breast cancer risk. Int. J. Cancer (2004) 111:543–547.[CrossRef][Web of Science][Medline]
  8. Matsuoka S, et al. Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. Proc. Natl Acad. Sci. USA (2000) 97:10389–10394.[Abstract/Free Full Text]
  9. Oldenburg RA, et al. The CHEK2*1100delC variant acts as a breast cancer risk modifier in non-BRCA1/BRCA2 multiple-case families. Cancer Res. (2003) 63:8153–8157.[Abstract/Free Full Text]
  10. Rudd MF, et al. Variants in the ATM-BRCA2-CHEK2 axis predispose to chronic lymphocytic leukaemia. Blood (2006) 108:638–644.[Abstract/Free Full Text]
  11. Seppala EH, et al. CHEK2 variants associate with hereditary prostate cancer. Br. J. Cancer (2003) 89:1966–1970.[CrossRef][Web of Science][Medline]
  12. Vahteristo P, et al. A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am. J. Hum. Genet. (2002) 71:432–438.[CrossRef][Web of Science][Medline]
  13. Cybulski C, et al. A large germline deletion in the Chek2 kinase gene is associated with an increased risk of prostate cancer. J. Med. Genet. (2006) 43:863–866.[Abstract/Free Full Text]
  14. Cybulski C, et al. A deletion in CHEK2 of 5395 basepairs predisposes to breast cancer in Poland. Breast Cancer Res. Treat (2006) 102:119–122.[Web of Science][Medline]
  15. Cybulski C, et al. Germline CHEK2 mutations and colorectal cancer risk: different effects of amissense and truncating mutations? Eur. J. Hum. Genet. (2007) 15:237–241.[CrossRef][Web of Science][Medline]
  16. Kilpivaara O, et al. CHEK2 I157T associates with familial and sporadic colorectal cancer. J. Med. Genet. (2006) 43:e34.[Abstract/Free Full Text]
  17. Brennan P, et al. Uncommon CHEK2 mis-sense variant and reduced risk of tobacco-related cancers: case-control study. Hum. Mol. Genet. (2007) 16:1794–1801.[Abstract/Free Full Text]
  18. Walsh T, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA (2006) 295:1379–1388.[Abstract/Free Full Text]
  19. Antoni L, et al. CHK2 kinase: cancer susceptibility and cancer therapy—two sides of the same coin? Nat. Rev. Cancer (2007) 7:925–936.[CrossRef][Web of Science][Medline]
  20. Hecht SS. Tobacco smoke carcinogens and lung cancer. J. Natl Cancer Inst. (1999) 91:1194–1210.[Abstract/Free Full Text]
  21. Le Calvez F, et al. TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke: distinct patterns in never, former, and current smokers. Cancer Res. (2005) 65:5076–5083.[Abstract/Free Full Text]
  22. Mounawar M, et al. Patterns of EGFR, HER2, TP53, and KRAS mutations of p14arf expression in non-small cell lung cancers in relation to smoking history. Cancer Res. (2007) 67:5667–5672.[Abstract/Free Full Text]
  23. Feki A, et al. Mutational spectrum of p53 mutations in primary breast and ovarian tumors. Crit. Rev. Oncol. Hematol. (2004) 52:103–116.[CrossRef][Web of Science][Medline]
  24. Zhou BB, et al. Targeting the checkpoint kinases: chemosensitization versus chemoprotection. Nat. Rev. Cancer (2004) 4:216–225.[CrossRef][Web of Science][Medline]
Received December 18, 2007; revised December 18, 2007; accepted February 2, 2008.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J. Med. Genet.Home page
C Cybulski, B Gorski, T Huzarski, T Byrski, J Gronwald, T Debniak, D Wokolorczyk, A Jakubowska, P Serrano-Fernandez, T Dork, et al.
Effect of CHEK2 missense variant I157T on the risk of breast cancer in carriers of other CHEK2 or BRCA1 mutations
J. Med. Genet., February 1, 2009; 46(2): 132 - 135.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
29/4/762    most recent
bgn044v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (5)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Cybulski, C.
Right arrow Articles by Narod, S. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cybulski, C.
Right arrow Articles by Narod, S. A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?