Abstract
Objective: To examine the genetic link between the CHEK2 gene and the development of heritable prostate cancer, and to identify the distribution of these CHEK2 mutations across several populations.
Background: Prostate cancer is the most common cancer among men and a genetic link between prostate cancer development and numerous somatic and sex-linked genes exists. Research has previously demonstrated the existence of a link between the CHK2 checkpoint homolog gene (CHEK2) and the increased vulnerability of a man developing prostate cancer.
Methods: A systematic review of relevant electronic databases was conducted including CSA Illumina and MEDLINE. The search terms used included prostate cancer, male, CHEK2 or CHK2, and mutation.
Results: This review demonstrated that significant associations existed between various CHEK2 mutations and an increase in prostate cancer development in five of the six studies examined. The 1100delC and 1157T mutations were the CHEK2 mutations of focus. Three studies found a significant association between the 1157T mutation and an increase in prostate cancer development. Three studies found a significant association between the 1100delC mutation and an increase in prostate cancer development.
Discussion: Despite limitations of the published studies, including lack of representative sampling of ages within the male populations of the various studies, the presence of multiple studies with similar results conducted by the same authors, geographical variations, and the homogeneity of control groups, and association between CHEK2 mutations and prostate cancer was reported in most studies.
Conclusions: CHEK2 mutations were found in most cases to have a significant link to the development of prostate cancer in the case groups studied.
Key Words: prostate cancer, male, CHEK2, mutation, population
Abbreviations:
CHEK2 - CHK2 checkpoint homolog gene
CHK2 - protein checkpoint kinase 2
Introduction
The Canadian Cancer Society and the Public Health Agency of Canada have reported that prostate cancer is the most common cancer among men in Canada (1,2). Factors that have been shown to increase a man’s susceptibility to prostate cancer include inheritance of genes, increasing age, high fat diets, and family history (1,2). One in eight men will develop prostate cancer during their lifetime and most of these cases will develop after the age of 60 years (1).
Research conducted on prostate cancer has included the investigation of a genetic link between various genes, such as BRCA1, and the increased development of prostate cancer (3). However, recent research has begun to look at the genetic effects of CHEK2, a tumour suppressor gene, on the development of heritable prostate cancer.
Recent studies have demonstrated a link between the CHK2 checkpoint homolog gene (CHEK2) and the increased risk of developing prostate cancer. The CHEK2 gene is a tumour suppressor gene located on the long arm of chromosome 22 that codes for the protein checkpoint kinase 2 (CHK2). CHEK2’s main role is to prevent targeted cells from dividing at a faster rate than normal (4). At the site of genetic damage, the CHEK2 gene produces the associated CHK2 protein, which in turn interacts with p53 and other regulatory proteins to stop the cell cycle in order to prevent further destruction of the cell (4).
In order to determine if a genetic link exists between the CHEK2 gene and prostate cancer development, case-control studies have been conducted in various populations to look at the possible mutations that exist in the CHEK2 gene, and if these mutations are associated with prostate cancer development. Many of these studies have also considered whether similar genetic mutations exhibit the same effects on prostate cancer development across populations. The National Cancer Institute of Canada has stated that prostate cancer has “strikingly different reported incidence rates between countries” (5). For example, prostate cancer is highly incident in Canada, the United States of America and Denmark. On the other hand, prostate cancer is not highly incident in England and other European countries (5).
Various mutations of the CHEK2 gene are examined in the articles of this review, and the main mutations of interest include the 1157T mutation and the 1100delC deletion mutation. To explore the relationship between CHEK2 gene mutations and the development of prostate cancer, as well as the distribution of these mutations across populations, a systematic review of the scientific literature was conducted. This review examines various mutations of the CHEK2 gene, with a particular focus on the 1157T mutation and the 1100delC deletion mutation.
Method
Search Strategy
Results were obtained for this review by searching the CSA Illumina database. Within this database, the following journal databases were searched for related journal articles: Abstracts in Social Gerontology, Biological Sciences, Biology Digest, Digital Dissertations, Health Sciences, MEDLINE, Plant Science, and TOXLINE. The follow search strategy was used: (Prostate cancer) AND (male) AND (CHEK2 OR CHK2) AND (polymorphism OR mutation). (Prostate cancer) and (CHEK2 OR CHK2) were limited to results in the TITLE field only, whereas (male) and (polymorphism OR mutation) were limited to results in the KEYWORD field. Limits for the search included studies published between January 1, 2000 and March 7, 2008, and studies published in English. The search resulted in eight articles.
Study Selection
Figure 1 demonstrates the inclusion criteria used for this review. The inclusion criteria included studies published in English and published after January 1, 2000. After meeting the inclusion criteria, we checked the full-text of each article for being relevant and appropriate for inclusion in the review. Eight articles met these criteria. Two of the eight studies were excluded because multiple journals published the same data. Subsequently, references for each article were checked for relevance for inclusion. No articles from the references were selected to be included in the study. Six articles were retained for this review.
Data Abstraction Procedures
For the six studies, the specific data elements that were abstracted from each article include the mutations of interest, inclusion criteria for selection of cases and controls, the results for cases and unselected controls, country of study, age of cases and controls, and major conclusions and findings.
Results
Study Population
Six studies were included in this review. Each study looked at a variety of different mutations in the CHEK2 gene. Three studies looked specifically at the 1157T mutation in the CHEK2 gene and three studies looked specifically at the CHEK2*1100delC mutation in the CHEK2 gene. The characteristics of the six studies are included in Table 1.
Quality of Studies
All six studies that were included in the review were critiqued with respect to their methodological quality using the Newcastle-Ottawa Quality Assessment Scale (6). This assessment scale, using a “star system”, was developed to provide a standard set of criteria for researchers to critique the studies used in their reviews and to ensure that studies that were used provide the most accurate, standardized information (6). The scale is currently being evaluated but has been demonstrated to have strong content validity and inter-rater reliability (6). All six studies in the review produced low scores (0-2 stars out of a possible 9 stars) on the assessment scale indicating the presence of methodological issues, which are discussed later in this review.
Conclusions from the Studies
The CHEK2 gene was analyzed in the six reviewed articles and various mutations of the CHEK2 gene were examined. In five of the studies, the CHEK2 mutations were found to be associated with the development of prostate cancer in the case groups studied. In the study conducted by Cybulski et al., various mutations of the CHEK2 gene were examined, including the 1157T and 1100delC mutations (7). They concluded that four CHEK2 gene mutations, 1157T being the most common of the mutations, predisposed the Polish population to prostate cancer, accounting for 7% of the prostate cancer cases in Polish males (7). Similarly, Cybulski et al. conducted a similar case control study in Poland examining the 1157T mutation in the CHEK2 gene (8). They concluded that the 1157T mutation conferred increased susceptibility to prostate cancer in Polish males (8). Seppala et al. also studied the CHEK2 gene and the presence of the 1157T mutation in relation to the development of prostate cancer in Finnish men. (9) They concluded after examining two cohorts of men with family histories of prostate cancer that the 1157T mutation contributes to a predisposition to developing prostate cancer at the population level (9).
Within these studies, mutations studied included the 1157T and 1100delC mutations, among others. Wu et al. performed genetic studies at the Mayo Clinic in the United States of America and focused their attention on the1100delC mutation on the CHEK2 gene, and its relationship with the development of prostate cancer (10). They concluded after comparing tumour tissues with normal tissues that the 1100delC mutation, in addition to other minute mutations, reduces CHEK2 kinase activity in males with prostate cancer. They found that this conclusion supports the hypothesis that CHEK2 mutations may contribute to prostate cancer development in an American population (10). Correspondingly, Dong et al. performed a study in the United States of America of the 1100delC mutation on the CHEK2 gene and how it affected prostate cancer development (10). Their study concluded that the 1100delC mutation may contribute to an increased prostate cancer risk (11).
Although five of the studies reported an increased risk, one of the six studies, reported somewhat different results. Wagenius et al. performed a case control study with four different groups of Swedish males looking at the 1100delC mutation on the CHEK2 gene, and its relationship with prostate cancer development (12). No significant association between the gene mutation and prostate cancer development was found in this population, based on a similar prevalence of cancer in both the case and control groups (12).
Discussion
Five of the six studies examined in this review reported a significant association between the genetic analyses of the mutations on the CHEK2 gene and the development of prostate cancer in male populations. However, one study showed a non-significant association between CHEK2 mutations, specifically, the 1100delC mutation, and the development of prostate cancer in the male Swedish population (12). Three other studies in this review, which also examined the 1100delC mutation, demonstrated a significant associated between the CHEK deletion mutation and the development of prostate cancer in their male populations (7-9).
A possible explanation for these differences in findings could be due to the composition of the countries from which the specific sub populations were sampled. Sweden, for example, has a relatively ethnically homogenous population. For example, in December 2007, Sweden had a total population of 9,184,000 people and an immigrant population of approximately 100,000 people. Studies in the other countries, such as the United States, have a more heterogeneous population. For example using 2007 data, the United States was shown to have 1/3, or 33% of its population born outside the country (13). Similarly, in countries such as Finland, approximately 15-20% of the inhabitants are born outside of the country (13). It is possible that the variation in the genetic diversity in the different countries under study partially explains the inconsistent findings. Further research is necessary in determining how the cultural diversity of a country affects the relationship between CHEK2 mutations and prostate cancer.
Two of the six studies were conducted by authors that were co-workers at the Mayo Clinic in the United States of America, while two of the six studies were conducted by authors that were co-workers at the Pomeranian Medical University in Poland. The results from the two Polish studies demonstrated a similarly significant effect of the CHEK2 mutations on the Polish male population. These two Polish studies stated that the I157T mutation conferred an increase in susceptibility to prostate cancer in Polish males (7,8). Similarly, the results from the two American studies showed a similar significant effect of the CHEK2 mutations on the American male population. The two studies stated that the majority of the mutations studied reduce CHEK2 kinase activity in males with prostate cancer, which supports the hypothesis that CHEK2 somatic and germ line mutations may contribute to prostate cancer development in an American population (10,11). Within these two groups of similar articles, conducted by authors from the same institution, there may be indicative bias, as there is a lack of replicability of the results by researchers in other geographic locations. Additionally, it is unknown that in articles affiliated with the same institution, if the same cases were ascertained for both studies. If similar cases were used for both studies, then the replicability of the results of the studies would be diminished. The association between gene mutations and the development of prostate cancer should be further explored by separate groups of researchers observing different populations.
All of the studies reviewed were case-control studies. The comparison groups for the majority of the studies were sampled from the general population, and were randomly chosen with respect to age, gender and race. This sampling was employed to produce comparison groups that were representative of the general population in each country. However, in the included studies, the age of the case participants was generally younger, between the ages of 43 and 75. The reviewed studies did not focus on including the cases of younger adults in any of the subpopulations. This may have occurred because of the low incidence of prostate cancer in younger men (7). However, more importantly, the studies in this review did not consider men over the age of 75 years old. For the countries that the studies were conducted in, the life expectancies of these countries are all increasing and are reaching upwards of 75 years. Therefore, it is important to note that a major limitation of these studies is a lack of representation of the older population of the studied countries, which decreases the generalizability of the study’s results to the entire population.
In all six studies, there was no indication of any major selection bias as the case and control groups were randomly selected using various sampling strategies.
Strengths of this review include clear inclusion search criteria as well as a clear search strategy. Also, comparisons were able to be made within and between populations, and there were large sample sizes for all studies. Limitations of this review include not examining the grey literature on the association of study. By including only formal sources of information on the examined association, all information on the association between CHEK2 and prostate cancer development may not be included in the study and some of the conclusions discussed in this paper may not be fully generalizable to the entire population. In future studies, all grey literature in addition to widely available formal literature should be included when examining the association of interest. In addition, the inclusion criteria of a case differed between each study. Finally, there was a lack of reporting of potential confounders in the studies.
This review demonstrated that significant associations existed in five of the six studies and differences in these associations could have been a result of the varying homogeneities of the countries themselves. Another issue that was discussed in this review includes the lack of representative sampling of ages within the male sub-populations of the various studies. In addition, multiple studies with similar results that existed in this review, conducted by the same authors in the same facilities, also highlighted a source of bias as their similar results could be a reflection of their previous work. Therefore, replicated studies, performed by other researchers, on the same populations, are warranted to ensure the accuracy of the associations found in the studies.
Conclusions
Upon examining the literature, an association between CHEK2 genes and prostate cancer development exists. However, the lack of quality study designs limits the ability to make definitive conclusions regarding the relationship.
References
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(2)Public Health Agency of Canada. Prostate Cancer. (cite May 27, 2009); Accessed from: http://www.phac-aspc.gc.ca/cd-mc/cancer/prostate_cancer-cancer_prostate-eng.php
(3)Rosen E, Fan S, Goldberg I. BRCA1 and prostate cancer. Cancer Invest, 2001. 19(4):396-412.
(4)Genetics Home Reference. CHEK2 - CHK2 checkpoint homolog (cited March 10, 2008); Accessed from: from http://ghr.nlm.nih.gov/gene=chek2.
(5)National Cancer Institute of Canada. International Comparisons (cited March 10, 2008); Accessed from: http://www.ncic.cancer.ca/ncic/internet/standard/0,3621,84658243_85787780_91036643_langId-en,00.html.
(6)Ottawa Health Research Institute. The Newcastle-Ottawa Scale for assessing the quality of nonrandomized studies in meta-analyses. (cited July 14, 2010); Access from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm
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(9)Seppala EH, Ikonen T, Mononen N, Autio V, Rokman A, Matikainen MP, et al., CHEK2 variants associate with hereditary prostate cancer. Br J Cancer, 2003. 89(10):1966-70.
(10) Wu X, Dong X, Liu W, Chen J., Characterization of CHEK2 mutations in prostate cancer. Hum Mutat, 2006. 27(8):742-7.
(11) Dong X, Wang L, Taniguchi K, Wang X, Cunningham JM, McDonnell SK, et al., Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet, 2003. 72(2):270-80.
(12) Wagenius M, Borg A, Johansson L, Giwercman A, Bratt O., CHEK2*1100delC is not an important high-risk gene in families with hereditary prostate cancer in southern Sweden. Scand J Urol Nephrol, 2006. 40(1):23-5.
(13) Statistics Sweden. Preliminary Figures (cited March 10, 2008); Accessed from: http://www.scb.se/templates/pressinfo____223452.asp.
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