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Cancer Epidemiology Biomarkers & Prevention Vol. 14, 748-752, March 2005
© 2005 American Association for Cancer Research

Short Communication

Chromosomal Instability in Peripheral Blood Lymphocytes and Risk of Prostate Cancer

Randa El-Zein, Yun Gu, Monica S. Sierra, Margaret R. Spitz and Sara S. Strom

Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Randa El-Zein, Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Box 189, Houston, TX 77030. Phone: 713-792-3020; Fax: 713-792-0807. E-mail: relzein{at}mdanderson.org


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Prostate cancer is an extremely complex disease, and it is likely that chromosomal instability is involved in the genetic mechanism of tumorigenesis. Several chromosomes have been labeled as "players" in the development of prostate cancer, among them chromosome 1 and X chromosome have been reported to harbor prostate cancer susceptibility loci. However, there is little information regarding the background levels of chromosome instability in these patients. In this pilot study, we examined spontaneous chromosome instability in short-term lymphocyte cultures from 126 study subjects, 61 prostate cancer patients, and 65 healthy controls. We evaluated chromosomal instability using a fluorescence in situ hybridization assay using two probes targeting specific regions on X chromosome and chromosome 1. Our results showed a significantly higher mean level of spontaneous breaks involving the X chromosome in patients compared with controls (mean ± SE, 2.41 ± 0.26 and 0.62 ± 0.08, respectively; P < 0.001). Similarly, chromosome 1 spontaneous breaks were significantly higher among cases compared with controls (mean ± SE, 1.95 ± 0.24 and 1.09 ± 0.16, respectively; P < 0.001). Using the median number of breaks in the controls as the cutoff value, we observed an odds ratio (95% confidence interval) of 15.53 (5.74 - 42.03; P < 0.001) for spontaneous X chromosome breaks and 3.71 (1.60 - 8.63; P < 0.001) for chromosome 1 breaks and risk of development of prostate cancer. In conclusion, our preliminary results show that spontaneous chromosome instability could be a risk factor for prostate cancer.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
In 2004, ~230,900 new cases of prostate cancer will be diagnosed in the United States and ~29,900 men will die of the disease (1). The age-specific incidence curve for prostate cancer has a steeper slope than for any other cancer, and with the present trend toward an aging population, prostate cancer is a major public health concern (2). Nevertheless, the etiology of prostate cancer has not been clearly elucidated, nor are the molecular mechanisms of the disease development and progression well characterized. The most generally accepted model of carcinogenesis postulates that cancer develops through the accumulation of genetic alterations that allow the cells to escape normal growth-regulatory mechanisms (3).

There has been an expanding literature on chromosomal aberrations in prostate cancer over the past few years. Initial studies suggested that ~75% of prostate cancer tumors had normal male karyotypes; however, there is now evidence by subsequent analysis over cell culture times that normal cells seem to be selected for in vitro (4, 5); therefore, growth of tumor cells was not ideal. Several candidate chromosomes have been suggested as playing a role in the development of prostate cancer, among which are chromosomes 1, 7, 8, 10, 17, and X (6-10). Recent reports indicate that chromosome 1p36 harbors a prostate cancer susceptibility locus (6), which might be a site of a general tumor suppressor gene. Chromosome 1q24-25 has also been reported to harbor another susceptibility locus (11). Two similar loci have been reported on X chromosome Xq27-28 (12, 13).

Prostate cancer is a complex disease, and chromosomal instabilities may be involved in the genetic mechanism of its tumorigenesis. In spite of the available reports in literature (14-16), little is known about the spontaneous background levels of chromosomal alterations in the peripheral blood lymphocytes of prostate cancer patients. To address this issue, we conducted a pilot study to investigate whether individuals with prostate cancer exhibit increased chromosomal instability that could account for their susceptibility to cancer. To detect such spontaneous or background instability, we used a molecular cytogenetic fluorescence in situ hybridization (FISH) assay to measure the level of chromosome aberrations at two loci. The probes used hybridize to large pericentromeric regions on chromosome 1 and X chromosome and allowed the detection of both structural and numerical aberrations simultaneously. These two chromosomes were selected for multiple reasons. First, prostate cancer susceptibility loci have been mapped to both chromosomes (11, 12). Second, both chromosomes have been suggested as playing a role in the development of prostate cancer (6-10). Third, previous studies with human lymphocytes have shown an elevated frequency of breakage in the heterochromatin regions at 1q and 9q after exposure to a variety of environmental clastogens, such as benzene, ionizing radiation, and pesticides (17-19). In addition, breaks affecting the centromeric and pericentromeric heterochromatin regions of human chromosomes could lead to mutations, chromosomal rearrangements, and increased genomic instability (20, 21). Therefore, by targeting these regions in a prostate cancer study, we would be able to determine if there is a role for chromosomal instability in the risk of development of prostate cancer.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Subjects
The cases were 61 patients with histopathologically confirmed, previously untreated prostate cancer who were registered at the University of Texas M.D. Anderson Cancer Center (Houston, TX) between 2000 and 2002 and enrolled in an ongoing prostate cancer case-control study. These study subjects were recruited with no age or ethnic restrictions, but based on study criteria, all presented with nonmetastatic disease. Patients with a previous history of cancer were excluded because the majority of such patients will have history of prior treatment. Age-matched healthy controls were accrued from the M.D. Anderson Cancer Center free prostate screening program. All controls had prostate-specific antigen (PSA) levels <4.0 mg/mL (81% had PSA levels <2.0 mg/mL) and normal digital rectal exam. Data on medical and family history of cancer, smoking habits, and occupational history were obtained through an interviewer-administered questionnaire as well as from review of the patients' hospital records.

FISH Analysis
For the FISH experiments, short-term blood cultures were established according to a standard procedure described in detail elsewhere (22). Slides for FISH were prepared by using Vysis protocols for chromosome 1 p11.1-q11.1 (spectrum orange) and X chromosome p11.1-q11.1 (spectrum green) human CEP probes. All scoring was done from coded, randomly ordered slides using a Nikon E-400 microscope with a fluorescence attachment equipped with a triple bandpass, spectrum orange, and FTIC filters. One thousand interphase nuclei randomly selected from each sample of cases and controls blinded to the examiner were analyzed and results were recorded as breaks per 1,000 cells. As indicated by two different chromosome probes, a normal cell had the interphase nuclei with three labeled FISH signals, two orange signals corresponding to the two copies of chromosome 1, and one green signal corresponding to the X chromosome (Fig. 1A). An abnormal cell had more than one labeled green signal (Fig. 1B, arrow), the size of which is smaller than that found in a normal cell, indicating a break in the X chromosome. A cell with more than two orange signals, the size of which are smaller than that found in a normal cell, would be indicative of a break in chromosome 1 (Fig. 1C, arrows). The advantage of using two different but equal-sized probes simultaneously is that one probe serves as an internal control for the other, where the differentiation between a break and an increase in copy number depends on the size of the resultant signal. A cell with more than one green signal or more than two orange signals, the size of which are equal to those of a normal cell, would be considered an aneuploid cell.



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  		Figure 1. A. Normal cells with one copy of X chromosome and two copies of chromosome 1. B. A cell with a break in X chromosome and normal chromosome 1. C. A cell with a break in chromosome 1 and normal X chromosome.

 
Statistical Analysis
The levels of chromosome breaks between both groups were compared using Mann-Whitney test. The median level of chromosome breaks in the control group was used as the cutoff value to calculate the odds ratio (OR). Point estimates of OR and the corresponding 95% confidence intervals (95% CI) associated with chromosome breaks were computed using multivariate logistic regression analysis, adjusting for age, smoking status, and family history of prostate cancer. P < 0.05 was required for statistical significance. All analysis was done using SPSS (version 10.1, Mathsoft, Inc., Seattle, WA) statistical software.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Subject Characteristics
From the ongoing prostate cancer case-control study that had enrolled 250 patients, we selected 61 patients who were diagnosed at the M.D. Anderson Cancer Center and had not had prior treatment including hormonal, chemotherapy, or radiation therapy. Selected characteristics of the study population are presented in Table 1. The mean ± SD age was 62 ± 7.6 years for the cases and 62 ± 8.3 years for the controls. Overall, 84% of the study subjects were Caucasians. We were able to match the Caucasian cases to the controls on age and ethnicity; however, the study included fewer African American cases than controls. A family history of prostate cancer was reported in a first-degree relative in 20% of the cases versus 19% of the controls. Among the prostate cancer patients, 26% had a Gleason score of <6, 46% had a Gleason score 7, and the remaining 28% had a Gleason score of >8. Sixty-six percent of the patients had a T2 pathologic stage and 80% had a preoperative PSA <10.


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  		Table 1. Demographic characteristics of prostate cancer cases and controls (White and African American)

 
Chromosome Aberration Frequencies
X Chromosome Aberrations. The frequency of spontaneous breaks on the X chromosome was significantly higher in the cases (mean ± SE, 2.41 ± 0.26) compared with the controls (mean ± SE, 0.62 ± 0.08; P < 0.001). On subgroup analysis (Table 2), cases had a significantly higher levels of spontaneous X chromosome aberration frequency in almost all the variables tested (age, smoking status, PSA level, and family history of prostate cancer). After confirming by bootstrap resampling techniques that the median number of breaks per 1,000 of the controls was the optimal cutoff value that generated a stable OR estimate, we used this value to dichotomize the population to calculate the ORs. The adjusted risk (for age, smoking status, and family history of cancer) of prostate cancer associated with X chromosome spontaneous breaks compared with the controls was 15.53 (95% CI, 5.74 - 42.03; P < 0.001; Table 3), indicating that the association between increased frequency of breaks and risk of developing prostate cancer was independent of other factors. Although the number of African American prostate cancer cases was small (n = 4), they had significantly higher levels of X chromosome aberrations (mean ± SE, 4.5 ± 1.56) compared with the Caucasian patients (mean ± SE, 2.26 ± 0.25; P < 0.001).


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  		Table 2. Frequency of X chromosome and chromosome 1 breaks by host characteristics among cases and controls

 

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  		Table 3. Multivariate logistic regression analysis of X chromosome and chromosome 1 breaks

 
Chromosome 1 Aberrations. The frequency of the chromosome 1 spontaneous breaks was also significantly higher among the cases (mean ± SE, 1.95 ± 0.24) compared with the controls (mean ± SE, 1.09 ± 0.16; P < 0.001). Table 2 shows that the cases had a significantly higher level of spontaneous chromosome 1 aberration frequency in almost all the variables tested with exception of never smokers and family history of prostate cancer. After confirming by bootstrap resampling techniques that the median number of breaks per 1,000 of the controls was the optimal cutoff value that generated a stable OR estimate, we used it to calculate the ORs. The adjusted risk (for age, smoking status, and family history of cancer) of prostate cancer associated with chromosome 1 spontaneous breaks compared with the controls was 3.71 (95% CI, 1.60 - 8.63; P < 0.001; Table 3), indicating that the association between increased frequency of breaks and risk of developing prostate cancer was independent of other factors. Similarly, the African American cases had a significantly higher chromosome 1 aberration frequency (mean ± SE, 2.67 ± 1.12) compared with the Caucasian cases (mean ± SE, 1.91 ± 0.25; P < 0.05). However, this observation was not seen in the African American controls when compared with the Caucasian controls.

Chromosome Aberrations and Clinical Variables
Among the cases, the level of chromosome aberrations on both X chromosome and chromosome 1 was also investigated in relation to the Gleason score, pathologic stage, and preoperative PSA levels at the time of the diagnosis. No significant differences were observed with either chromosome breaks on chromosome 1 or X chromosome in relation to the clinical variables analyzed.

In addition, we investigated the association between levels of chromosome aberrations and PSA among controls with PSA levels <2.0 mg/mL compared with those with PSA levels >2 and <4.0 mg/mL. The mean ± SE was 0.63 ± 0.10 for PSA <2.0 mg/mL and 0.73 ± 0.24 for PSA >2.0 mg/mL for the X chromosome and 1.08 ± 0.18 for PSA <2.0 mg/mL and 1.45 ± 0.51 for PSA >2.0 mg/mL for chromosome 1. Furthermore, we compared the levels of chromosome aberrations and PSA in the controls to the cases with low preoperative PSA levels (<4.0 mg/mL). The mean ± SE aberration frequency in the cases was 3.07 ± 0.65 for the X chromosome and 2.00 ± 0.38 for chromosome 1 compared with the controls 0.62 ± 0.08 for the X chromosome and 1.09 ± 0.16 for chromosome 1. These results suggest that there is a distinct difference in distribution of chromosome aberration levels in the cases and the controls that is not confounded by PSA level.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Cancer is a consequence of genetic or epigenetic alterations in a variety of genes that are fundamental to the process of growth, cell proliferation, differentiation, and programmed cell death (23). Each alteration, whether an initiating or a progression-associated event, may be mediated through gross chromosomal change and hence has the potential to be detected cytogenetically (24). The relationship between presence of high frequencies of chromosome aberrations and predisposition to cancer has been established in syndromes, such as ataxia telangiectasia, Bloom's syndrome, and Fanconi's anemia. However, a low level of chromosomal instability is also detectable in the peripheral blood lymphocytes of patients with skin, breast, and bladder cancers and lymphomas (25-28). An increased frequency of chromosome aberrations in circulating lymphocytes is generally considered indicative of increased cancer risk for those exposed to DNA-damaging agents. Bonassi and Abbondandolo (29) and Hagmar et al. (30) reported a significant increase in the mortality ratio for all cancers in subjects who had shown increased levels of chromosomal aberrations in their lymphocytes. Importantly, the data from both these studies when pooled indicated that the frequency of chromosome instability in peripheral blood lymphocytes is a relevant biomarker for cancer risk in humans, reflecting early biological effects of genotoxic carcinogens and individual cancer susceptibility (31, 32). Chromosomal instability has been described in many human dysplastic lesions and is considered a primary event in neoplastic transformation as well as a marker of progression to cancer (33-36).

In this study, we used interphase cytogenetics to detect the level of damage at two chromosomes reported to be involved in prostate cancer susceptibility (11, 12). Individuals with higher levels of background chromosome instability had significantly elevated risks of developing prostate cancer depending on the target site. Interestingly, 63% of the controls had low aberration frequency at both chromosomal loci compared with only 15% of cases. On the other hand, 41% of the cases exhibited high aberration frequency involving both chromosomes compared with only 5% of the controls. Although previous studies have shown the presence of chromosome instability in prostate tumors (14-16), to our knowledge, this is the first molecular cytogenetic study to investigate the role of background chromosome instability in the peripheral blood lymphocytes of previously untreated prostate cancer patients. Levels of chromosome instability in prostate cancer patients reported by us and others (37, 38) were found to be lower than that found in Hodgkin's disease patients (26) and bladder carcinoma (27) but higher than that found in patients with carcinoma of the cervix uteri (39) and breast (40). Our findings suggest that accumulated chromosomal damage in peripheral blood lymphocytes may be an important biomarker for identifying individuals at risk of developing the disease.

The X chromosome FISH probe used in this study targeted the Xp11.1-Xq11.1, which is in close proximity to several important genes that have been implicated in prostate cancer. The androgen receptor gene maps to Xq11.2-q12 and alterations in this gene have been reported to dramatically affect its function in the cell (41). Because of the multiple functions and the complex expression pattern of the androgen receptor in the prostate, questions concerning the androgen receptor function and its specific target genes remain unanswered. Direct androgen-regulated genes in cell cycle stimulation (cell proliferation), suppression of apoptosis (cell survival), and prostate function (differentiation) have been postulated but not yet fully understood (41). In addition, the phosphoglycerate kinase (PGK1), a metabolic housekeeping enzyme, is located within Xq11-Xq13 and is closely linked to the androgen receptor (42). It is plausible to speculate that the presence of chromosome instability in the vicinity of such key genes may lead to alteration of their functions and ultimately contribute to the genomic instability of the cell, thus facilitating the carcinogenic transformation process.

Chromosome 1 has a breakage-prone site, which has been reported to be sensitive to environmental clastogens (17-19) and is thought to be involved in both early and late stages of tumor development (20, 21). Several reports suggest that chromosome 1 is involved in prostate cancer whether through the presence of prostate cancer susceptibility genes or through the disruption of common pathways involved in cancer development. Lundgren et al. (43) reported structural chromosomal changes in prostatic tumor tissues. The rearrangements were in the form of deletions, duplications, and translocations involving 18 of the 22 autosomes and the X chromosome. Chromosome 1 was among the most frequently affected chromosomes with breakpoints affecting both short and long arms. Atkin and Baker (44) and Casalone et al. (45) reported that chromosome 1 was the chromosome most frequently involved in sporadic rearrangements. Vastag (46) and Carpten et al. (47) reported recently that mutations on the RNASEL gene (a tumor suppressor gene) on chromosome 1 were responsible for a small fraction of all prostate cancer cases, particularly the most aggressive phenotypes. Another suggested function of the RNASEL gene is its role in triggering apoptosis. When the gene is mutated, the cell loses the ability to break down RNA. Because the degradation of RNA triggers apoptosis, the cell may forget to self-destruct. These cells then survive and divide in an uncontrolled manner, a mechanism that can lead to cancer. It should be noted that in our study the break frequency observed for both chromosomes was not associated with the smoking status (ever or never smokers) in either cases or controls. This is consistent with our findings from previous studies (48, 49), which suggest that the chromosomal instability was constitutional and independent of smoking status.

Significant differences in break frequency on both chromosomes were observed among African American cases compared with Caucasian cases with a 2-fold increase in the aberrations on the X chromosome and 1.4-fold increase in the aberrations on chromosome 1. No differences were found in controls. Based on the small number of African American patients in this study, no specific conclusions could be drawn. However, our data support the possible differences in chromosome instability among the different ethnic groups, an observation that has been addressed in different studies (50, 51) and that clearly warrants further investigation in view of the well-known higher incidence of prostate cancer among African Americans.

In conclusion, in this pilot study, we showed that chromosomal instability in peripheral blood lymphocytes may be a potential biomarker for prostate cancer susceptibility. To date, the molecular genetic events associated with the initiation and progression of prostate cancer remain poorly understood. It has long been considered that genetic instability plays a pivotal role in the development and progression of human cancer (52), and as with most types of human cancer, multiple genetic changes are probably necessary for prostate carcinogenesis. As in any case-control study, there are inherent limitations, one of which is the fact that the M.D. Anderson Cancer Center is a tertiary center where patients are subject to the vagaries of referral patterns and neither the cases nor the controls are being identified through population-based registries. These results are preliminary and larger population-based studies with diverse ethnic subgroups are clearly needed to corroborate our results. In addition, the correlation between genetic instability in the lymphocytes and cytogenetic changes in the prostate needs to be investigated.


   Footnotes
 
Grant support: National Cancer Institute grants CA90270, CA84964, CA88301, and NIEHS ES07784 and M.D. Anderson Prostate Cancer Research Program.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 3/25/04; revised 8/ 6/04; accepted 9/ 1/04.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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