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Clinical Cancer Research Vol. 7, 3139-3143, October 2001
© 2001 American Association for Cancer Research

Regular Articles

Deletions on Chromosome 8p22 May Predict Disease Progression As Well As Pathological Staging in Prostate Cancer1

Hideyasu Matsuyama2, Yi Pan, Kazuo Oba, Satoru Yoshihiro, Kenji Matsuda, Lars Hägarth, David Kudren, Katsusuke Naito, Ulf S. R. Bergerheim3 and Peter Ekman

Department of Urology, Yamaguchi University School of Medicine, Ube, Yamaguchi 755-8505, Japan [H. M., K. O., S. Y., K. M., K. N.], and Department of Urology, Karolinska Hospital, Stockholm 171-76, Sweden [Y. P., L. H., D. K., U. S. R. B., P. E.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: A recent report demonstrated that the deletion of chromosome 8p22 could predict disease progression in stage III (capsular penetrating) prostate cancer. We studied if the status of chromosomal deletions of 8p22 could reflect pathological stage as well as patient prognosis, thereby serving as a diagnostic tool to optimize the treatment strategy in prostate cancer.

Experimental Design: A total of 97 patients (41 Japanese and 56 Swedish) were studied by the fluorescence in situ hybridization technique. Seventy-seven patients (23 pT2, 18 pT3, and 36 pN+ tumors) underwent surgery (radical prostatectomy or lymph node dissection). The specimens were prepared by touch biopsy. From another 20 cases, fine-needle aspiration biopsies were obtained.

Results: 8p22 deletions were detected in 47 (61%) and 11 (55%) specimens of 77 touch biopsies and 20 fine-needle aspiration biopsies, respectively. No significant difference was found in the frequency of 8p22 deletion between different preparations of specimens, as well as between different races (Japanese versus Swedish). The frequency of 8p22 deletion was statistically higher in patients with pT3 or more than in those with pT2 (P < 0.01). Disease progression was evaluated in 57 patients. The Cox proportional hazards model revealed 8p22 deletion to be the strongest parameter to predict disease progression (hazards ratio = 5.75; P = 0.0001).

Conclusions: Studies on chromosomal deletions of 8p22 by fluorescence in situ hybridization technique may serve as a genetic marker to optimize the treatment strategy in patients with prostate cancer to the optimal treatment.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The natural course of human prostate cancer is highly variable, and we still lack reliable tools to predict the outcome in the individual case. Radical prostatectomy is generally regarded as an efficient way of curing the disease. However, a lack of convincing preoperative information has hampered a correct clinical staging leading to a significant understaging compared with pathological staging. It should be of crucial importance to identify efficient diagnostic procedures for a more reliable preoperative work up. PSA4 has been used as a valuable marker for diagnosis and follow-up, whereas PSA falls short in staging newly diagnosed prostate cancer and prognosticating the course of the disease in individual patients. To date, nomograms using the clinical parameters of stage, grade, and PSA have proved to be the best tools to predict advanced disease at the time of diagnosis or risk of recurrence (1) .

Genetic markers like the elevated expression of caveolin-1, which is mapped on chromosome 7q31, have been demonstrated to be an independent predictor of time to progression after prostatectomy (2) . Sato et al. (3) recently reported that the deletion of chromosome 8p22 and/or 8q amplification, as measured by FISH technique, was linked to disease progression in stage III (capsular penetrating) prostate cancer. We have reported previously that the deletion of 8p22 had a close correlation with pathological stage, as well as tumor grade, and that the deletion of 16q24 was linked to a metastatic potential of the tumor (4 , 5) .

There is a significant geographical and racial variation in the incidence of clinically manifest prostate cancer. The incidence of prostate cancer is much lower in East Asian countries, as compared with the Western world. Nutritional and environmental factors may have an influence on the promotion of the disease, because the incidence of latent cancer is similar in Japan as in the United States (6) . A combination of genetic and epigenetic factors may, however, partly explain the disproportionate incidence and mortality of prostate cancer between different races. A recent report demonstrated that the patterns of specific chromosomal changes, including chromosomes 8p and 16q deletions, were similar in tumors from African-Americans and Caucasian-Americans, as measured with comparative genomic hybridization technique (7) .

The aims of this study were: (a) to explore if the status of chromosomal deletions of 8p22 could be linked to risk of disease progression as well as pathological stage; (b) to see if 8p22 deletion could correctly be detected by using FNAB material; (c) to study if sporadic prostate cancers from Japanese and Swedish men differed with regard to 8p22 deletion pattern; and (d) to see if studies of 8p22 deletion could be used as a universal genetic marker to select patients most likely to benefit from radical prostatectomy.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Totally, 97 patients (41 Japanese and 56 Swedish) with prostate cancer were studied. All specimens were collected from patients who were treated at the Karolinska Hospital (Stockholm, Sweden), the Yamaguchi University Hospital (Ube, Japan), and Hara Sanshin General Hospital (Fukuoka, Japan). Written informed consent was obtained from each subject. The patient characteristics of the study were noted in Table 1Citation . The mean age of the patients was 67 years ranging from 48 to 86 years. Radical prostatectomy was undertaken in 59 patients, and pelvic lymph node dissection was undertaken in 18 cases. Twenty cases were subject to biopsy only. The clinical stages of those cases were T2 in 3, T3 in 8, and M+ in 9. The tumor grade was classified as well, moderately well, and poorly differentiated adenocarcinoma in 5, 9, and 6 cases, respectively. The mean preoperative PSA was 31.4 ranging from 2.5 to 240 ng/ml. Prognostic evaluation was based on disease progression, including biological failure in 57 subjects that had undergone either radical prostatectomy (39 cases) or regional lymph node dissection (18 cases) from 1985 to 1994 at the Karolinska Hospital and from 1992 to 1997 at Yamaguchi University Hospital. The cohort cases were consecutively enrolled to the prognostic evaluation either when the disease-free follow-up period reached 36 months or when disease progression developed. Eight cases were lost of follow-up, and 12 were <36 months of follow-up. The median follow-up period was 59 months, ranging from 3 to 118 months, and was calculated from the date of surgery. Disease progression was defined as either the appearance of metastatic lesions on radiographic examinations or consecutive elevations (three times) of PSA values above the nadir (8) .


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  		Table 1 Patient characteristics of the study

 
Tumor stage was classified according to the tumor-node-metastasis classification (9) . All histological specimens were graded according to the WHO classification system (10) , and the cytological grade of the FNAB specimen was classified according to the classification system suggested by Esposti (11) .

FISH and Evaluation of the Signals.
The status of deletion on 8p22 was studied by dual-color FISH technique in 97 cases. The FISH experiments were conducted either in 1994 for Swedish materials or in 1997 for Japanese materials. The FISH technique was performed as described previously (4 , 12) . In brief, digoxigenin-labeled cosmid probes (114C11/LPL/8p22 kindly provided by Dr. S. Wood, Vancouver, Canada; Ref. 13 ) and biotin-labeled centromeric probes (pJM 128/D8Z2 provided by American Type Culture Collection) of the corresponding chromosomes were cohybridized on cytological specimens.

More than 150 nuclei were analyzed in a blinded manner by two or more independent observers (H. M., Y. P., or K. O.) without any information regarding patient clinical characteristics. To minimize the subjective bias on signal counting, the interindividual variation was evaluated as the difference of decreased fraction between two observers (H. M. and Y. P.). The mean variation was 6.8% ranging from 0 to 35% (correlation coefficient, 0.89; P < 0.01).

Chromosomal numerical aberrations were diagnosed based on centromeric probes as chromosomal losses (monosomy) or gains (trisomy or tetrasomy) when the percentage of nuclei with one, three, or four signals, respectively, exceeded 10% (14) . Chromosomal deletion was defined as when the fraction of nuclei with a lower number of cosmid signals than centromeric signals (decreased fraction) exceeded 35% of >150 nuclei counted by two independent observers. The cutoff level for classifying a deletion was set at 35% based on the upper limit (mean + 2 x SD) of decreased fractions in 8 specimens of benign prostate hyperplasia [17 ± 8 (mean ± SD) for LPL]. If no spots for cosmid probes were identified in >20% of all nuclei counted, the specimen was excluded from the study; such specimens were regarded as having insufficient hybridization.

Statistical Analysis.
A contingency table with either Fisher’s exact test or {chi}2 test and a Kaplan-Meier curve with a Log-rank test were used for univariate analyses (15) . The Cox proportional hazards model was used for a multivariate procedure with a step-down regression analysis, which was continued until all remaining factors were significant (16) . All Ps reported were generated from two-sided statistical tests, with <0.05 regarded as significant.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Background between Swedish and Japanese Prostrate Cancer.
Table 2Citation depicts patient characteristics between Swedish and Japanese prostate cancer patients. There was no statistical difference between Swedish and Japanese prostate cancer in terms of frequency of 8p22 deletion, distribution of pathological grade, or pathological stage. A significant difference was observed regarding age of onset (64 ± 7 years in Swedish versus 71 ± 7 years in Japanese). When the decreased fraction of nuclei with 8p22 deletion was compared, the mean percentages with SD were 40.6 ± 18.2 and 40.1 ± 22.8% for Swedish and Japanese, respectively.


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  		Table 2 Patient characteristics between Swedish and Japanese

 
Background between Touch and FNAB Specimens.
There was no statistical difference between touch specimens and FNAB specimens regarding distribution of pathological grade, frequency of 8p22 deletion, decreased fraction of 8p22, and numerical aberrations of chromosome 8 (data not shown).

Relation of Chromosomal Deletion to Tumor Grade and Stage.
In total, 58 of the 97 specimens (60%) had chromosomal deletions of 8p22. As for relation of pathological stage to neoadjuvant androgen-deprivation therapy, no statistical difference was found in a frequency of pT2 tumor between cases with neoadjuvant therapy (5 of 17 cases, 29%) and those without therapy (18 of 60 cases, 30%). The 8p22 deletion was found in pT2, pT3, and pN+ for 39, 61, and 75%, respectively. The frequency of 8p22 deletion was statistically higher in cases with pT3 or more (71%, 38 of 54) than in those with pT2 (39%, 9 of 23; P < 0.05, Fisher’s test). A statistical correlation was found between advancing tumor grade and the frequency of 8p deletions (Table 3)Citation .


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  		Table 3 Relation of 8p deletion to stage and grade

 
The status of chromosome 8p22 could predict pathologically organ-confined tumors with an overall accuracy of 68% (sensitivity: 61% and specificity: 70%), whereas Partin’s nomograms could predict with an overall accuracy of 77% (sensitivity: 43% and specificity: 93%, data not shown).

Relation of 8p22 Deletion to Disease Progression.
Of the 57 cases (16 pT2, 14 pT3, and 27 pN1 tumors) with follow-up, 37 (65%) developed disease progression, including biochemical failure (sole PSA elevation), local recurrence, bone metastases, and systemic progression (involving two or more organs) in 22, 1, 9, and 5 cases, respectively. In 39 patients who had undergone radical prostatectomy, the percentage of disease progression in pT2, pT3, and pN1 were 31, 71, and 60%, respectively. Patients whose tumors had 8p22 deletions had a significantly shorter period from surgery to disease progression than those whose tumors retained 8p22 (Fig. 1(a)Citation , P < 0.01, Log-rank test). When only studying patients with moderately differentiated adenocarcinoma (b) or those who had radical prostatectomy (c), patients whose tumors had 8p22 deletions had a significantly shorter period from surgery to disease progression than those whose tumors retained 8p22 (Fig. 1, (b)Citation , P < 0.05 and (c), P < 0.01, Log-rank test). Ploidy pattern (diploid versus aneuploid) or adjuvant therapy (yes versus no) had statistically no relation to disease progression. Individual regression analysis demonstrated that the 8p22 deletion, 8p22 deletion plus chromosome 8 gain (3 copy number or more), pathological stage, tumor grade, and serum PSA value at diagnosis were all significant predictors of disease progression. A Cox hazards proportional analysis revealed 8p22 deletion to be the strongest parameter to predict disease progression (hazards ratio = 5.75; 95% confidence interval = 2.31–17.63; P = 0.0001; Table 4Citation ).



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  		Fig. 1. Progression-free survival of all patients with follow-up (a), patients who were pathologically diagnosed with moderately differentiated adenocarcinoma (b), and patients who underwent radical prostatectomy stratified by 8p22 deletion (c). Patients whose tumors had 8p22 deletions had a significantly shorter period from surgery to disease progression than those whose tumors retained 8p22 in all classifications. The numbers in parentheses represent the patient number in each category.

 

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  		Table 4 Individual and multiple regression model for disease progression

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Despite attempts to restrict radical prostatectomy to patients with organ-confined disease, as many as 50% of the patients are found to have extraprostatic disease at the time of surgery (17) . In this study, the frequency of 8p22 deletion was statistically higher in cases with pT3 or more than in those with pT2. When the clinical significance of 8p22 deletion is limited to predict the pathologically organ-confined tumor, 8p22 deletion has no more benefit than Partin’s nomogram. However, the most important benefit of 8p22 deletion analysis is to predict the disease progression, which Partin’s nomogram cannot. The chromosomal status of 8p22 could predict disease progression of organ-confined tumor with sensitivity, specificity, and overall accuracy in 67, 80, and 75%, respectively (data not shown). Our data suggest that patients whose tumors had 8p22 deletion were likely to have advanced (beyond capsular penetration) prostate cancer and be at high risk of disease progression, although radical prostatectomy had been performed. These results support partially the report that the chromosomal deletion of 8p22 and amplification (allelic imbalance) of 8q24 were statistically linked to disease progression in stage III prostate cancer by FISH study (3) .

Because there are evidence for two, or possibly three, tumor suppressor genes on chromosome 8p (18, 19, 20, 21) , it is difficult to identify the specific region which is relevant for the oncogenesis or tumor progression in prostate cancer. We have demonstrated a high frequency of deletions on 8p21 (NEFL locus) and a possible break point between 8p21 and 8p12 by using RFLP technique (22) . Both 8p22 and 8p21 may be involved in the minimally deleted regions (20, 21, 22) . Allelic imbalance of chromosomal region between 8p22–21.3 has been reported to be associated with advancing tumor grade (21) , pathological stage (20) , or systemic progression and with prostate cancer death (23) . He et al. (24) suggested that the NKX3.1 gene plays an important role in the androgen-driven maintenance of the prostate tissue phenotype and that the loss of this region results in the progression of prostate cancer. Comparative genomic hybridization analysis revealed that loss of the entire 8p arm, associated with gain of the entire 8q arm, most likely occurred by isochromosome 8q formation in a significant number of prostate cancers (25, 26, 27) .

Our results clearly demonstrate that the genetic pattern was similar in Swedish and Japanese prostate cancers in terms of frequency of 8p22 deletion when comparing the same tumor grades and pathological stages. The results indicate that 8p22 deletion is a common alteration in sporadic prostate cancer irrespective of different races, leading to the conclusion that 8p22 deletion could be a universal genetic marker for predicting disease progression.

Our data indicate that genetic information can be obtained preoperatively by applying FNAB materials in combination with FISH technique, although the genotypic heterogeneity must be carefully considered (28) . The utility of FISH analysis for preoperative diagnosis has been reported in combination with either FNAB (29) or core needle biopsy specimens (30) , leading to the assumption that FISH analysis using FNAB specimens as well as core needle biopsy materials are useful for genetic work up.

In conclusion, only patients who retained 8p22 detected by preoperative specimens may actually enjoy surgical benefit. Otherwise, patients may be candidates for early endocrine therapy rather than radical local treatment. More cohorts of patients with longer follow-up will be needed to confirm these preliminary results.


   ACKNOWLEDGMENTS
 
We thank Drs. Kazuyiki Sagiyama and Mitsuru Kinjo (Hara Sanshinkai Hospital, Fukuoka, Japan) for supplying FNAB specimens and Dr. S. Wood (Vancouver, Canada) for providing the cosmid probes used in this study.


   FOOTNOTES
 
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.

1 Supported in part by grants from the Swedish Cancer Society (Grant 1192/B97-09XAA), The Swedish Society of Medicine, The funds of the Karolinska Institute, The Swedish Cancer Foundation, and by Grant in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (07671733). Back

2 To whom requests for reprints should be addressed, at Department of Urology, Yamaguchi University School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan. Phone: 81-836-22-2276; Fax: 81-836-22-2276; E-mail: hidde{at}ymg.urban.ne.jp Back

3 Present address: Danderyd Hospital, Stockholm, Sweden. Back

4 The abbreviations used are: PSA, prostate-specific antigen; FISH, fluorescence in situ hybridization; FNAB, fine-needle aspiration biopsy. Back

Received 2/14/01; revised 7/10/01; accepted 7/12/01.


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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