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Clinical Cancer Research Vol. 8, 526-533, February 2002
© 2002 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Gain of 5p15 Detected by Comparative Genomic Hybridization as an Independent Marker of Poor Prognosis in Patients with Esophageal Squamous Cell Carcinoma1

Takashi Ueno2, Akira Tangoku, Shigefumi Yoshino, Toshihiro Abe, Hiroaki Toshimitsu, Tomoko Furuya, Shigeto Kawauchi, Atsunori Oga, Masaaki Oka and Kohsuke Sasaki

Departments of Pathology [T. U., H. T., T. F., S. K., A. O., K. S.] and Surgery II [T. U., A. T., S. Y., T. A., H. T., M. O.], Yamaguchi University School of Medicine, Ube 755-8505, Japan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Comparative genomic hybridization was applied to 51 primary esophageal squamous cell carcinomas (ESCCs) to clarify the relation between DNA sequence copy number aberrations (DSCNAs) and the clinicopathology of the disease. The average number of DSCNAs was 10.9 DSCNAs/tumor (6.1 gains and 4.9 losses), ranging from 1–30 DSCNAs/tumor. Gain of 3q26-qter and loss of 18q22-qter were detected in >60% of stage I tumors and considered to play an important role in the development of ESCC. Whereas gain of 8q24-qter was observed in 82.6% (19 of 23) of stage III and IV cancers, it was seen in 27.3% (3 of 11) of stage I tumors. It is suggested that gain of 8q24-qter plays an important role in tumor progression. Gains of 8q24-qter and 20q12-qter and loss of 11q22–23 were linked to nodal metastasis (P = 0.0006, 0.002, and 0.02, respectively). Gains of 5p15 and 14q21 were associated with distant organ metastasis after surgery (P = 0.006 and 0.02, respectively). These observations suggest that nodal and distant organ metastases involve different genes. Gains of 5p15, 8q24-qter, and 14q21 were significantly associated with unfavorable prognosis (P = 0.0002, 0.007, and 0.04, respectively). Multivariate analysis revealed the 5p15 gain to be an independent prognostic marker with a higher significance than that of nodal status (risk ratio = 5.95; P = 0.001). The present findings indicate that comparative genomic hybridization analysis may be used to predict the likelihood of a poor or favorable outcome in cases of ESCC.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Esophageal cancer, which is very frequent worldwide, is a solid tumor that continues to have a high mortality rate, although diagnostic and therapeutic modalities have improved considerably. There is a need for accurate prognostic indicators to distinguish high-risk patients from other patients so that optimal treatment protocols can be designed on a case-by-case basis. ESCC,3 in particular, requires such indicators because it is highly malignant. Although histopathological examination allows us to diagnose the tumor, it provides little biological information such as metastatic potential and sensitivity and resistance to radiation and anticancer drugs. Pathologists are expected to report pathological diagnosis together with the biological characteristics for each, but it is difficult to do so, and patient prognosis remains undefined.

Multiple genetic changes are found in malignant solid tumors including ESCC (1, 2, 3, 4, 5) . The biological behavior of a tumor is affected primarily by genetic alterations of tumor cells. This suggests that when detailed examination of genetic changes in a tumor is possible, the biological behavior of the tumor can be determined. However, gene alterations underlying malignant behavior have been only partially identified.

CGH, a molecular cytogenetic technology, provides for global overview of chromosomal gains and losses within the tumor (6 , 7) . The number of DSCNAs detected by CGH is correlated with the disease stage and biological behavior of a tumor (8, 9, 10, 11) ; thus, comprehensive analysis of genetic alterations in biopsy specimens may permit us to determine the biological characteristics of each tumor and to predict the prognosis of each patient at the time of diagnosis.

This study demonstrates that some genetic changes detected by CGH carry prognostic information useful for patients with ESCC and that these genetic changes have prognostic value beyond that of the classical indicators. Our findings suggest CGH to be a useful diagnostic and prognostic laboratory tool.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Tumor Tissue Specimens.
We examined surgically resected human ESCCs from 51 patients. The patients comprised 44 men and 7 women with an average age of 63.9 years (age range, 45–83 years). All underwent esophagectomy with esophageal reconstruction without preoperative radiotherapy and/or chemotherapy. Tumor stage and grade were determined on the basis of the surgical staging system of the International Union against Cancer (12) . Family histories were noncontributory for all patients. The clinicopathological data are summarized in Table 1Citation . Tumor tissue specimens were frozen and kept in a freezer at -80°C until use. A microdissection technique was used as described previously to reduce the contamination of normal tissues (13, 14, 15) . The study protocol was approved by the Institutional Review Board for Human Use at the Yamaguchi University School of Medicine in May 1995, and informed consent for this study was obtained from all patients.


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  		Table 1 Clinical data

 
DNA Extraction.
High molecular weight genomic DNA was extracted from each tumor specimen with a DNA extraction kit (SepaGene; Sankojunyaku Co., Ltd., Tokyo, Japan) according to the manufacturer’s instructions. Control DNA was extracted from peripheral blood lymphocytes.

CGH and Digital Image Analysis.
CGH and digital image analyses were carried out as described previously (13 , 16, 17, 18, 19) . Briefly, DNA extracted from tumors and lymphocytes was labeled by nick-translation with SpectrumGreen (Vysis, Inc., Downers Grove, IL) and SpectrumRed (Vysis, Inc.), respectively. Each labeled DNA sample (200 ng) and 10 µg of Cot-1 DNA (Life Technologies, Inc., Gaithersburg, MD) were mixed in 10 µl of hybridization buffer and cohybridized onto normal denatured metaphase chromosomes for 72 h at 37°C. The slides were mounted in anti-fade solution containing 0.15 mg/ml 4',6-diamidino-2-phenylindole as counterstain. Images were captured with an Olympus BX60 fluorescence microscope equipped with a 100x UplanApo objective lens and a cooled charge-coupled device camera (SenSys 1400; Photometrics Ltd., Tucson, AZ). Approximately 20 (but at least 10) representative images were analyzed. Increases and decreases in DNA sequence copy number were defined by green:red ratios of 1.2 and 0.8, respectively, as described previously (9 , 15) . High-level copy number increases in subregions (amplifications) in contrast to whole arm gains were defined by a tumor:control ratio of 1.4. The number of DSCNAs is the total number of chromosomal regions with alterations in DNA sequence copy number.

Statistical Analysis.
Statistical analysis was performed with Statview software (SAS Institute Inc., Cary, NC). Fisher’s exact test was performed to test differences between DSCNAs and clinicopathological features and to test reciprocal relations among DSCNAs. Differences in the total number of DSCNAs in the patients were tested by the nonparametric Mann-Whitney U test. Probability of survival was calculated by the Kaplan-Meier method, and statistical differences were evaluated by the log-rank test. To analyze the simultaneous effect of all variables and control for variation in follow-up, Cox’s proportional hazards model was used. For all statistical tests, P < 0.05 was considered significant.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Number of DSCNAs.
The number of DSCNAs ranged from 1–30 DSCNAs/tumor, with an average of 10.9 DSCNAs/tumor (6.1 gains and 4.9 losses, respectively). The average number of DSCNAs was smaller in stage I tumors than in stage II-IV tumors (7.2 versus 11.9 DSCNAs/tumor; P < 0.05). The average number of DSCNAs was also significantly different between stage I tumors and stage II tumors (7.2 versus 12.0 DSCNAs/tumor; P < 0.05) and stage III-IV tumors (7.2 versus 11.9 DSCNAs/tumor; P < 0.05). However, there were no significant differences in the average number of DSCNAs among stage II, III, and IV tumors.

Chromosomal Regions with DSCNAs.
Although DSCNAs were found in various chromosomal regions, they were detected preferentially in certain regions. Representative changes were as follows: gains of 3q, 8q, and 11q13 with minimal overlapping regions at 3q26-qter, 8q24-qter, and 11q13 were the most frequent aberrations (76.5%, 60.8%, and 52.9% of cases, respectively). Recurrent decreases in DNA copy number were found at 3p11–21 (64.7%) and 18q22-qter (51.0%). Amplification of 11q13 was seen in six tumors (16%). The cytogenetic aberrations detected by CGH are summarized in Fig. 1, A and BCitation .



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  		Fig. 1. Summary of DNA copy number gains and losses in ESCCs detected by CGH. A, gains are shown to the right of the chromosome ideograms. Amplified regions are indicated by thick lines. B, losses are shown to the left of the chromosome ideograms.

 
Reciprocal Relation among DSCNAs.
Statistical correlation was found for some of the aberrations (Table 2)Citation Citation . Gains of 2p21–22 and 7q22 and losses of 4p15 and 5q14–21 were frequently accompanied by other recurrent aberrations. Gain of 2p21–22 was associated with losses of 5q14–21, 9p21–23, 9q21, and 13q14 and gains of 7q22 and 20q12-qter. Gain of 7q22 was significantly linked with gains of 2p21–22, 3q26-qter, and 18p and losses of 4p15, 4q32–34, and 9q21. Loss of 5q14–21 was significantly associated with gains of 2p21–22, 3q26-qter, and 12p12-pter and losses of 3p11–21.1, 4p15, 4q32–34, and 9q21. Although gains of 5p15 and 14q21 were frequent (37.3% and 21.6%, respectively) in ESCCs, both gains were independent of other aberrations. They were, however, coupled with distant organ metastasis during follow-up after surgery and unfavorable prognosis, as shown below.


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  		Table 2 Statistical correlations among DSCNAsa

 

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  		Table 2A Continued

 
Relation between DSCNAs and Pathological Features of ESCC.
We found that the average number of DSCNAs depended on the stage of disease. In stage I tumors, gains of 3q26-qter, 7q22, 8q24-qter, and 11q13 and losses of 3p11–21.1, 4q32–34, 9p21–23, and 18q22-qter were frequent. In addition to the increase in the frequency of these changes, gains of 5p15, 14q21, and 20q12-qter and losses of 9p21–23 and 11q22–23 were recurrent in stage III and IV tumors. However, histological grade did not affect the number of DSCNAs or the number of chromosomal regions with aberrations. Twenty-seven (77.1%) of 35 patients with lymph node metastasis exhibited a gain of 8q24-qter (sensitivity, 77.1%; specificity, 75.0%; Table 3Citation ). Gains of 8q24-qter and 20q12-qter and loss of 11q22–23 were dependent on the status of lymph node metastasis (P = 0.0006, 0.02, and 0.002, respectively; Table 3Citation ). Gains of 5p15 and 14q21 were associated with distant organ metastasis after surgery (P = 0.006 and 0.02, respectively; Table 4Citation ).


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  		Table 3 Relation of DSCNAs to lymph node metastasis

 

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  		Table 4 Relation of DSCNAs to distant organ metastasis after surgery

 
Relation between Clinicopathological Features and Patient Outcome.
Survival was examined with respect to clinicopathological parameters including patient age, histological differentiation, depth of tumor invasion, tumor stage, and the absence or presence of nodal metastasis. Univariate Kaplan-Meier analysis showed patient survival to be significantly short as a function of nodal metastasis and disease stage [(stage I versus others) P = 0.02 and 0.02, respectively; Fig. 2, A and BCitation ].



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  		Fig. 2. A, overall survival according to status of lymph node metastasis; B, overall survival according to stage; C, overall survival according to gain of 5p15; D, overall survival according to gain of 8q24-qter; E, overall survival according to gain of 14q21; F, overall survival according to gains of 5p15, 8q24-qter, and 14q21.

 
Relation between DSCNAs and Patient Prognosis.
Univariate analysis revealed that the survival of patients with ESCC was negatively affected by gains of 5p15, 8q24-qter, and 14q21 (P = 0.0002, 0.007, and 0.04, respectively; Fig. 2, C-ECitation ). Approximately 80% of patients with 5p15 gain died within 2 years. In contrast, the 2-year survival rate was approximately 75% in patients without this aberration (Fig. 2C)Citation . Interestingly, the difference in survival rate was distinct between tumors without (n = 11) and with (n = 5) these three aberrations (Fig. 2F)Citation . Multivariate analysis revealed the 5p15 gain to be an independent prognostic marker with a higher significance than that of nodal status (risk ratio = 5.95; P = 0.001; Table 5Citation ).


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  		Table 5 Multivariate analysis of risk factors for nonsurvival in patients with ESCC

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
It has been reported that the biological characteristics of individual tumors can be evaluated by a comprehensive analysis of genetic changes in the tumors (8, 9, 10, 11) . CGH detects DSCNAs in a single experiment. Examination of the relation between DSCNAs and the clinical outcome of patients can be used to clarify which genetic aberrations might relate to the malignancy that leads to the early death of cancer patients. This is the first report that discusses the relationship between genetic changes and prognosis of patients with ESCC. Our study correlated specific DSCNAs with the biological behavior of ESCC. The survival of patients with ESCC was associated with gains of 5p15, 8q24-qter, and 14q21. In addition, only a 5p15 gain was found to be an independent prognostic marker with a higher significance than that of nodal status.

Gains of 8q24-qter and 20q12-qter and loss of 11q22–23 were significantly associated with nodal metastasis, as reported previously (4) , whereas gains of 5p15 and 14q21 were significantly linked with distant organ metastasis after surgery. These genetic alterations were relatively unique to metastasis. The 5p15 and 14q21 gains, in particular, were independent of other alterations. Our data suggest that detection of specific DSCNAs in biopsy specimens may allow for prediction at the time of diagnosis of nodal metastasis and distant organ metastasis after surgery. It is also suggested that nodal and distant organ metastases involve different genes.

The gain of 5p was occasionally detected in malignant tumors such as carcinomas of the head and neck (8 , 13 , 20) , lung (21) , bladder (22) , cervix (23) , and breast (24) . To our knowledge, the relationship between 5p gain and patient prognosis has not been examined in those tumors. However, there are reports that the expression of hTERT gene mapping to the most distal site of chromosome 5p (25) is associated with patient prognosis in carcinomas of the breast and lung (26 , 27) . We are attempting to identify the gene(s) affecting the prognosis of patients with ESCC.

In ESCC, amplification of some genes has been reported. In particular, 11q13 harbors several cancer-related genes, including CCND1, FGF3 (INT2), FGF4 (INT4), and EMS1 (28, 29, 30) . Amplification of the CCND1 and EMS1 genes has been correlated with unfavorable prognosis in patients with squamous cell carcinoma of the head and neck (28 , 31) . No significant relation was found between gain of this chromosomal region and the biological characteristics examined in the present study. We found no report suggesting that amplification of MYC on 8q24 directly affects nodal metastasis. Although 20q gain has been preferentially found in colorectal cancers with liver metastasis (32 , 33) , no such relation has been found in head and neck squamous cell carcinomas (28) . In the present study, 20q12-qter gain was associated with nodal metastasis in ESCCs, but not with distant organ metastasis after surgery.

The average number of DSCNAs differed significantly between stage I tumors and stage II-IV tumors. There are reports that the average number of DSCNAs generally parallels the disease stage (8, 9, 10, 11) . This may be explained by the widely held notion that with tumor progression, the number of genetic alterations increases due to the inherent genetic instability of malignant tumors.

The data suggest that we can use CGH to predict the prognosis of patients together with the metastatic potential of tumors from the same biopsy specimens used to diagnose ESCC. Unfortunately, CGH analysis may be unsuitable for clinical use for technical and economical reasons. The practical application of these molecular cytogenetic markers requires the development of a simple and inexpensive method providing information comparable with CGH analysis.


   ACKNOWLEDGMENTS
 
We thank Drs. Takuo Murakami, Tetsushi Uchiyama, Atsushi Adachi, and Kohji Shimoda of the Department of Surgery, Iwakuni Medical Center (Iwakuni City, Japan) for cooperation.


   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 This work was supported by Grants-in-Aid for Science Research 12557019 and 13877027 from the Ministry of Education, Science, Sports and Culture of Japan. Back

2 To whom requests for reprints should be addressed, at Department of Pathology, Yamaguchi University School of Medicine, 1-1-1 Minami-kogushi, Ube 755-8505, Japan. Phone: 81-836-22-2221; Fax: 81-836-22-2223; E-mail: tueno{at}po.cc.yamaguchi-u.ac.jp Back

3 The abbreviations used are: ESCC, esophageal squamous cell carcinoma; CGH, comparative genomic hybridization; DSCNA, DNA sequence copy number aberration. Back

Received 8/20/01; revised 11/ 8/01; accepted 11/14/01.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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A. Hirasawa, F. Saito-Ohara, J. Inoue, D. Aoki, N. Susumu, T. Yokoyama, S. Nozawa, J. Inazawa, and I. Imoto
Association of 17q21-q24 Gain in Ovarian Clear Cell Adenocarcinomas with Poor Prognosis and Identification of PPM1D and APPBP2 as Likely Amplification Targets
Clin. Cancer Res., June 1, 2003; 9(6): 1995 - 2004.
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