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Clinical Cancer Research Vol. 6, 3193-3198, August 2000
© 2000 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Allelic Loss at 1p34–36 Predicts Poor Prognosis in Node-negative Breast Cancer1

Yoshihito Utada, Mitsuru Emi2, Masataka Yoshimoto, Fujio Kasumi, Futoshi Akiyama, Goi Sakamoto, Shunsuke Haga, Tetsuro Kajiwara and Yusuke Nakamura

Department of Gerontology, Nippon Medical School, Kawasaki 211-8533 [Y. U., M. E.]; Department of Surgery and Pathology, Cancer Institute, Toshima-ku 170-8455 [Y. U., M. Y., F. K., F. A., G. S.]; Department of Surgery, Daini Hospital, Tokyo Women’s Medical University, Tokyo 116-8567 [Y. U., S. H., T. K.]; and Laboratory of Molecular Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639 [Y. N.], Japan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Allelic losses of specific chromosomal regions in the DNA of tumor cells, which imply loss of tumor suppressor genes normally resident at those loci, may become useful postoperative prognostic indicators for breast cancers that have not yet metastasized to lymph nodes. To examine whether specific allelic losses might correlate with postoperative disease-free survival, we tested tumors from a cohort of 228 node-negative breast cancer patients for allelic losses at 18 microsatellite loci chosen to represent either a known tumor suppressor gene or a region where genetic alterations are frequent in breast tumors. We followed the patients clinically for 5 years or until death (if patient death occurred before completion of 5 years of follow-up). Patients whose tumors had lost an allele at 1p34–36 bore significantly higher risks of postoperative recurrence than those whose tumors retained both alleles of the markers in that region [the 5-year recurrence rate was 15% among patients with losses versus 2% among patients with retention (P = 0.001)]. Multivariate analysis demonstrated that allelic loss at 1p34–36 was an independent postoperative predictor of shorter disease-free survival (hazard ratio, 5.8; P = 0.0117). Thus, allelic losses at 1p34–36 in a tumor might have a potential to serve as a negative prognostic indicator to guide postoperative management of breast cancer patients, especially in the selection of high-risk women who will benefit from adjuvant chemotherapy and endocrine therapy.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Among the various types of genetic alteration involved in development and progression of breast cancers, allelic loss (LOH3 ) of a particular chromosomal region in a tumor is thought to indicate that a tumor suppressor gene normally resident there has been deleted (1 , 2) . Specific losses could become new diagnostic markers for prognosis. Although the prognosis for patients whose breast cancers have not metastasized to lymph nodes (node-negative breast cancer) is better than the prognosis for patients with metastasis, 16% of node-negative patients in Japan experience relapse within 10 years of initial surgery (3) . The differences in individual outcomes might reflect differences in the pattern of alterations among the many genes that play roles in carcinogenesis.

Postoperative prognosis for patients with node-negative breast cancer has increased in importance in view of the variety of adjuvant therapies that are now available. Prognostic markers that assist in identifying patients who are likely to relapse after surgery would help high-risk individuals to benefit from appropriate postoperative adjuvant therapies. Others would benefit by avoiding unnecessary, inconvenient, and unpleasant side effects of those therapies. Treatment decisions for individual node-negative breast cancer patients are currently made on the basis of conventional indicators such as size of the tumor and status of hormone receptors (4 , 5) .

During serial efforts to prepare breast cancer deletion maps for each chromosome, we examined an average of 200 primary breast cancers for LOH, using more than 150 polymorphic microsatellite markers (simple repeat sequences) located throughout the human genome. Those studies resulted in the definition of several regions where allelic losses tend to occur frequently in primary breast cancers. Some of those target regions corresponded to the locations of known tumor suppressor genes (6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18) .

In the present study, we examined 18 loci representing either known tumor suppressor genes or regions where many breast cancers exhibit allelic losses. To identify specific allelic losses that might predict postoperative outcome, we attempted to correlate allelic loss at each of the tested loci with postoperative prognosis in 228 node-negative breast cancer patients whose postoperative courses were followed for 5 years.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients, Specimens, and DNA Preparation.
The study population consisted of 228 patients without lymph node metastasis who underwent surgery for breast cancer between 1989 and 1993 at the Cancer Institute Hospital (Tokyo, Japan). Written informed consent was obtained from each patient in advance of surgery. All patients were then followed clinically for 5 years or until death (if patient death occurred before completion of 5 years of follow-up); all of the clinical and histopathological data were obtained from an electronic data base maintained by the Cancer Institute Hospital in a recording format established by the Japanese Breast Cancer Society (19) . Seven categories of data for our cohort of 228 patients are presented in Table 1Citation . No patient had metastasis to distant organs at the time of surgery; the median age was 52.9 years, and all patients were females. The average time and the median time of postoperative follow-up in survival analysis were 62.9 and 63.0 months, respectively. With regard to postoperative adjuvant therapy, all patients were treated according to the Postoperative Clinical Protocol for Breast Cancer of the Cancer Institute Hospital. In principle, the choice of adjuvant therapy for each patient (low- or high-dose chemotherapy, hormones, radiation, and/or various combinations of therapies) was determined strictly on the basis of type of surgery, status of lymph node metastasis, and the presence of local or distant metastases. Tumors and corresponding noncancerous tissues were excised, frozen immediately, and stored at -80°C. Genomic DNAs were extracted later from the frozen materials according to methods described previously (13) .


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  		Table 1 Clinical characteristics of 228 node-negative breast cancer patients

 
LOH Analysis.
DNAs from matched normal and cancerous tissues were examined for LOH with respect to 18 microsatellite markers at 18 loci selected from a comprehensive genetic map of the human genome (20) . Microsatellite sequences were amplified by the PCR using 10 ng of genomic DNA, 30 mM Tris-HCl (pH 8.8), 50 mM KCl, 2 mM MgCl2, 5 mM 2-mercaptoethanol, 100 µM deoxynucleotide triphosphate, 1.6 pmol each of [{gamma}-32P]ATP-end-labeled forward primer and unlabeled reverse primer, and 0.25 unit of Taq polymerase in a total volume of 10 µl (13) . Cycling conditions were 94°C for 3.5 min, followed by 30 cycles of 94°C for 30 s, 55°C to 68°C for 30 s, and 72°C for 30 s, with a final extension step of 10 min at 72°C in a Gene Amp PCR 9600 System (Perkin-Elmer, Norwalk, CT). PCR products were electrophoresed in 0.3-mm-thick denaturing 6% polyacrylamide gels containing 36% formamide and 8 M urea at 1900 V for 2–6 h (13) . After transfer of the gel patterns to filter papers, the filters were dried at 80°C and exposed to autoradiographic films at room temperature for 16–20 h.

Definition of LOH.
Signal intensities of polymorphic alleles were quantified by a Hoefer GS-300 scanning densitometer; peak areas corresponding to each signal were calculated by electronic integration using the GS-370 electrophoresis data system (Hoefer Scientific Instruments, San Francisco, CA). When the signal intensities of alleles of tumor tissue DNAs were compared with those of corresponding normal tissue DNAs, a reduction in signal intensity of >50% was judged to demonstrate LOH. We distinguished LOH from chromosome multiplication by normalizing each signal to the signal obtained when the same DNA was analyzed with markers for loci on other chromosomes.

Statistical Analysis.
The main outcome for which the study was designed was postoperative disease-free survival, measured from the date of surgery to the date of last follow-up or relapse. Survival curves were constructed according to the method of Kaplan-Meier, and the significance of differences in survival rate was tested using the log-rank test as a univariate analysis. Cox’s proportional-hazards model for the risk ratio was used to assess the simultaneous contribution of each covariate in the multivariate analysis. Prediction of postoperative prognosis and treatment decision for patients with node-negative breast cancer are currently made on the basis of conventional indicators such as tumor size and status of hormone receptors ER and PgR, as described in Refs. 4 and 5 . Therefore, we carried out multivariate analysis for postoperative prognosis in the present study with those conventional parameters. Ps < 0.05 were considered statistically significant. All calculations were performed using StatView version 4.5 software (SAS Institute Inc., San Francisco, CA).


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Allelic losses (LOH) at each of the 18 loci representing either known locations of tumor suppressor genes or a target region of LOH in breast cancers were detected at frequencies of 24–55% among the 228 node-negative tumors (Table 2)Citation . Among the 18 markers examined, D16S413 (at 16q24.3) detected the highest frequency of LOH [93 of 168 tumors (55%)]. Representative autoradiograms demonstrating LOH in our panel of breast cancers are displayed in Fig. 1Citation ; the tumor DNAs in these panels show LOH at D1S1612 and D1S552 on 1p34–36.


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  		Table 2 Chromosomal regions, polymorphic markers, and LOH frequencies at the 18 loci examined in node-negative breast cancers

 


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  		Fig. 1. Representative autoradiograms demonstrating LOH in the chromosomal regions indicated. N and T, normal DNA and tumor DNA, respectively, from the same patient.

 
Fig. 2Citation documents our analysis of postoperative disease-free survival with regard to LOH status in the region of chromosome 1p, where significant correlation was observed. Kaplan-Meier analysis of overall survival revealed that postoperative recurrence risk was increased in patients whose tumors showed LOH on 1p34 and 1p36 compared with patients whose tumors retained both alleles of markers representing those loci. Table 3Citation shows our analysis of postoperative recurrence rate with regard to LOH status at the 18 chromosomal loci. A log-rank test was carried out to test statistical significance in univariate analysis (also shown in Table 3Citation ). No markers from the other 16 frequently deleted regions showed any correlation of LOH with prognosis.



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  		Fig. 2. Kaplan-Meier curves of disease-free postoperative survival for patients whose tumors retained both alleles (thin lines) or had lost one allele (LOH, thick lines) of a marker at 1p36 (A), 1p34 (B), or 1p36–1p34 (C).

 

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  		Table 3 Correlation between LOH at 18 loci and prognosis in node-negative breast cancers

 
Fig. 2Citation A shows that of the 164 patients whose tumors were informative at 1p36, 16% of those with LOH relapsed within 5 years after surgery, as compared with a 3% recurrence rate among patients whose tumors retained both alleles of the 1p36 marker (4.6 times relative risk of recurrence; P = 0.0033, log-rank test; Table 3Citation ). Similarly, Fig. 2Citation B shows the correlation found at 1p34, i.e., a 5-year recurrence rate of 16% among those with LOH and 4% among those with retention (3.7 times relative risk of recurrence; P = 0.0209). When calculations were combined for both 1p36 and 1p34 (Fig. 2Citation C), among 204 patients whose tumors were informative at either 1p34 or 1p36, 15% of those with LOH relapsed within 5 years after surgery, compared with a 2% recurrence rate among patients whose tumors retained both alleles of the 1p34–36 loci (6.6 times relative risk; P = 0.001, log-rank test).

The results of multivariate analyses using the Cox proportional hazards regression model are presented in Table 4Citation . Allelic loss at 1p34–36 was an independent predictor of shorter postoperative disease-free survival. The hazard ratio for LOH at 1p34–36 was 5.8 (95% confidence interval, 1.8–18.8; P = 0.0117).


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  		Table 4 Univariate and multivariate analyses of disease-free survival among 228 node-negative breast cancer patients

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Researchers have long sought prognostic indicators that could determine the grade of malignancy, accurately predict postoperative recurrence risk, and guide adjuvant therapy for patients with breast cancers. Prediction of likely postoperative course has become increasingly important for node-negative breast cancer patients because patients at low risk could avoid side effects from unnecessary adjuvant treatment, whereas high-risk node-negative patients would benefit from appropriate therapies. Routine postoperative decisions for individual patients currently rely on consideration of conventional prognostic factors such as tumor size and hormone receptor status (4 , 21) .

Several previous studies have attempted to determine the value of genetic alterations as prognostic markers for postoperative node-negative breast cancer patients. These include amplification of the HER-2/erbB2 gene (22) , mutations of p53 (23 , 24) , the level of cathepsin D and plasminogen activator type 1 inhibitor (25) , or the expression level of cyclin E (26) .

It is generally recognized that an inactivating mutation in a tumor suppressor gene is recessive at the somatic cell level; mutations on the mutant allele are unmasked when loss of chromosomal material eliminates a normal allele. The process of allelic loss is identified as a LOH in tumor DNA by means of the polymorphic nature of microsatellite markers that enables distinction of maternal and paternal alleles. Frequent LOH observed at specific chromosomal loci in cancers has implied the presence of putative tumor suppressor genes in the regions where deletions were detected. Association of particular LOH with clinical parameters suggested that inactivation of some tumor suppressor genes exerts their effects in a gene-specific manner and that LOH may be useful in diagnosing the grade of malignancy and in predicting prognosis accurately. Thus, we chose to examine LOH at multiple tumor suppressor loci or in regions showing allelic loss in breast cancers in the present study. However, because LOH analysis is often hampered by contamination of normal cells, unavailability of normal counterpart, or artifacts associated with PCR-based assay, future development of new diagnostic technology that abbreviates these limitations would be appreciated.

Correction for the multiple test is sometimes necessary in certain case-control population association studies that have the risk of having false positives by chance. On the contrary, it is not applicable in a survival analysis based on LOH status because no matter how many markers are used in finding the significance, the risk of type 1 errors remains manageably low in these types of study. In fact, every individual recruited in the present study represented a "case" of breast cancer; no control population is used in the survival analysis. We measured directly somatic changes that had occurred during the development of breast cancers. Thus, the parameters we used in the survival analysis (i.e., LOH status or loss of an allele) represent an actual loss of genetic materials that occurred during carcinogenesis rather than anonymous markers and postulation of linkage disequilibrium. Accordingly, because most survival analyses use P < 0.05 as a significance level without correction for multiple test, we followed this convention.

1p34–36, the region containing those two markers, overlapped with regions described as commonly deleted in colorectal carcinoma (27 , 28) , hepatocellular carcinoma (29 , 30) , gastric carcinoma (31 , 32) , neuroblastoma (33, 34, 35) , glioma (36 , 37) , meningioma (38) , malignant melanoma (39) , and multiple endocrine neoplasia type 2a (40) . The p73 gene at 1p36.3 is frequently deleted in neuroblastoma and is considered to be a candidate gene for that type of tumor (37) . We (18) previously observed allelic loss on 1p in 143 sporadic breast cancers and defined target regions at 1p36, 1p34, and 1p22–31 through a high-resolution deletion mapping with 15 microsatellite markers on 1p. The most distal commonly deleted region is located in a 26-cM interval between D1S468 and D1S1597 at band 1p36, the middle commonly deleted region is located in a 10-cM interval between D1S522 and D1S1622 at 1p34, and the most proximal commonly deleted region is located in an 11-cM interval between D1S551 and D1S534 at 1p22–31 (18) . We selected highly informative markers for various chromosomal regions including the above-mentioned regions and examined LOH at all 18 loci for correlation with postoperative prognosis.

We (18) have shown previously that in primary breast cancers, LOH on 1p36 and 1p34 was more frequent in aggressive tumors, i.e., solid-tubular and scirrhous histological types. Kuroki et al. (30) observed an association of LOH on 1p with poorly differentiated hepatocellular carcinomas; moreover, Ishino et al. (38) reported an association of LOH on 1p with malignant progression of meningiomas and found this feature to be an effective prognostic indicator. These results have implied that loss or inactivation of tumor suppressor genes located anywhere on 1p may play a role in the progression of human cancers.

In the present study, we observed a 30% frequency of LOH at 1p34–36 among node-negative breast cancers (162 of 204 informative cases). Our postoperative follow-up revealed that patients whose tumors had lost alleles in that region had a significantly shorter disease-free survival time, i.e., a higher risk of cancer recurrence than those with retention of both alleles of markers at 1p34–36 (15% versus 2%; P = 0.0010). That is, allelic losses at 1p34–36 in our cohort of node-negative breast cancer patients were associated with a more aggressive clinical phenotype. Thus, diagnosis of LOH at these loci may have a potential use as a prognostic marker for node-negative breast cancer, particularly in the classification of these patients according to the risk of postoperative recurrence and in the selection of the patients who would benefit most from appropriate postoperative adjuvant therapies. However, because our study is small in scale, further confirmation by several independent studies would be warranted before clinical application is attempted to draw a definitive clinical decision on prognostic factors in cancer.


   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 by Grants-in-Aid for the Priority Areas of Cancer Research and Genome Science from the Ministry of Education, Science, Sports and Culture of Japan; by a Research Grant for Cancer Research from the Ministry of Health and Welfare of Japan; and by the Vehicle Racing Commemorative Foundation. Back

2 To whom requests for reprints should be addressed, at Department of Molecular Biology, Institute of Gerontology, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki 211-8533, Japan. Phone: 81-44-733-5230; Fax: 81-44-733-5192; E-mail: memi{at}nms.ac.jp Back

3 The abbreviations used are: LOH, loss of heterozygosity; ER, estrogen receptor; PgR, progesterone receptor. Back

Received 8/26/99; revised 5/18/00; accepted 5/24/00.


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Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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A. Hirano, M. Emi, M. Tsuneizumi, Y. Utada, M. Yoshimoto, F. Kasumi, F. Akiyama, G. Sakamoto, S. Haga, T. Kajiwara, et al.
Allelic Losses of Loci at 3p25.1, 8p22, 13q12, 17p13.3, and 22q13 Correlate with Postoperative Recurrence in Breast Cancer
Clin. Cancer Res., April 1, 2001; 7(4): 876 - 882.
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