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Clinical Cancer Research Vol. 5, 1417-1425, June 1999
© 1999 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Loss of Heterozygosity Accumulation in Primary Breast Carcinomas and Additionally in Corresponding Distant Metastases Is Associated with Poor Outcome

Monika Hampl1, Jürgen A. Hampl, Gilfe Reiss, Gabriele Schackert, Hans-D. Saeger and Hans K. Schackert

Departments of General/Thoracic and Vascular Surgery [M. H., H-D. S.], Neurosurgery [J. A. H., G. R., G. S.], and Surgical Research [H. K. S.], Medical Faculty Carl Gustav Carus of the Technical University of Dresden, 01307 Dresden, Germany


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The occurrence of distant metastases is the most feared manifestation of breast cancer, often occurring years after the primary surgery and associated with poor survival. The dominant metastatic clone is characterized by an accumulation of genetic alterations, but it is not actually known at what stage of the metastatic cascade these alterations have occurred. We investigated allelic losses during breast cancer progression in a series of 17 primary breast carcinomas and 22 corresponding brain, liver, lung, and bone metastases (mean metastasis-free interval, 31 months) by analyzing 19 microsatellite markers on seven breast cancer- or metastasis-related chromosomal regions and correlated the incidence of combined loss of heterozygosity (LOH) with metastasis-free and postmetastatic survival. We found that, in comparison with the corresponding primary tumor, additional LOH events are frequently found in metastases and that the incidence of combined LOH in the primary tumor, plus the occurrence of additional LOH events in the distant metastases, correlated significantly with decreased postmetastatic survival. Combined LOH of the three breast cancer-related chromosomal regions alone or in combination with allelic loss at the p53 gene region seems to have a specific influence on the aggressive behavior of metastases. We hypothesize that the occurrence of additional LOH events is either involved in termination of dormancy of micrometastatic tumor cells at distant organ sites or acquired during further progression of metastases.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The metastatic spread of malignant tumor cells from the primary tumor to distant organ sites is the most life-threatening manifestation of breast cancer disease, and most patients ultimately die because of metastatic dissemination. Metastasis formation is a highly selective and multistep process involving complex interactions between tumor and host cells (1) . To metastasize, tumor cells detach from the primary tumor, invade the host stroma, and penetrate into the vessels, where they disseminate, extravasate, and start to grow at susceptible organ sites. All of the steps must be completed successfully for the tumor cell to avoid elimination. Survival of a minor subpopulation of cells with increased metastatic potential is favored within the population of heterogeneous primary tumor cells (2) . According to the clonal evolution theory (3) , this cell clone, usually the most aggressive one, has an additional selective growth advantage over its nonmetastatic counterparts: the capacity to overgrow the primary tumor and to metastasize ("clonal dominance"; Ref. 4 ). Metastatic cell clones are characterized by increased genetic instability and the accumulation of genetic alterations affecting various genes such as proto-oncogenes, tumor/metastasis suppressor genes, and genes involved in the DNA repair pathway (5, 6) . It is not known whether this accumulation of genetic alterations is restricted to the time of selective growth in the primary tumor or is acquired during later stages of the metastatic process.

Many studies on primary breast tumors have reported a positive correlation between high LOH2 frequency in various tumor suppressor gene loci and clinical parameters of increased tumor malignancy (7, 8, 9, 10, 11, 12, 13, 14) , which suggests that the malignant behavior of the primary tumor is influenced by the LOH frequency. In other studies, no such correlation could be found (15 , 16) , perhaps because the growth of this metastatic cell clone is influenced by specific genetic alterations in the parental tumor ("seed") as well as the microenvironment of the host organ ("soil"; Ref. 17 ).

Comparative LOH analyses of a variety of tumor entities such as non-small cell lung carcinomas and squamous cell carcinomas of the head and neck have shown that metastases are characterized by additional genetic alterations in comparison with the primary tumor (18, 19, 20, 21) . However, studies on primary breast carcinomas and corresponding distant metastases have in the past been restricted to single cases (22) .

The aim of this study was to investigate at what stage of the metastatic cascade genetic alterations occur in a series of sporadic breast carcinomas and to determine whether LOH frequency could be correlated with the clinical course and outcome.

To elucidate this question, we performed a comparative LOH analysis using 19 microsatellite markers in a series of 17 primary sporadic breast tumors and 22 corresponding metastases to the brain, liver, lung, or bone with a mean MFI of 31 months. We selected three chromosomal regions (17q21, 13q12–13, and 11q22–23) known to harbor genes associated with breast cancer (23, 24, 25) and three putative breast cancer metastasis-related gene loci (17q21.3, 1q32–41, and 16q22.2–23.2; Refs. 26, 27, 28 ) as well as the 17p13.1 locus harboring the p53 gene ("guardian of the genome"; 29 ), and we correlated the LOH incidence with patients’ MFIs and PMS times.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Samples.
Peripheral blood and tumor samples from 17 breast cancer patients as well as 22 corresponding metastases to the brain (CM, n = 15), liver (LM, n = 2), lung (PM, n = 2) and bone (BM, n = 3) were collected during surgery. From four patients, up to three different distant metastases were available (Table 1)Citation . We excluded lymph node metastases from our examination because they are normally gained during primary surgery, nor did we use local recurrences because they may arise from residual tumor cells. Fourteen of the 17 corresponding primary breast tumor specimens were archival paraffin tissue samples. Histopathological diagnosis and tumor stage (tumor-node-metastasis, stage I-IV) were determined by pathologists according to the WHO criteria. At the time of first diagnosis, 1 breast tumor was classified as stage I, 10 tumors as stage II, 3 tumors as stage III, and 3 tumors as stage IV. All except one tumor (lobular carcinoma) were diagnosed as invasive ductal breast carcinomas, 10% were grade I, 20% were grade II, and 70% were grade III tumors. Two tumors were ER/PR positive, four tumors were ER positive/PR negative, one tumor was ER negative/PR positive, and six tumors were negative for both receptors. The mean interval between primary surgery and surgery of distant metastases (MFI), and the mean PMS times were used as clinically relevant prognostic factors. The mean MFI was 31 months (range, 0–136 months), and the mean observation time of the patients after the first diagnosis of breast cancer was 40 months (range, 7–156 months; Table 1Citation ). Patients underwent different adjuvant hormone, radiation, and chemotherapies according to standard treatment guidelines.


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  		Table 1 LOH in 17 sporadic breast carcinomas and 22 corresponding distant metastases in seven chromosomal regions, harboring breast cancer or metastasis-related genes and one control locus (ß-actin)

 
DNA Extraction.
Immediately after surgery, microscopically identified tumor tissue was snap-frozen in liquid nitrogen and stored at -80°C. For paraffin-embedded samples, tumor regions were harvested by the microdissection of 10-µm tissue sections. Extraction of genomic DNA from frozen or paraffin-embedded tumor samples and peripheral blood leukocytes was performed using the QIAamp blood and tissue kit (QIAGEN) according to the manufacturer’s instructions.

Microsatellite Analysis.
Allelic loss (LOH) at three breast cancer-related loci (chromosome 11q22–23, 13q12–13, 17q21), three metastasis-related chromosomal regions (chromosome 1q32–41, 16q22.2–23.2, 17q21.3), and the p53 locus (17p13.1) was examined using 19 polymorphic microsatellite markers (listed in Table 1Citation ). The ß-actin locus on 15q11 was used as control.

Microsatellite analysis was performed as described previously (30) . Briefly, paired peripheral blood leukocyte and tumor DNAs were amplified by PCR in a Gene Amp 9600 thermocycler (Perkin-Elmer). PCR products were analyzed by gel electrophoresis on an automated laser fluorescence (A.L.F.) sequencer (Pharmacia Biotech; Fig. 1Citation ), and calculation of allelic loss was determined semiquantitatively using the Fragment Manager software. Resulting values of >=1.5 (imbalance factor), reflecting allele reduction of one-third or more in tumor DNA, were defined as the LOH cutoff point. LOH of one chromosomal locus was defined if at least one of the markers analyzed for this region showed LOH.



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  		Fig. 1. Illustration of LOH. Examples of computer print-outs of polyacrylamide gel analyses of PCR products by an automated DNA sequencer. Shown are PCR products from selected breast tumors (second row), distant metastases (third to fifth rows), and corresponding blood samples (first row), amplified with different microsatellite primers. The microsatellite alleles are represented by two (heterozygote) peaks, LOH at one allele (arrows) corresponds to a significant reduction in one of the two peaks (imbalance factor, >=1.5). Homozygosity (one allele only) is not shown in these.

 
Statistical Methods.
The combined LOH at several gene loci was chosen as study criteria based on the assumption that the accumulation of genetic alterations in several gene loci has a major influence on the metastatic process. We used a combination of the seven chromosomal regions together to evaluate a general influence; for gene-specific influence, subgroups were formed as defined in Table 3Citation . Groups were proven to be homogeneous regarding their tumor stage using {chi}2 test. Differences in the distribution of LOH between the different groups of samples were tested by using the one-tailed {chi}2 test or Fisher’s exact test. Significance of differences between the MFIs or PMS times of patients were tested by Student’s t test (MFI) and the log-rank test (PMS), respectively. PMS rates of patients were estimated by the Kaplan-Meier method.


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  		Table 3 Correlation of the combination of LOH incidence in primary tumors plus additional LOH in distant metastases with MFI and PMS

 

   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Incidence of Allelic Losses in Primary Breast Tumors and Distant Metastases.
LOH frequencies at the different chromosomal regions in 17 primary breast tumors and 22 distant metastases are listed in Tables 1Citation and 2Citation . At each locus examined, the incidence of allelic loss was higher in the group of distant metastases compared with the group of primary tumors. By the {chi}2 test, allelic loss in metastases was significantly higher at 17p13.1, 13q12–13, and 16q22.2–23.2 (P < 0.05), whereas at 17q21, 11q22–23, 17q21.3, and 1q32–41 the observed increases did not reach statistical significance. We also observed an insignificant increase at the ß-actin control locus.


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  		Table 2 Incidence of LOH in primary breast tumors and corresponding distant metastases

 
Correlation of Combined LOH with MFIs and PMS.
To investigate whether the incidence of LOH in either the primary tumor group or the group of distant metastases may be used as a prognostic factor, we correlated combined LOH frequencies of each group with patients’ MFIs and PMS times. In the group of primary breast tumors, we observed a correlation of increased combined LOH events with decreased MFIs as well as with decreased PMS for all of the loci groups examined, although results did not reach statistical significance. Unexpectedly, in the group of distant metastases, we found an inverse correlation of LOH events with the MFIs (mean MFI of patients with high LOH, 32.9 months versus 30.8 months for patients with LOH; P = 0.707). But again, patient samples exhibiting a high combined LOH in the metastases had a shorter (although not significantly) PMS than those with low LOH.

Correlation of Combined LOH Frequency in Primary Tumors plus Additional LOH Events in Distant Metastases and Clinical Course.
On the basis of our observation of a correlation of increased numbers of LOH events with decreased patient survival times and according to the established theory that the metastatic potential of a tumor cell seems to be characterized by the accumulation of genetic alterations, we hypo-thesized that both the incidence of LOH in the primary lesion plus the occurrence of additional LOH events in the distant metastases may determine the malignant behavior of metastatic tumors. For statistical evaluation, we defined two patient groups for each of the four gene loci combinations based on their LOH status in primary tumors plus the occurrence of additional LOH events in their distant metastatic tumor samples; group 1 consisted of patients with low LOH, whereas group 2 comprised patients with high LOH according to the definition in Table 3Citation .

The results of this statistical evaluation are summarized in Table 3Citation . Briefly, we found significant differences in the correlation of these defined criteria with the PMS ((Table 3B)Citation for the combination of seven chromosomal regions (P = 0.0017) and the combination of p53 with the three breast cancer-related regions (P = 0.0203) as well as the breast cancer regions alone (P = 0.0241). Patients with high combined LOH events showed a significant reduced PMS in comparison with those with low LOH (Fig. 2A and B)Citation . In correlation with the MFIs, these three groups showed positive trends without reaching statistical significance (Table 3A)Citation . In contrast, the three metastasis-related chromosomal regions revealed a surprising inverse correlation with the MFIs (P = 0.431) and an insignificant correlation with the PMS times (P = 0.0805). These results suggest that the occurrence of combined genetic alterations in the three putatively metastasis-related chromosomal regions has no major influence on the aggressive behavior of metastasis in breast carcinomas.



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  		Fig. 2. PMS curves of patients with low and high LOH. A, decreased PMS of patients with >= 2 LOH in primary breast tumor plus additional >= 2 LOH in the distant metastases at 17p13.1, 17q21, 13q12–13, 11q22–23, 1q32–41, 16q22.2–23.2, and 17q21.3 (group 2) in comparison with those not following this criteria (group 1; log-rank test, P = 0.0017). *, census survival times. B, decreased PMS of patients with LOH at 17p13.1 in primary tumor plus additional >=1 LOH in their metastases at 17q21, 13q12–13, or 11q22–23 (group 2) compared with those that are heterozygous at 17p13.1 independent of the LOH events found in distant metastases in the three breast cancer-related regions (group 1; log-rank test, P = 0.0203).

 
Accumulation of Allelic Losses during Tumor Progression in Corresponding Tumors.
We found that concurrent as well as different LOH patterns in primary and corresponding metastatic tumor samples were observed at a similar frequency (Table 1)Citation . However, in 14 of the 17 cases, a different LOH pattern was present in at least one of the seven regions examined. We never observed the phenomenon that LOH was present in the primary tumor but absent in the corresponding distant metastatic lesion, which, therefore, excluded random events. Two patients (48 and 692, both stage IV) were operated on simultaneously for breast carcinomas and distant metastases. Both tumor sets revealed additional LOH events in the metastatic lesions, which suggested that the additional allelic losses had been acquired by the metastatic clone after detachment from the parental tumor.

Up to three distant metastases, removed at different time intervals, were available from four patients (see Table 1Citation ): the BM and CM of patient 660 revealed a different LOH pattern, which suggested an independent development; and, in addition, both metastatic lesions accumulated LOH events compared with the primary tumor. Patient 677 developed a local recurrence in the brain (CM/II) 7 months after the removal of the first metastatic lesion (CM/I). The first metastasis (CM/I) had accumulated two additional LOH events in comparison with the primary breast tumor, whereas in the local recurrence (CM/II), four additional LOH events were obvious. Assuming that the recurrence may have developed from residual tumor cells, this example suggests that these cells are susceptible to further genetic instability during the time course. In contrast, the brain and lung metastases of patient 1137 revealed an identical LOH pattern and only one additional LOH event compared with the primary tumor. Patient 1401 was operated on for a first breast cancer CM (CM/I) 3 months before she developed a local recurrence (CM/II) and a further CM contralaterally (CM/III). The recurrent lesion and the contralateral metastasis had an identical LOH pattern, whereas, again, an increase of LOH during progressive disease was observed. We conclude that residual cancer cells gave rise to the local recurrence and acquired one additional LOH event during the time course, whereas the independent lesion located in the opposite brain hemisphere probably derived from the recurrent lesion, revealing an identical LOH pattern (Fig. 1A)Citation .


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this LOH analysis on a series of primary sporadic breast carcinomas and corresponding distant metastases, we found that in comparison with their primary tumor distant metastatic lesions showed an accumulation of additional genetic alterations. These observations confirm the data of several studies analyzing a variety of tumor entities and reporting higher LOH frequencies in metastases than in primary tumors (18, 19, 20, 21, 22 , 27 , 31, 32, 33, 34) . Most of these studies compared primary tumors and noncorresponding metastases (27 , 31, 32, 33) , whereas reports of comparative LOH analyses of primary tumors with their corresponding distant metastases are rare, are based on small patient numbers, and—to our knowledge—have not been performed in breast carcinomas (18 , 20 , 21 , 34) . In contrast, the comparison of LOH frequencies in primary breast tumors and corresponding axillary lymph node metastases showed an identical LOH pattern in all of the cases (35, 36, 37, 38) . This discrepancy may be due to the fact that lymph-node metastases are mainly harvested during primary operations, whereas distant metastases are characterized by hematogenous spread and a distinct time interval. In this comparative analysis of 17 primary breast tumors and 22 corresponding distant metastases, we observed that the incidence of LOH in the group of distant metastases was always higher than in primary tumors. It was significantly increased in three of the seven breast cancer- and metastasis-related chromosomal regions examined (17q21, 13q12–13, and 16q22.2–23.2; Table 2Citation ). The correlation of high combined LOH incidence with decreased MFI and PMS showed a positive trend but failed to reach statistical significance in the primary tumor group, which suggests that the LOH frequency in primary tumors does not seem to be the only relevant factor for the malignant behavior of metastatic tumors. This result confirms the discordant observations of previous LOH studies in primary breast carcinomas, some of which reported a positive correlation of single or combined LOH frequencies with decreased survival or clinicopathological markers of enhanced malignancy (7, 8, 9, 10, 11, 12, 13, 14 , 39, 40, 41) and others unable to confirm these findings (15 , 16) .

Comparison of the LOH patterns of the corresponding tumor samples revealed that 14 of the 17 patients acquired additional LOH events in their metastatic lesions. When combined LOH in primary tumors plus the occurrence of additional LOH events in the distant metastases were correlated with the defined clinical parameters, we observed a significant correlation with decreased PMS (P = 0.0017; Table 3BCitation and Fig. 2ACitation ). These results suggest that the increase of genetic instability during metastasis seems to accelerate disease progression. Evaluation of a gene-specific influence showed that the combined inactivation of the breast cancer-related regions alone (P = 0.0241; Table 3BCitation ), as well as the combination of LOH at the p53 locus in primary tumors with maintenance during progression plus the acquisition of additional LOH events in metastases in the three breast cancer-related regions (Fig. 2BCitation ; P = 0.0203) correlated significantly with decreased postmetastatic patient survival. This result can be brought in accordance with recent studies that suggest a mutual dependency of p53 and BRCA abnormalities in breast carcinogenesis (42) .

According to the clonal evolution theory (3) , distant metastases arise from a selected clone in the primary tumor that has acquired and accumulated a variety of genetic alterations necessary for its metastatic behavior. This clone will finally overgrow the primary tumor because of a growth advantage over its counterparts and, therefore, become the dominant clone in the late stage of tumor development (4) . Following this theory, one would suspect an identical LOH pattern in the primary tumor and distant metastases, at least in the later stages of tumor growth and progression. The discordant LOH pattern in our tumor series may be due to the fact that the metastatic clone in the primary tumor is not yet the dominant one. In this case, the LOH pattern of the distant metastasis might be considered as a representative of the most aggressive clone of the primary tumor; and, based on previous data (11, 12, 13 , 39) , one could expect a correlation of high combined LOH frequencies in the distant metastases with decreased MFIs. Our contrary results of an inverse correlation suggest that the increase of LOH events in the distant metastases may be due to the accumulation of additional genetic alterations in the metastatic cell clone after detachment from the parental tumor.

To further specify the time point in the metastatic cascade at which these additional genetic alterations occur, we developed the following hypothetical model based on data of patients presenting with multiple recurrent distant metastases:

(a) a characteristic feature of breast cancer disease is the development of metastases many years after resection of the primary neoplasm. According to Paget’s "seed and soil" theory (17) , the growth at susceptible distant organ sites is influenced by environmental host factors as well as the aggressive potential of the metastatic clone itself. Reduced patient immunity or the release of angiogenic factors (43) have a major influence on the sudden growth of dormant cells. However, the question remains: Why in some patients does a single metastasis arise at a certain organ site, whereas others develop multiple lesions at the same time? The occurrence of additional genetic events in a single one of the multiple quiescent, metastatic clones may represent a critical event, being involved in the sudden termination of the dormancy state and consecutively favoring the development of a single metastatic lesion. In contrast, an enhanced influence of host factors may rather favor the sudden growth of multiple metastatic clones at distant organ sites (for illustration, see Fig. 3Citation ).



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  		Fig. 3. Model of the multistep process of metastasis, hypothesized according to the reported results of LOH analysis in our series of primary breast carcinomas and corresponding distant metastases. According to this hypothetical model, the malignant behavior of a metastatic tumor is determined by the incidence of LOH in the primary tumor with maintenance during progression, plus the acquisition of additional LOH events in the metastatic clone after detachment from the parental tumor. The additional LOH event(s) may play a role in the termination of the dormancy stage of quiescent metastatic clones at distant organ sites in cooperation with host factors (bold arrows, enhanced influence; thin arrows, lower influence) and/or accumulated during further progression of metastasis. Metastases that are characterized by the accumulation of multiple LOH events show a more aggressive behavior and are associated with a significantly reduced PMS and poor patient outcome.

 
(B) alternatively or additionally, the increased LOH incidence in metastatic lesions may be acquired during the progressive growth of the distant metastatic tumor cell clones (see patients 1401 and 677) and would be responsible for the increased malignant behavior of metastases and poor patient outcome (Fig. 2Citation ; for illustration, see Fig. 3Citation ).

In conclusion, the results of this comparative study of primary breast carcinomas and corresponding distant metastases suggest that the aggressive behavior of a metastatic breast tumor seems to be determined by the incidence of genetic alterations accumulated during selective growth in the primary tumor plus the acquisition of additional genetic alterations further down in the metastatic cascade (Fig. 3)Citation . In addition, our data suggest a specific influence of combined LOH—at the three breast cancer-associated chromosomal regions on 17q21, 13q12–13, and 11q22–23 alone or in combination with allelic loss at the p53 locus—on the malignant behavior of breast cancer metastases.


   ACKNOWLEDGMENTS
 
We thank M. Reichmann and U. Neumeister for the excellent technical assistance and U. Schwanebeck for help with statistical analysis of the data. We thank Alice Brown and Peter Marks for helpful discussions and critical reading of the article.


   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 To whom requests for reprints should be addressed, at Dana-Farber Cancer Institute, Department of Adult Oncology, 44 Binney Street, M 457, Boston, MA 02115. Phone: (617) 632-2249; Fax: (617) 632-4760; E-mail: monika_hampl{at}macmailgw.dfci.harvard.edu Back

2 The abbreviations used are: LOH, loss of heterozygosity; MFI, metastasis-free interval; PMS, postmetastatic survival; ER, estrogen receptor; PR, progesterone receptor; CM, brain metastasis/metastases; LM, liver metastasis; PM, pulmonary metastasis; BM, bone metastasis. Back

Received 1/12/98; revised 3/ 4/99; accepted 3/ 9/99.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Fidler I. J. Cancer metastasis. Br. Med. Bull., 47: 157-177, 1991.[Abstract/Free Full Text]
  2. Fidler I. J., Hart I. R. Biological diversity in metastatic neoplasms: origins and implications. Science (Washington DC), 217: 998-1003, 1982.[Abstract/Free Full Text]
  3. Nowell P. C. The clonal evolution of tumor cell populations. Science (Washington DC), 194: 23-28, 1976.[Abstract/Free Full Text]
  4. Kerbel R. S. Growth dominance of the metastatic cancer cell: cellular and molecular aspects. Adv. Cancer Res., 55: 87-132, 1990.[Medline]
  5. Fidler I. J., Radinsky R. Search for genes that suppress cancer metastasis. J. Natl. Cancer Inst., 88: 1700-1703, 1996.[Free Full Text]
  6. Nowell P. C. Mechanisms of tumor progression. Cancer Res., 46: 2203-2207, 1986.[Free Full Text]
  7. Nagai M. A., Medeiros A. C., Brentani M. M., Brentani R. R., Marques L. A., Mazoyer S., Mulligan L. M. Five distinct deleted regions on chromosome 17 defining different subsets of human primary breast tumors. Oncology (Basel), 52: 448-453, 1995.[Medline]
  8. Kelsell D. P., Spurr N. K., Barnes D. M., Gusterson B., Bishop D. T. Combined loss of BRCA1/BRCA2 in grade 3 breast carcinomas. Lancet, 347: 1554-1555, 1996.[Medline]
  9. Beckmann M. W., Picard F., An H. X., van Roeyen C. R., Dominik S. I., Mosny D. S., Schnurch H. G., Bender H. G., Niederacher D. Clinical impact of detection of loss of heterozygosity of BRCA1 and BRCA2 markers in sporadic breast cancer. Br. J. Cancer, 73: 1220-1226, 1996.[Medline]
  10. Kerangueven F., Eisinger F., Noguchi T., Allione F., Wargniez V., Eng C., Padberg G., Theillet C., Jacquemier J., Longy M., Sobol H., Birnbaum D. Loss of heterozygosity in human breast carcinomas in the ataxia telangiectasia, Cowden disease and BRCA1 gene regions. Oncogene, 14: 339-347, 1997.[Medline]
  11. van den Berg J., Johannsson O., Hakansson S., Olsson H., Borg A. Allelic loss at chromosome 13q12–q13 is associated with poor prognosis in familial and sporadic breast cancer. Br. J. Cancer, 74: 1615-1619, 1996.[Medline]
  12. Bieche I., Champeme M. H., Merlo G., Larsen C. J., Callahan R., Lidereau R. Loss of heterozygosity of the L-myc oncogene in human breast tumors. Hum. Genet., 85: 101-105, 1990.[Medline]
  13. Bieche I., Champeme M. H., Matifas F., Hacene K., Callahan R., Lidereau R. Loss of heterozygosity on chromosome 7q and aggressive primary breast cancer. Lancet, 339: 139-143, 1992.[Medline]
  14. Borg A., Zhang Q. X., Olsson H., Wenngren E. Chromosome 1 alterations in breast cancer: allelic loss on 1p and 1q is related to lymphogenic metastases and poor prognosis. Genes Chromosomes Cancer, 5: 311-320, 1992.[Medline]
  15. Bieche I., Nogues C., Rivoilan S., Khodja A., Latil A., Lidereau R. Prognostic value of loss of heterozygosity at BRCA2 in human breast carcinoma. Br. J. Cancer, 76: 1416-1418, 1997.[Medline]
  16. Schmutzler R. K., Fimmers R., Bierhoff E., Lohmar B., Homann A., Speiser P., Kubista E., Jaeger K., Krebs D., Zeillinger R., Wiestler O. D., Deimling A. V. Association of allelic losses on human chromosomal arms 11Q and 16Q in sporadic breast cancer. Int. J. Cancer, 69: 307-311, 1996.[Medline]
  17. Paget S. The distribution of secondary growth in cancer of the breast. Lancet, 1: 571-573, 1889.
  18. Shiseki M., Kohno T., Nishikawa R., Sameshima Y., Mizoguchi H., Yokota J. Frequent allelic losses on chromosomes 2q, 18q, and 22q in advanced non-small cell lung carcinoma. Cancer Res., 54: 5643-5648, 1994.[Abstract/Free Full Text]
  19. Schwendel A., Langreck H., Reichel M., Schrock E., Ried T., Dietel M., Petersen I. Primary small-cell lung carcinomas and their metastases are characterized by a recurrent pattern of genetic alterations. Int. J. Cancer, 74: 86-93, 1997.[Medline]
  20. Adachi J., Shiseki M., Okazaki T., Ishimaru G., Noguchi M., Hirohashi S., Yokota J. Microsatellite instability in primary and metastatic lung carcinomas. Genes Chromosomes Cancer, 14: 301-306, 1995.[Medline]
  21. Frank C. J., McClatchey K. D., Devaney K. O., Carey T. E. Evidence that loss of chromosome 18q is associated with tumor progression. Cancer Res., 57: 824-827, 1997.[Abstract/Free Full Text]
  22. Nishizaki T., DeVries S., Chew K., Goodson W. H., III, Ljung B. M., Thor A., Waldman F. M. Genetic alterations in primary breast cancers and their metastases: direct comparison using modified comparative genomic hybridization. Genes Chromosomes Cancer, 19: 267-272, 1997.[Medline]
  23. Savitsky K., Bar Shira A., Gilad S., Rotman G., Ziv Y., Vanagaite L., Tagle D. A., Smith S., Uziel T., Sfez S., et al A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science (Washington DC), 268: 1749-1753, 1995.[Abstract/Free Full Text]
  24. Wooster R., Bignell G., Lancaster J., Swift S., Seal S., Mangion J., Collins N., Gregory S., Gumbs C., Micklem G. Identification of the breast cancer susceptibility gene BRCA2. Nature (Lond.), 378: 789-792, 1995.[Medline]
  25. Miki Y., Swensen J., Shattuck Eidens D., Futreal P. A., Harshman K., Tavtigian S., Liu Q., Cochran C., Bennett L. M., Ding W., et al A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science (Washington DC), 266: 66-71, 1994.[Abstract/Free Full Text]
  26. Lee J. H., Welch D. R. Suppression of metastasis in human breast carcinoma MDA-MB-435 cells after transfection with the metastasis suppressor gene. KiSS-1. Cancer Res., 57: 2384-2387, 1997.[Abstract/Free Full Text]
  27. Driouch K., Dorion Bonnet F., Briffod M., Champeme M. H., Longy M., Lidereau R. Loss of heterozygosity on chromosome arm 16q in breast cancer metastases. Genes Chromosomes Cancer, 19: 185-191, 1997.[Medline]
  28. Steeg P. S., Bevilacqua G., Kopper L., Thorgeirsson U. P., Talmadge J. E., Liotta L. A., Sobel M. E. Evidence for a novel gene associated with low tumor metastatic potential. J. Natl. Cancer Inst., 80: 200-204, 1988.[Abstract/Free Full Text]
  29. Lane D. P. Cancer. p53, guardian of the genome. Nature (Lond.), 358: 15-16, 1992.[Medline]
  30. Frank S., Müller J., Plaschke J., Hahn M., Hampl J., Hampl M., Pistorius S., Schackert G., Schackert H. K. The putative tumor suppressor gene FHIT at 3p14.2 is rarely affected by loss of heterozygosity in primary brain tumors. Cancer Res., 57: 2638-2641, 1997.[Abstract/Free Full Text]
  31. Andersen T. I., Gaustad A., Ottestad L., Farrants G. W., Nesland J. M., Tveit K. M., Borresen A. L. Genetic alterations of the tumour suppressor gene regions 3p, 11p, 13q, 17p, and 17q in human breast carcinomas. Genes Chromosomes Cancer, 4: 113-121, 1992.[Medline]
  32. Champeme M-H., Bieche I., Lizard S., Lidereau R. 11q13 amplification in local recurrence of human primary breast cancer. Genes, Chromosomes Cancer, 12: 128-133, 1995.[Medline]
  33. Driouch K., Briffod M., Bieche I., Champeme M. H., Lidereau R. Location of several putative genes possibly involved in human breast cancer progression. Cancer Res., 58: 2081-2086, 1998.[Abstract/Free Full Text]
  34. Wick W., Petersen I., Schmutzler R. K., Wolfarth B., Lenartz D., Bierhoff E., Hummerich J., Muller D. J., Stangl A. P., Schramm J., Wiestler O. D., von Deimling A. Evidence for a novel tumor suppressor gene on chromosome 15 associated with progression to a metastatic stage in breast cancer. Oncogene, 12: 973-978, 1996.[Medline]
  35. Radford D. M., Phillips N. J., Fair K. L., Ritter J. H., Holt M., Donis-Keller H. Allelic loss and the progression of breast cancer. Cancer Res., 55: 5180-5183, 1995.[Abstract/Free Full Text]
  36. Tsuda H., Hirohashi S. Identification of multiple breast cancers of multicentric origin by histological observations and distribution of allele loss on chromosome 16q. Cancer Res., 55: 3395-3398, 1995.[Abstract/Free Full Text]
  37. Chen L. C., Kurisu W., Ljung B. M., Goldman E. S., Moore D., II, Smith H. S. Heterogeneity for allelic loss in human breast cancer. J. Natl. Cancer Inst., 84: 506-510, 1992.[Abstract/Free Full Text]
  38. Bonsing B. A., Devilee P., Cleton-Jansen A. M., Kuipers-Dijkshoorn N., Fleuren G. J., Cornelisse C. J. Evidence for limited molecular genetic heterogeneity as defined by allelotyping and clonal analysis in nine metastatic breast carcinomas. Cancer Res., 53: 3804-3811, 1993.[Abstract/Free Full Text]
  39. Winqvist R., Hampton G. M., Mannermaa A., Blanco G., Alavaikko M., Kiviniemi H., Taskinen P. J., Evans G. A., Wright F. A., Newsham I., Cavenee W. K. Loss of heterozygosity for chromosome 11 in primary human breast tumors is associated with poor survival after metastasis. Cancer Res., 55: 2660-2664, 1995.[Abstract/Free Full Text]
  40. Harada Y., Katagiri T., Ito I., Akiyama F., Sakamoto G., Kasumi F., Nakamura Y., Emi M. Genetic studies of 457 breast cancers. Clinicopathologic parameters compared with genetic alterations. Cancer (Phila.), 74: 2281-2286, 1994.[Medline]
  41. Takita K., Sato T., Miyagi M., Watatani M., Akiyama F., Sakamoto G., Kasumi F., Abe R., Nakamura Y. Correlation of loss of alleles on the short arms of chromosomes 11 and 17 with metastasis of primary breast cancer to lymph nodes. Cancer Res., 52: 3914-3917, 1992.[Abstract/Free Full Text]
  42. Brugarolas J., Jacks T. Double indemnity: p53, BRCA and cancer p53 mutation partially rescues developmental arrest in Brca1 and Brca2 null mice, suggesting a role for familial breast cancer genes in DNA damage repair. Nat. Med., 3: 721-722, 1997.[Medline]
  43. Folkman J. The role of angiogenesis in tumor growth. Semin. Cancer Biol., 3: 65-71, 1992.[Medline]



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