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[Cancer Research 60, 2831-2835, June 1, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

Loss of p53 in Benzene-induced Thymic Lymphomas in p53+/- Mice: Evidence of Chromosomal Recombination

Scott E. Boley, Elizabeth E. Anderson, John E. French, Lawrence A. Donehower, Dana B. Walker and Leslie Recio1

Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709 [S. E. B., E. E. A., L. R.]; National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 [J. E. F.]; Division of Molecular Virology, Baylor College of Medicine, Houston, Texas 77030 [L. A. D.]; and United States Environmental Protection Agency, Research Triangle Park, North Carolina 27709 [D. B. W.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
The purpose of this study was to examine the role of chromosomal recombination in mediating p53 loss in benzene-induced thymic lymphomas in C57BL/6-Trp53 haploinsufficient (N5) mice (p53+/- mice). We characterized loss of heterozygosity (LOH) on chromosome 11 using seven microsatellite markers in 27 benzene-induced and 6 spontaneous thymic lymphomas. Eleven patterns of LOH were found between the induced and spontaneous tumors, with only one pattern being in common between the tumor groups. Nearly 90% (24 of 27) of benzene-induced tumors exhibited loss of the functional p53 allele locus, and 83% (20 of 24) of these tumors retained two copies of the disrupted p53 allele. The results indicate that benzene induces a high frequency of LOH on chromosome 11 in p53+/- mice, likely mediated by aberrant chromosomal recombination.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
Loss of p53 function is the most common genetic alteration in human cancer (1 , 2) . The p53 gene encodes a transcription factor that directs the transcription of genes involved in a variety of cellular processes, including cell cycle regulation, DNA repair, and apoptosis (reviewed in Ref. 3 ). Loss of p53 function is associated with genomic instability and unregulated growth (4 , 5) , and these results support the importance of examining the mechanism of p53 loss in tumor development. The C57BL/6-Trp53 haploinsufficient (N5) mouse [p53+/- transgenic mouse (6) ] contains a single functional copy of p53 and provides an in vivo model to study the role of p53 loss in tumor development (reviewed in Ref. 7 ). Genetic analysis of tumors derived from p53+/- mice has revealed loss of the functional p53 allele in most induced tumors (8, 9, 10) and to a lesser degree in spontaneous tumors (11) . There is little information concerning the mechanism of p53 loss in these tumors, with most reports only examining the status of the p53 locus in the tumors (8, 9, 10, 11) . We are interested in studying the mechanism of p53 loss in tumors by examining the status of chromosome 11 in the region of p53. Therefore, p53+/- mice provide a valuable model for studying the mechanism of p53 loss in tumorigenesis.

Inhaled benzene induced a high frequency of thymic lymphomas in p53+/- mice (7) . At 34 weeks of exposure, the incidence of thymic lymphomas in the exposed animals was >80%, with no grossly observable tumors occurring in the control animals. To examine the mechanism of p53 loss in tumors induced in p53+/- mice, samples of genomic DNA from 27 benzene-induced thymic lymphomas and 6 spontaneous thymic lymphomas from previous studies (6 , 8) were subjected to p53 genotyping and LOH2 analysis of chromosome 11. Seven informative microsatellite markers distributed along chromosome 11 were used to examine the extent of LOH that accompanied p53 loss.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Genomic DNA Isolation from Thymic Lymphomas.
Samples of benzene-induced thymic lymphomas were obtained from p53+/- mice involved in an ongoing benzene inhalation study at Chemical Industry Institute of Toxicology.3 Spontaneous thymic lymphoma samples that arose in the same line of mice and used for comparison of LOH patterns were obtained from previous studies (6 , 8) . Genomic DNA was isolated from ~50 mg of thymic lymphoma tissue using the Puregene DNA isolation kit (Gentra Systems, Inc., Minneapolis, MN), following the manufacturer’s recommended protocol. For control purposes, genomic DNA was also isolated from the liver of tumor-bearing mice, following the same procedure as for the tumor tissue. The genomic DNA for all samples was quantified spectrophotometrically and diluted to 50 ng/µl for subsequent analysis.

Microsatellite Analysis of Chromosome 11.
The p53+/- mice used in this study were generated by crossing p53-/- males with p53+/+ females and backcrossed five times on a C57BL/6 background. The genetic makeup of the mouse is therefore predominantly C57BL/6, with the exception of the disrupted p53 allele, which resides on the 129/Sv-derived copy of chromosome 11. This represents the source of heterozygosity that allowed the LOH analysis on chromosome 11. Microsatellite analysis was carried out in 25-µl PCR reactions containing 400 nM each deoxynucleotide triphosphate, 400 nM each primer, 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 1.5 mM MgCl2, and 250 ng of genomic DNA as template. A list of the primer sequences used for microsatellite analysis is given in Table 1Citation . The distribution of the microsatellite loci on chromosome 11 is shown in Fig. 1Citation . PCR amplification was performed using a Perkin-Elmer Corp. GeneAmp PCR System 9600 (Perkin-Elmer, Foster City, CA) and a PCR profile of 4 min at 94°C, followed by 30 cycles of 94°C for 20 s, 60°C for 20 s, and 72°C for 40 s, and concluded by holding at 4°C. PCR products were separated on a 3% agarose gel and visualized using UV light. LOH was defined as loss of one of two bands that defined a particular informative locus (Fig. 2Citation ) and tumors were placed into groups based on the LOH pattern that each exhibited.


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  		Table 1 Chromosome 11 microsatellite primer informationa

 


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  		Fig. 1. Relative location of microsatellite loci on mouse chromosome 11. The centromere is located at the top of the figure, with the 129/Sv-derived chromosome on the right and the C57BL/6-derived chromosome on the left. The seven informative microsatellite markers used in the LOH analysis of thymic lymphomas in p53+/- mice and their relationship to the p53 locus are shown. For the relative distances between the markers, see Table 1Citation .

 


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  		Fig. 2. Representative agarose gel depicting LOH at D11 Mit327 on chromosome 11. Lane 1 contains the amplification product using p53+/- mouse liver DNA and demonstrates the two products representing the two alleles of the microsatellite locus; the products are labeled as to the chromosome from which they are derived. Lanes 2–6, LOH at this microsatellite locus in benzene-induced thymic lymphomas. Lane 7, negative PCR control. Lane 4, LOH of the alternate allele as described in the text.

 
PCR-based Genotyping Analysis.
Multiplex PCR was used to genotype the tumors using published genotyping primers (12) . To amplify the wild-type p53 sequence, primer WT1 (5'-GTG TTT CAT TAG TTC CCC ACC TTG AC-3') and WT2 (5'-ATG GGA GGC TGC CAG TCC TAA CCC-3') were used. To amplify the disrupted p53 allele, primer KO1 (5'-GTG GGA GGG ACA AAA GTT CGA GGC C-3') and KO2 (5'-TTT ACG GAG CCC TGG CGC TCG ATG T-3') were used. The PCR reaction components and conditions were essentially the same as in the microsatellite analysis described above, except the primer concentrations were as follows: primers WT1 and WT2 were at 240 nM, and primers KO1 and KO2 were at 160 nM. PCR products were separated on 2% agarose gels and visualized using UV light. A 320-bp product indicated the presence of a wild-type p53 allele, and a 150-bp product indicated the presence of the disrupted p53 allele.

Southern Blot-based Genotyping Analysis.
Southern blot hybridization analysis of p53 in thymic lymphomas was performed as described previously (8, 9, 10, 11) . Briefly, 5–10 µg of genomic DNA were digested overnight with BamHI and resolved on a 0.8% agarose gel. The DNA was transferred to a nitrocellulose membrane, hybridized with a 32P-labeled murine p53 cDNA probe specific for exons 2–6, washed, exposed to Kodak XAR-S film overnight, and developed. The presence of a wild-type p53 allele was evidenced by the appearance of a 5.0-kb band, whereas the mutant allele gave a 6.5-kb band, and the p53 pseudogene gave a 10-kb band.

The copy number of the disrupted p53 allele was determined by comparing the intensity of the signal for the p53 pseudogene, which represents a single-copy gene, to the signal for the disrupted p53 allele. A 1:1 signal ratio (pseudogene:disrupted allele) would indicate a single copy of the disrupted p53 allele, whereas a ratio of 1:2 would indicate two copies of the disrupted allele.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Tumor Diagnosis.
All 27 benzene-induced thymic lymphomas were diagnosed based on impression smears stained with CMS Protocol HEMA 3 Stain Set (Biochemical Sciences, Swedesboro, NJ). The tumors were composed predominantly of large round cells with lymphoid appearance and blast cell characteristics.

Analysis of p53 Status.
PCR analysis showed loss of the functional p53 allele in most of the thymic lymphomas (data not shown). These results were confirmed by Southern analysis (Fig. 3Citation ). The benzene-induced tumors showed loss of the wild-type p53 allele in nearly 90% of thymic lymphomas (24 of 27 tumors). Loss of the wild-type p53 allele among the spontaneous lymphomas was 67% (4 of 6 tumors), but this was based on a limited number of tumors. A previous study had shown that loss of the wild-type p53 allele occurs in less than half of spontaneous tumors in p53+/- mice (11) . All liver samples showed the presence of both the wild-type and disrupted p53 alleles (data not shown).



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  		Fig. 3. Loss of p53 heterozygosity in tumors from benzene-treated mice. The bands corresponding to the wild-type p53 gene (WT), the mutant allele (Mut), and the p53 pseudogene are indicated. Lane N, p53 hybridizing bands from normal p53+/- tail DNA; the remaining 13 lanes show p53 hybridization patterns from individual p53+/- tumors. Note that only 1 of the p53+/- tumors shown here retained its wild-type allele.

 
p53 Copy Number Analysis.
Comparison of the intensity of the band corresponding to the p53 pseudogene with the band corresponding to the disrupted p53 allele indicated that 20 of 24 tumors exhibiting loss of the functional p53 allele contained two copies of the disrupted allele.

Microsatellite Analysis of Chromosome 11.
Analysis of liver DNA from 129/Sv and C57BL/6 mice revealed that the upper band for all microsatellite loci except D11 Mit177 corresponded to the 129/Sv-derived chromosome and that the remaining band correlated with the C57BL/6-derived chromosome. After completing the analysis of 27 benzene-induced tumors, six different patterns of LOH emerged. The results can be seen in TableCitation 2 and are summarized in Fig. 4Citation . The patterns ranged from LOH at all loci tested (pattern A; Fig. 4ACitation ) to retention of heterozygosity at all loci (pattern F; Fig. 4ACitation ). In addition, four of the six patterns were exhibited by over 90% (25 of 27) of benzene-induced tumors (patterns A, B, C, and D; Fig. 4ACitation ). Analysis of the six spontaneous tumors revealed six patterns of LOH (Fig. 4BCitation ). LOH at all loci tested was the only pattern in common between the benzene-induced (15 of 27) and spontaneous tumors (1 of 6). Most LOH involved of the C57BL/6 allele. However, a few tumors showed loss of the 129/Sv allele (Fig. 2Citation , Lane 4). Loss of the 129/Sv allele involved only three of the microsatellite loci, D11 Mit136, D11 Bhm148, and D11 Mit327. At D11 Mit327, 21% (7 of 33) of thymic lymphomas lost the 129/Sv allele, whereas at D11 Mit136 the frequency of loss involving the 129/Sv allele was 12% (4 of 33) and at D11 Bhm148 the frequency was only 3% (1 of 33; Fig. 4Citation ). The only tumor that showed loss of the 129/Sv allele at D11 Bhm148 was a spontaneous tumor.



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  		Fig. 4. Summary of LOH patterns exhibited by benzene-induced and spontaneous thymic lymphomas. Boxes with vertical stripes, loss of the C57BL/6 allele; boxes with cross-hatching, retention of heterozygosity; and boxes with diagonal stripes, loss of the 129/Sv allele. A, LOH patterns exhibited by benzene-induced thymic lymphomas. B, LOH patterns exhibited by spontaneous thymic lymphomas.

 
When the status of microsatellite loci on chromosome 11 in liver DNA from tumor-bearing mice was determined, virtually all samples showed heterozygosity at all loci tested. Of the liver samples tested, 18% (5 of 27) showed loss of the 129/Sv allele at D11 Mit136, and 4 of these were from mice that exhibited loss of the 129/Sv allele at this locus in the thymic lymphoma. In addition, 18% (5 of 27) of liver samples showed loss of the 129/Sv allele at D11 Mit327, and 3 of these samples were from mice that also showed loss of the 129/Sv allele in the thymic lymphoma.


   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
The primary goal of the present study was to examine the mechanism of p53 loss in thymic lymphomas and provide insights into carcinogen-induced tumorigenesis in p53+/- mice. Loss of the functional p53 allele is a common event in tumors induced in these mice (8, 9, 10) and is consistent with loss of p53 function as a common feature of human tumors (1 , 2) . The mechanism of p53 loss in tumors is uncertain but is likely to occur by a two-step process. p53+/- mice have already undergone a first step of the process, the inactivation of one p53 allele. Therefore, these animals represent a valuable model to study the mechanisms of carcinogen-induced p53 loss.

The analysis of both benzene-induced and spontaneous thymic lymphomas in p53+/- mice revealed that LOH along chromosome 11 was a common feature of these tumors. The analysis of liver DNA from these animals indicated that LOH at a particular microsatellite locus occurs at a low frequency (9 of 189 loci tested) in non-tumor tissue. The high frequency of LOH at multiple microsatellite loci in tumor tissue suggests that the loss of the second p53 allele is not the result of a small genetic alteration, such as a point mutation or small deletion, but rather that the mechanism through which p53 is lost affects a large portion of chromosome 11. This may be the result of a gross deletion, genetic recombination, chromosomal loss, or nondisjunction followed by duplication. When the patterns of the induced and spontaneous tumors are compared, nearly 60% of the benzene-induced tumors showed the same pattern of LOH, but all six spontaneous tumors showed a unique pattern of LOH, five of which were not seen in the benzene-induced tumors. The predominance of common LOH patterns among the benzene-induced tumors and lack thereof in spontaneous tumors strongly suggest that benzene exposures are causal in the LOH patterns seen in the induced tumors.

Although most LOH at microsatellite loci observed in thymic lymphomas in this study involved loss of the C57BL/6 allele, 5% of LOH (11 of 231 loci tested) involved loss of the 129/Sv allele. Loss of the C57BL/6 allele correlates with loss of the functional p53 gene that resides on the C57BL/6-derived chromosome. In contrast, tumors that exhibited loss of the 129/Sv allele, which corresponds to the chromosome containing the disrupted p53 gene, did not show loss of the disrupted p53 gene. In addition, liver DNA samples from the same mice also exhibited loss of the 129/Sv allele at these loci. LOH at these loci could therefore be a reflection of instability at these loci or may be the consequence of meiotic recombination that occurred in parental germ cells.

Benzene is a clastogenic carcinogen that induces DNA strand breaks, chromosomal mutations, and aneuploidy in mammalian cells (reviewed in Ref. 13 ). As stated earlier, there are a number of pathways that could lead to the LOH observed in the benzene-induced thymic lymphomas such as deletions, recombination, chromosomal loss, or nondisjunction followed by duplication. Analysis of the copy number of disrupted p53 alleles showed that most (20 of 25) of the benzene-induced thymic lymphomas that showed loss of the wild-type p53 allele contained two copies of the disrupted allele. In addition, preliminary results from chromosome 11 painting indicate that the tumors contain two copies of chromosome 11.4 These data support that chromosome 11 LOH observed in these tumors is not the result of chromosomal loss but may be attributable to aberrant chromosomal recombination or nondisjunction followed by duplication. It is difficult to distinguish between these possibilities in the present study. However, recombination is a common mechanism by which heterozygous loci are reduced to homozygosity in mouse cells (14 , 15) as well as in human lymphocytes (16) . In addition, recombination at the glycophorin A locus occurs at an increased frequency in erythrocytes of humans exposed to benzene (17) . These studies support the LOH seen in the benzene-induced tumors occurring as a result of mitotic recombination.

LOH in human cancer is associated with the loss of a functional tumor suppressor gene. Retinoblastomas occur from LOH at the Rb locus at a young age in individuals who have inherited a mutated Rb gene, and these tumors have been studied to examine the genetic mechanisms involved in LOH of a tumor suppressor gene. The mechanisms responsible for LOH at the Rb locus in retinoblastoma tumors are primarily mitotic recombination and nondisjunction followed by duplication, and these occur at similar frequencies (18 , 19) . LOH on chromosome 3 or 7 has been implicated as a causal event in certain types of human leukemia (20 , 21) . Because the LOH at the p53 locus in the benzene-induced thymic lymphomas in the present study most likely involved mitotic recombination or nondisjunction followed by duplication, our results have relevance toward the mechanism of tumor suppressor loss in human tumorigenesis. In addition, analysis of human tumors for LOH of p53 have shown that loss of p53 can involve alteration of surrounding loci on chromosome 17 (22, 23, 24, 25) , suggesting that the mechanism(s) involved in p53 loss in benzene-induced thymic lymphomas reflect aspects of p53 loss in human tumors. The results support p53+/- mice as a useful animal model for studying mechanisms of p53 mutagenesis in tumor development.


   Acknowledgments
 
We acknowledge Dr. Laura N. Healy for her work on the benzene inhalation study. In addition, the expert technical assistance of Linda Pluta and the Inhalation and Necropsy staff at Chemical Industry Institute of Toxicology is also acknowledged. The critical review of the manuscript by Drs. Barbara Kuyper, Byron Butterworth, and Greg Kedderis is also greatly appreciated.


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  		Table 2 Results of LOH analysis of benzene-induced and spontaneous thymic lymphomas

 

   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 Chemical Industry Institute of Toxicology, 6 Davis Drive, Research Triangle Park, NC 27709. Phone: (919) 558-1329; Fax (919) 558-1300. Back

2 The abbreviation used is: LOH, loss of heterozygosity. Back

3 L. Recio, S. E. Boley, J. Everitt, R. A. James, D. Janszen, L. N. Healy, L. Pluta, K. Roberts, D. Walker, and J. E. French. Cancer bioassay and genotoxicity of inhaled benzene in p53+/- and C57Bl/6 mice, manuscript in preparation. Back

4 D. Abernethy and L. Recio, personal communication. Back

Received 12/ 9/99. Accepted 4/18/00.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

  1. Greenblatt M. S., Bennett W. P., Hollstein M., Harris C. C. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res., 54: 4855-4878, 1994.[Free Full Text]
  2. Hollstein M., Rice K., Greenblatt M. S., Soussi T., Fuchs R., Sorlie T., Hovig E., Smith-Sorensen B., Montesano R., Harris C. C. Database of p53 gene somatic mutations in human tumors and cell lines. Nucleic Acids Res., 22: 3551-3555, 1994.
  3. Ko L. J., Prives C. p53: puzzle and paradigm. Genes Dev., 10: 1054-1072, 1996.[Free Full Text]
  4. Livingstone L. R., White A., Sprouse J., Livanos E., Jacks T., Tlsty T. D. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell, 70: 923-935, 1992.[Medline]
  5. Harvey M., Sands A. T., Weiss R. S., Hegi M. E., Wiseman R. W., Pantazis P., Giovanella B. C., Tainsky M. A., Bradley A., Donehower L. A. In vitro growth characteristics of embryo fibroblasts isolated from p53-deficient mice. Oncogene, 8: 2457-2467, 1993.[Medline]
  6. Donehower L. A., Harvey M., Slagle B. L., McArthur M. J., Montgomery C. A., Jr., Butel J. S., Bradley A. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature (Lond.), 356: 215-221, 1992.[Medline]
  7. Donehower L. A. The p53-deficient mouse: a model for basic and applied cancer studies. Semin. Cancer Biol., 7: 269-278, 1996.[Medline]
  8. Harvey M., McArthur M. J., Montgomery C. A., Jr., Butel J. S., Bradley A., Donehower L. A. Spontaneous and carcinogen-induced tumorigenesis in p53-deficient mice. Nat. Genet., 5: 225-229, 1993.[Medline]
  9. Kemp C. J., Wheldon T., Balmain A. p53-deficient mice are extremely susceptible to radiation-induced tumorigenesis. Nat. Genet, 8: 66-69, 1994.[Medline]
  10. Dunnick J. K., Hardisty J. F., Herbert R. A., Seely J. C., Furedi-Machacek E. M., Foley J. F., Lacks G. D., Stasiewicz S., French J. E. Phenolphthalein induces thymic lymphomas accompanied by loss of the p53 wild type allele in heterozygous p53-deficient (+/-) mice. Toxicol. Pathol., 25: 533-540, 1997.[Abstract/Free Full Text]
  11. Venkatachalam S., Shi Y. P., Jones S. N., Vogel H., Bradley A., Pinkel D., Donehower L. A. Retention of wild-type p53 in tumors from p53 heterozygous mice: reduction of p53 dosage can promote cancer formation. EMBO J., 17: 4657-4667, 1998.[Medline]
  12. Timme T. L., Thompson T. C. Rapid allelotype analysis of p53 knockout mice. Biotechniques, 17: 462-463, 1994.
  13. Dean B. J. Recent findings on the genetic toxicology of benzene, toluene, xylenes and phenols. Mutat. Res., 154: 153-181, 1985.[Medline]
  14. Liechty M. C., Scalzi J. M., Sims K. R., Crosby H., Jr., Spencer D. L., Davis L. M., Caspary W. J., Hozier J. C. Analysis of large and small colony L5178Y tk-/- mouse lymphoma mutants by loss of heterozygosity (LOH) and by whole chromosome 11 painting: detection of recombination. Mutagenesis, 13: 461-474, 1998.[Abstract/Free Full Text]
  15. Preisler V., Caspary W. J., Hoppe F., Hagen R., Stopper H. Aflatoxin B1-induced mitotic recombination in L5178Y mouse lymphoma cells. Mutagenesis, 15: 91-97, 2000.[Abstract/Free Full Text]
  16. Morley A. A., Grist S. A., Turner D. R., Kutlaca A., Bennett G. Molecular nature of in vivo mutations in human cells at the autosomal HLA-A locus. Cancer Res., 50: 4584-4587, 1990.[Abstract/Free Full Text]
  17. Rothman N., Haas R., Hayes R. B., Li G-L., Wiemels J., Campleman S., Quintana P. J. E., Xi L-J., Dosemici M., Titenko-Holland N., Meyer K. B., Lu W., Zhang L. P., Bechtold W., Wang Y-Z., Kolachana P., Yin S-N., Blot W., Smith M. T. Benzene induces gene-duplicating but not gene-inactivating mutations at the glycophorin A locus in exposed humans. Proc. Natl. Acad. Sci. USA, 92: 4069-4073, 1995.[Abstract/Free Full Text]
  18. Zhu X., Dunn J. M., Goddard A. D., Squire J. A., Becker A., Phillips R. A., Gallie B. L. Mechanisms of loss of heterozygosity in retinoblastoma. Cytogenet. Cell Genet., 59: 248-252, 1992.[Medline]
  19. Hagstrom S. A., Dryja T. P. Mitotic recombination map of 13cen–13q14 derived from an investigation of loss of heterozygosity in retinoblastomas. Proc. Natl. Acad. Sci. USA, 96: 2952-2957, 1999.[Abstract/Free Full Text]
  20. Tanaka K., Mansoor A. M., Shigeta C., Oguma N., Kamada N. Loss of heterozygosity at D3S2 locus of short arm of chromosome 3 in chronic myelogenous leukemia. Cancer Genet. Cytogenet., 61: 42-45, 1992.[Medline]
  21. Kiuru-Kuhlefelt S., Kristo P., Ruutu T., Knuutila S., Kere J. Evidence for two molecular steps in the pathogenesis of myeloid disorders associated with deletion of chromosome 7 long arm. Leukemia (Baltimore), 11: 2097-2104, 1997.[Medline]
  22. Phillips N. J., Ziegler M. R., Radford D. M., Fair K. L., Steinbrueck T., Xynos F. P., Donis-Keller H. Allelic deletion on chromosome 17p13. 3 in early ovarian cancer. Cancer Res., 56: 606-611, 1996.
  23. Varley J. M., Thorncroft M., McGown G., Appleby J., Kelsey A. M., Tricker K. J., Evans D. G. R., Birch J. M. A detailed study of the loss of heterozygosity on chromosome 17 in tumours from Li-Fraumeni patients carrying a mutation to the TP53 gene. Oncogene, 14: 865-871, 1997.[Medline]
  24. Barrett M. T., Sanchez C. A., Prevo L. J., Wong D. L., Galipeau P. C., Paulson T. G., Rabinovitch P. S., Reid B. J. Evolution of neoplastic cell lineages in Barrett oesophagus. Nat. Genet., 22: 106-109, 1999.[Medline]
  25. Nunn J., Scholes A. G. M., Liloglou T., Nagini S., Jones A. S., Vaughan E. D., Gosney J. R., Rogers S., Fear S., Field J. K. Fractional allele loss indicates distinct genetic populations in the development of squamous cell carcinoma of the head and neck. Carcinogenesis (Lond.), 20: 2219-2228, 1999.[Abstract/Free Full Text]



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