Cancer Research Annual Meeting 2010 Sign up for Cancer Research eTOC's
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Vilkki, S.
Right arrow Articles by Shibata, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Vilkki, S.
Right arrow Articles by Shibata, D.
[Cancer Research 61, 4541-4544, June 1, 2001]
© 2001 American Association for Cancer Research

Regular Articles

Extensive Somatic Microsatellite Mutations in Normal Human Tissue1

Susa Vilkki, Jen-Lan Tsao, Anu Loukola, Minna Pöyhönen, Outi Vierimaa, Riitta Herva, Lauri A. Aaltonen and Darryl Shibata2

Department of Medical Genetics, University of Helsinki, FIN-00014 Helsinki, Finland [S. V., A. L., L. A. A.]; Department of Pathology, Norris Cancer Center, University of Southern California School of Medicine, Los Angeles, California 90033 [J-L. T., D. S.]; Departments of Pathology [R. H.] and Clinical Genetics [O. V.], Oulu University Hospital, FIN-90220 Oulu, Finland; and The Family Federation of Finland, FIN-00101 Helsinki, Finland [M. P.]


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Microsatellite (MS) instability occurs in tumors with DNA mismatch repair (MMR) deficiencies but is typically absent in adjacent normal tissue. However, MS mutations have been observed in normal tissues from rare individuals with congenital MMR deficiencies. Autopsy tissues from a 4-year-old with congenital MMR deficiency (MLH1-/-) were examined for MS mutations. Insertions and deletions were observed in CA-repeat MS loci. Approximately 0.26 to 1.4 mutations per MS locus per cell were estimated to be present in normal heart, lymph node, kidney, and bladder epithelium. These findings illustrate that phenotypically normal MMR-deficient cells commonly accumulate MS mutations. Loss of MMR and the accumulation of some MS mutations may occur early in MMR-deficient tumor progression, even before a gatekeeper mutation.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Normal human tissues harbor somatic mutations at low frequencies. For example, HPRT mutation frequencies reach approximately 10-4 in normal adult epithelial cells (1) . Mutations in normal tissues can also be detected in some patients with cancer (2 , 3) but tumors generally contain many more mutations (4 , 5) . Mutation frequencies increase with histological progression (6) , which suggests that genomic instability increases with progression (7) .

Genetic progression is synonymous with histological progression because tumors are the only natural sources of cells with large numbers of somatic mutations. Although clonal expansion facilitates detection, mutations in normal cells may be rare because of high replication fidelity and efficient recognition and repair of DNA damage (4 , 5 , 8) . Cells with DNA damage often fail to progress through cell cycle checkpoints and may be eliminated through apoptosis (9) .

Rare individuals have congenital defects in MMR3 because of bi-allelic or dominant negative germ-line mutations (10, 11, 12) . Such individuals, similar to MMR-deficient mice (13) , are tumor prone but otherwise develop normally. Mutations in simple repeat sequences or MS loci, characteristic of MMR deficiencies (14) , are present in their phenotypically normal tissues (10, 11, 12) . Here, we identify another such individual and perform a quantitative mutation analysis to determine whether the large numbers of mutations expected to occur in the absence of MMR accumulate in the absence of tumorigenesis.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient.
An asymptomatic 4-year-old female died unexpectedly of hemorrhage caused by a glioma, and genotyping (15) revealed her to be homozygous for a germ-line exon 16 MLH1 deletion. Tissues saved at autopsy were brain, kidney, heart, liver, bladder, lymph node, and glioma.

MS Analysis.
DNA was extracted from fixed autopsy brain, kidney, heart, lymph node, and microdissected bladder epithelium. For controls, DNA was isolated from lymphocytes and fixed normal colon from MMR-proficient individuals. CA-repeat MS loci DXS556, 1060, and 453 were amplified using 42 cycles and incorporating 33dCTP during PCR (16) . The DNA was extensively diluted before PCR and ~30–70% of reactions had products that suggested that most products represented single molecules. Between 42 and 56 molecules were genotyped for each autopsy tissue at each locus. Frameshifts in the A-10 region of TGFBRII were assayed by dilution and PCR (17 , 18) of DNA isolated from peripheral blood lymphocytes.

Quantitative Analysis.
MS alleles were plotted as frequency size distributions. Variances were calculated for the unimodal distributions of DXS556, and separately for each of the modes of DXS1060 and DXS453. Assuming stepwise mutation and starting with germ-line-sized alleles in all of the cells, the variance of a MS frequency distribution is approximately equal to the average number of mutations at the locus (16) . For example, with a variance of 1, on average, each locus has mutated once, although there will be a distribution of allele sizes among cells. This analysis can count absolute numbers of single repeat unit changes, although counteracting stepwise additions and deletions will tend to return mutant alleles back to germ-line sizes. Numbers of division are estimated by: number of divisions = number of mutations ÷ mutation rate.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Autopsy of an untreated, asymptomatic 4-year-old female revealed brain hemorrhage, caused by a glioma, and cafe au lait spots including multiple axillary freckles characteristic of neurofibromatosis type 1. No other abnormalities were found. Both parents had familial histories of HNPCC with heterozygous germ-line exon 16 MLH1 deletions. Genotyping revealed inheritance of the HNPCC mutation from both parents because the patient was homozygous (MLH1-/-) for the exon 16 deletion (Fig. 1)Citation .



View larger version (28K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 1. MLH1 exon 16 deletion genotyping. Wild-type allele yields a 475-bp PCR fragment, whereas the mutant allele produces a 634-bp fragment. The 4-year-old patient (b) harbors a homozygous deletion of MLH1 exon 16 (MLH1-/-). Positive HNPCC (MLH1+/-, a, c–e) and wild-type (f) controls are illustrated.

 
DNA was extracted from normal heart, kidney, lymph node, and bladder epithelium. Other tissues such as the colon or the brain were unavailable, or their DNA was too degraded for analysis. Sizes of CA-repeat MS alleles were determined by dilution to essentially single copies followed by PCR (Fig. 2Citation ; Table 1Citation ). Somatic mutations were commonly present in the MLH1-/- autopsy tissues (15–32% mutant alleles) but not in MMR-proficient control tissues (<5% mutant alleles). Stepwise mutations lead to progressively broader allele distributions centered around germ-line sizes (16) . Consistent with stepwise mutation, allele frequency distribution modes (unimodal for DXS556 and bimodal for DXS1060 and DXS453) were identical between tissues and likely represent germ-line allele sizes (Fig. 3)Citation . Variances were between 0.26 and 1.4 and were similar among tissues (Table 1Citation ; Fig. 4aCitation ), which suggested approximately equal numbers of mutations because numbers of MS mutations are proportional to variances of MS mutation frequency distributions (16) . Frameshift mutations in the A-10 coding region of TGFBRII were not increased in lymphocytes compared with a MMR-proficient control individual when ~100 molecules were examined (Table 1)Citation .



View larger version (43K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 2. Autoradiographs of DXS453 MS alleles from DNA diluted from normal MLH1-/- kidney (a) or MMR-proficient lymphocytes (b). {blacktriangleup}, mutant alleles; {triangleup}, germ-line alleles.

 

View this table:
[in this window]
[in a new window]

  		Table 1 Mutation data

 


View larger version (34K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 3. MS allele frequency distributions. a, distributions from normal tissues of the MLH1-/- autopsy. Circled, distribution modes allele sizes (likely represent germ-line alleles). b, comparisons with other MMR-deficient tissues; 41-day-old xenograft of the MLH1-/- colon cancer cell line HCT116 (data from Ref. 35 ), MMR-proficient male lymphocytes (no mutations), and a MLH1-/- HNPCC colon tumor (data from Ref. 16 ).

 


View larger version (20K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 4. Variances of MS allele frequency distributions. a, variances of the MLH1-/- normal tissues. The variances for DXS1060 and DXS453 represent averages of their two distribution modes. b, variances of other MMR-deficient tissues. Variances of normal intestines of pms2-deficient mice increase with age (23) from 53 to 407 days.

 
For comparison, frequency distributions from MSI+ tumors are generally broader than from the MMR-deficient normal tissues (Fig. 3b)Citation . However, the MMR-deficient normal tissues contained greater numbers of MS mutations compared with a 47-day-old xenograft of the MMR-deficient tumor cell line HCT116 or intestines from a 53-day-old MMR-deficient (pms2-/-) mouse (Fig. 3b)Citation . By 1 year of age the variances of the repair-deficient murine intestines exceeded most of the variances observed in the normal autopsy tissues (Fig. 4b)Citation .


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Somatic MS mutations have been detected in normal tissues of individuals with congenital MMR deficiencies (10, 11, 12) . Here, we further analyze autopsy tissues of one such 4-year-old MLH1-deficient individual and demonstrate that large numbers of MS mutations are compatible with normal phenotypes. MS mutations are a function of cell division because slippage occurs during DNA replication (14) . Assuming stepwise MS mutation, allele frequency distributions estimate mutation numbers (16) . The observed variances (between 0.26 and 1.4) represent, on average, 0.26–1.4 mutations per MS locus per cell. Therefore, virtually all of the normal cells contained mutations considering the thousands of MS loci per genome. Assuming a MS mutation rate consistent with tissue culture studies (5 x 10-3 per division; Refs. 19 , 20 ), the cells divided about 52–280 times.

Mutations may be rare in normal tissues because cells with DNA damage can fail to progress through the cell cycle (9) . However, MLH1-deficient cell lines exhibit G2-M checkpoint deficiencies in response to agents that form mispairs (21) , which may allow MLH1-deficient normal cells to divide despite unrepaired slippage. In addition, DNA damage is less than the mutation burden because most base mispairs would be corrected after the next DNA replication. These somatic mutations are detectable by experimental comparisons, but a cell could not easily recognize a previously mispaired base. Many MS mutations could accumulate despite intact checkpoint mechanisms because damage during any single cell cycle may be below an activation threshold. For example, base substitution frequencies are similar regardless of p53 status (22) .

Although MSI+ tumors and these normal tissues both lack MLH1, MSI+ colorectal tumors have greater numbers of MS mutations (about 10 mutations per locus) and exhibit modal shifts from germ line (16) . More mutations in MSI+ tumors may simply reflect greater numbers of divisions between loss of MMR and tumor removal as MMR-deficient cells accumulate mutations with division (16 , 19 , 20 , 23) . The fewer numbers of mutations in the normal tissues are consistent with their lack of mitotic activity and the young age of death. Lymphocytes may undergo variable numbers of divisions, but the majority divide infrequently (24) . The only available epithelium came from the bladder, which is not characterized by high turnover (25) . Of note, frequencies of single-base alterations but not dinucleotide MS mutations vary with specific MMR component deficiencies (26) , and mutations inactivating p53 or leading to chromosomal instability and aneuploidy are rare in MSI+ colorectal cancers (6 , 27 , 28) .

Numbers of divisions should correlate with numbers of mutations in noncoding MS loci and coding loci. Tumor suppressor genes such as APC, TGFBRII, and BAX frequently have frameshift mutations characteristic of MMR deficiency in MSI+ tumors (18 , 29 , 30) . Base substitutions and short mononucleotide repeat deletions are increased ~100-fold with MMR deficiency (31 , 32) , but they would still be relatively rare, with mutation rates approximately 10-5 to 10-6 per division versus the 10-2 to 10-3 estimated for CA-repeat MS loci (19 , 20 , 33) . Consistent with these estimates, whereas CA-repeat mutations were between 0.26 and 1.4 per cell per locus, somatic mutations in the A-10 region of TGFBRII were not increased compared with MMR-proficient controls when ~100 molecules were examined.

A combination of mutations are needed for transformation of human cells (34) , and, therefore, some tumor mutations may accumulate in the absence of histological alterations or prior to a gatekeeper mutation (6) . Somatic mutations have been described in normal but presumably clonally expanded tissues adjacent to cancers (2 , 3) . The present study illustrates that large numbers of noncoding MS mutations can accumulate in normal tissues in the absence of tumorigenesis or abnormal clonal expansion. The prevalence and length of an occult period in which mutations accumulate before a gatekeeper mutation is an uncharacterized challenge. A molecular tumor clock analysis suggests that this interval can be long because the majority of somatic MS mutations may accumulate before clinically detectable tumorigenesis (16) .


   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 National Cancer Institute Grant CA70858. Back

2 To whom requests for reprints should be addressed, at Department of Pathology, Norris Cancer Center, University of Southern California School of Medicine, Los Angeles, CA 90033. E-mail: dshibata{at}hsc.usc.edu Back

3 The abbreviations used are: MS, microsatellite; MMR, mismatch repair; HNPCC, hereditary nonpolyposis colorectal cancer; MSI+, mutator phenotype. Back

Received 11/ 3/00. Accepted 4/ 3/01.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Martin G. M., Ogburn C. E., Colgin L. M., Gown A. M., Edland S. D., Monnat R. J., Jr. Somatic mutations are frequent and increase with age in human kidney epithelial cells. Hum. Mol. Genet., 5: 215-221, 1996.[Abstract/Free Full Text]
  2. Park I. W., Wistuba I. I., Maitra A., Milchgrub S., Virmani A. K., Minna J. D., Gazdar A. F. Multiple clonal abnormalities in the bronchial epithelium of patients with lung cancer. J. Natl. Cancer Inst. (Bethesda), 91: 1863-1868, 1999.[Abstract/Free Full Text]
  3. Deng G., Lu Y., Zlotnikov G., Thor A. D., Smith H. S. Loss of heterozygosity in normal tissue adjacent to breast carcinomas. Science (Wash. DC), 274: 2057-2059, 1996.[Abstract/Free Full Text]
  4. Loeb L. A. Mutator phenotype may be required for multistage carcinogenesis. Cancer Res., 51: 3075-3079, 1991.[Free Full Text]
  5. Loeb L. A. Cancer cells exhibit a mutator phenotype. Adv. Cancer Res., 72: 25-56, 1998.[Medline]
  6. Kinzler K. W., Vogelstein B. Lessons from hereditary colorectal cancer. Cell, 87: 159-170, 1996.[Medline]
  7. Nowell P. C. The clonal evolution of tumor cell populations. Science (Wash. DC), 194: 23-28, 1976.[Abstract/Free Full Text]
  8. Kunkel T. A., Bebenek K. DNA replication fidelity. Annu. Rev. Biochem., 69: 497-529, 2000.[Medline]
  9. Wang J. Y. Cellular responses to DNA damage. Curr. Opin. Cell. Biol., 10: 240-247, 1998.[Medline]
  10. Parsons R., Li G. M., Longley M., Modrich P., Liu B., Berk T., Hamilton S. R., Kinzler K. W., Vogelstein B. Mismatch repair deficiency in phenotypically normal human cells. Science (Wash. DC), 268: 738-740, 1995.[Abstract/Free Full Text]
  11. Ricciardone M. D., Ozcelik T., Cevher B., Ozdag H., Tuncer M., Gurgey A., Uzunalimoglu O., Cetinkaya H., Tanyeli A., Erken E., Ozturk M. Human MLH1 deficiency predisposes to hematological malignancies and neurofibromatosis type 1. Cancer Res., 59: 290-293, 1999.[Abstract/Free Full Text]
  12. Wang Q., Lasset C., Desseigne F., Frappaz D., Bergeron C., Navarro C., Ruano E., Puisieux A. Neurofibromatosis and early onset of cancers in hMLH1-deficient children. Cancer Res., 59: 294-297, 1999.[Abstract/Free Full Text]
  13. Prolla T. A., Abuin A., Bradley A. DNA mismatch repair deficient mice in cancer research. Semin. Cancer Biol., 7: 241-247, 1996.[Medline]
  14. Strand M., Prolla T. A., Liskay R. M., Petes T. D. Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair. Nature (Lond.), 365: 274-276, 1993.[Medline]
  15. Nystrom-Lahti M., Kristo P., Nicolaides N. C., Chang S. Y., Aaltonen L. A., Moisio A. L., Jarvinen H. J., Mecklin J. P., Kinzler K. W., Vogelstein B., et al Founding mutations and Alu-mediated recombination in hereditary colon cancer. Nat. Med., 1: 1203-1206, 1995.[Medline]
  16. Tsao J. L., Yatabe Y., Salovaara R., Jarvinen H. J., Mecklin J. P., Aaltonen L. A., Tavaré S., Shibata D. Genetic reconstruction of individual colorectal tumor histories. Proc. Natl. Acad. Sci. USA, 97: 1236-1241, 2000.[Abstract/Free Full Text]
  17. Loukola A., Salovaara R., Kristo P., Moisio A. L., Kaariainen H., Ahtola H., Eskelinen M., Harkonen N., Julkunen R., Kangas E., Ojala S., Tulikoura J., Valkamo E., Jarvinen H., Mecklin J. P., de la Chapelle A., Aaltonen L. A. Microsatellite instability in adenomas as a marker for hereditary nonpolyposis colorectal cancer. Am. J. Pathol., 155: 1849-1853, 1999.[Abstract/Free Full Text]
  18. Markowitz S., Wang J., Myeroff L., Parsons R., Sun L., Lutterbaugh J., Fan R. S., Zborowska E., Kinzler K. W., Vogelstein B., et al Inactivation of the type II TGF-B receptor in colon cancer cells with microsatellite instability. Science (Wash. DC), 268: 1336-1338, 1995.[Abstract/Free Full Text]
  19. Bhattacharyya N. P., Skandalis A., Ganesh A., Groden J., Meuth M. Mutator phenotypes human colorectal carcinoma cell lines. Proc. Natl. Acad. Sci. USA, 91: 6319-6323, 1994.[Abstract/Free Full Text]
  20. Shibata D., Peinado M. A., Ionov Y., Malkhosyan S., Perucho M. Genomic instability in simple repeat sequences is a very early somatic event in colorectal tumorigenesis that persists after transformation. Nat. Genet., 6: 273-281, 1994.[Medline]
  21. Hawn M. T., Umar A., Carethers J. M., Marra G., Kunkel T. A., Boland C. R., Koi M. Evidence for a connection between the mismatch repair system and the G2 cell cycle checkpoint. Cancer Res., 55: 3721-3725, 1995.[Abstract/Free Full Text]
  22. Sands A. T., Suraokar M. B., Sanchez A., Marth J. E., Donehower L. A., Bradley A. p53 deficiency does not affect the accumulation of point mutations in a transgene target. Proc. Natl. Acad. Sci. USA, 92: 8517-8521, 1995.[Abstract/Free Full Text]
  23. Tsao J. L., Davis S. D., Baker S. M., Liskay R. M., Shibata D. Intestinal stem cell divisions and genetic diversity: a computer and experimental analysis. Am. J. Pathol., 151: 573-579, 1997.[Abstract]
  24. Sprent J., Tough D. F. Lymphocyte life-span and memory. Science (Wash. DC), 265: 1395-400, 1994.[Abstract/Free Full Text]
  25. Limas C. Proliferative state of the urothelium with benign and atypical changes. Correlation with transferrin and epidermal growth factor receptors and blood group antigens. J. Pathol., 171: 39-47, 1993.[Medline]
  26. Yao X., Buermeyer A. B., Narayanan L., Tran D., Baker S. M., Prolla T. A., Glazer P. M., Liskay R. M., Arnheim N. Different mutator phenotypes in Mlh1- versus Pms2-deficient mice. Proc. Natl. Acad. Sci. USA, 96: 6850-6855, 1999.[Abstract/Free Full Text]
  27. Simms L. A., Radford-Smith G., Biden K. G., Buttenshaw R., Cummings M., Jass J. R., Young J., Meltzer S. J., Leggett B. A. Reciprocal relationship between the tumor suppressors p53 and BAX in primary colorectal cancers. Oncogene, 17: 2003-2008, 1998.[Medline]
  28. Lengauer C., Kinzler K. W., Vogelstein B. Genetic instability in colorectal cancers. Nature (Lond.), 386: 623-627, 1997.[Medline]
  29. Huang J., Papadopoulos N., McKinley A. J., Farrington S. M., Curtis L. J., Wyllie A. H., Zheng S., Willson J. K. V., Markowitz S. D., Morin P., Kinzler K. W., Vogelstein B., Dunlop M. G. APC mutations in colorectal tumors with mismatch repair deficiency. Proc. Natl. Acad. Sci. USA, 93: 9049-9054, 1996.[Abstract/Free Full Text]
  30. Rampino N., Yamamoto H., Ionov Y., Li Y., Sawai H., Reed J. C., Perucho M. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science (Wash. DC), 275: 967-969, 1997.[Abstract/Free Full Text]
  31. Narayanan L., Fritzell J. A., Baker S. M., Liskay R. M., Glazer P. M. Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene Pms2. Proc. Natl. Acad. Sci. USA, 94: 3122-3127, 1997.[Abstract/Free Full Text]
  32. Andrew S. E., Xu X. S., Baross-Francis A., Narayanan L., Milhausen K., Liskay R. M., Jirik F. R., Glazer P. M. Mutagenesis in PMS2- and MSH2-deficient mice indicates differential protection from transversions and frameshifts. Carcinogenesis (Lond.), 21: 1291-1295, 2000.[Abstract/Free Full Text]
  33. Eshleman J. R., Lang E. Z., Bowerfind G. K., Parsons R., Vogelstein B., Willson J. K., Veigl M. L., Sedwick W. D., Markowitz S. D. Increased mutation rate at the hprt locus accompanies microsatellite instability in colon cancer. Oncogene, 10: 33-37, 1995.[Medline]
  34. Hahn W. C., Counter C. M., Lundberg A. S., Beijersbergen R. L., Brooks M. W., Weinberg R. A. Creation of human tumour cells with defined genetic elements. Nature (Lond.), 400: 464-468, 1999.[Medline]
  35. Tsao J. L., Zhang J., Salovaara R., Li Z. H., Jarvinen H. J., Mecklin J. P., Aaltonen L. A., Shibata D. Tracing cell fates in human colorectal tumors from somatic microsatellite mutations: evidence of adenomas with stem cell architecture. Am. J. Pathol., 153: 1189-1200, 1998.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Cancer Res.Home page
H. Feitsma, R. V. Kuiper, J. Korving, I. J. Nijman, and E. Cuppen
Zebrafish with Mutations in Mismatch Repair Genes Develop Neurofibromas and Other Tumors
Cancer Res., July 1, 2008; 68(13): 5059 - 5066.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
E. C. Chao and S. M. Lipkin
Molecular models for the tissue specificity of DNA mismatch repair-deficient carcinogenesis
Nucleic Acids Res., February 6, 2006; 34(3): 840 - 852.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
S. Gill, N. M. Lindor, L. J. Burgart, R. Smalley, O. Leontovich, A. J. French, R. M. Goldberg, D. J. Sargent, J. R. Jass, J. L. Hopper, et al.
Isolated Loss of PMS2 Expression in Colorectal Cancers: Frequency, Patient Age, and Familial Aggregation
Clin. Cancer Res., September 15, 2005; 11(18): 6466 - 6471.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
M. R. Campbell, P. N. Nation, and S. E. Andrew
A Lack of DNA Mismatch Repair on an Athymic Murine Background Predisposes to Hematologic Malignancy
Cancer Res., April 1, 2005; 65(7): 2626 - 2635.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
H. Alazzouzi, E. Domingo, S. Gonzalez, I. Blanco, M. Armengol, E. Espin, A. Plaja, S. Schwartz, G. Capella, and S. Schwartz Jr
Low levels of microsatellite instability characterize MLH1 and MSH2 HNPCC carriers before tumor diagnosis
Hum. Mol. Genet., January 15, 2005; 14(2): 235 - 239.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
M. R. Velangi, E. C. Matheson, G. J. Morgan, G. H. Jackson, P. R. Taylor, A. G. Hall, and J. A.E. Irving
DNA mismatch repair pathway defects in the pathogenesis and evolution of myeloma
Carcinogenesis, October 1, 2004; 25(10): 1795 - 1803.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
P. Calabrese, J.-L. Tsao, Y. Yatabe, R. Salovaara, J.-P. Mecklin, H. J. Jarvinen, L. A. Aaltonen, S. Tavare, and D. Shibata
Colorectal Pretumor Progression Before and After Loss of DNA Mismatch Repair
Am. J. Pathol., April 1, 2004; 164(4): 1447 - 1453.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
J.-L. Tsao, S. Dudley, B. Kwok, A. E. Nickel, P. W. Laird, K. D. Siegmund, R. M. Liskay, and D. Shibata
Diet, cancer and aging in DNA mismatch repair deficient mice
Carcinogenesis, November 1, 2002; 23(11): 1807 - 1810.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
K.-M. Kim, R. Salovaara, J.-P. Mecklin, H. J. Jarvinen, L. A. Aaltonen, and D. Shibata
PolyA Deletions in Hereditary Nonpolyposis Colorectal Cancer : Mutations Before a Gatekeeper
Am. J. Pathol., April 1, 2002; 160(4): 1503 - 1506.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
D. Whiteside, R. McLeod, G. Graham, J. L. Steckley, K. Booth, M. J. Somerville, and S. E. Andrew
A Homozygous Germ-Line Mutation in the Human MSH2 Gene Predisposes to Hematological Malignancy and Multiple Cafe-au-Lait Spots
Cancer Res., January 1, 2002; 62(2): 359 - 362.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
A. L. Bacon, M. G. Dunlop, and S. M. Farrington
Hypermutability at a poly(A/T) tract in the human germline
Nucleic Acids Res., November 1, 2001; 29(21): 4405 - 4413.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Vilkki, S.
Right arrow Articles by Shibata, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Vilkki, S.
Right arrow Articles by Shibata, D.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online