Skip to main content

Advertisement

SpringerLink
Log in

Mutational Targets in Colorectal Cancer Cells with Microsatellite Instability

  • Published:
Familial Cancer Aims and scope Submit manuscript

Abstract

Cancers arise from the sequential acquisition of genetic alterations in specific genes. The high number of mutations in cancer cells led to the hypothesis that an early step in tumor progression is the generation of a genetic instability. The potent role of genetic instability in initiation and progression of colorectal cancers has been well defined in hereditary nonpolyposis colon cancer (HNPCC) syndrome. HNPCC is a common hereditary disorder caused by germline mutations of DNA mismatch repair (MMR) genes. Somatic loss of the normal allele of the predisposition gene leads to a strong “mutator phenotype”, characterized by a high rate of mutations in repetitive sequences. Nevertheless, the observation of frequent alterations of key growth regulatory genes in MMR-deficient cells such as NF1, APC, p53, K-Ras, with no significant excess of frameshift mutations and changes at short coding repeats, suggest that even in the presence of an inherited tendency to genomic instability, tumor progression is mainly driven by a process of natural selection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. AL Jackson LA Loeb (1998) ArticleTitleThe mutation rate and cancer Genetics 148 IssueID4 1483–90 Occurrence Handle1:CAS:528:DyaK1cXks1eitb8%3D Occurrence Handle9560368

    CAS  PubMed  Google Scholar 

  2. PC Nowell (1976) ArticleTitleThe clonal evolution of tumor cell populations Science 194 IssueID4260 23–8 Occurrence Handle1:STN:280:CSmB2s7hsFU%3D Occurrence Handle959840

    CAS  PubMed  Google Scholar 

  3. ER Fearon B Vogelstein (1990) ArticleTitleA genetic model for colorectal tumorigenesis Cell 61 IssueID5 759–67 Occurrence Handle10.1016/0092-8674(90)90186-I Occurrence Handle1:CAS:528:DyaK3cXktlyhtrg%3D Occurrence Handle2188735

    Article  CAS  PubMed  Google Scholar 

  4. CA Klein TJ Blankenstein O Schmidt-Kittler et al. (2002) ArticleTitleGenetic heterogeneity of single disseminated tumor cells in minimal residual cancer Lancet 360 IssueID9334 683–39 Occurrence Handle10.1016/S0140-6736(02)09838-0 Occurrence Handle1:CAS:528:DC%2BD38Xmsl2nsL0%3D Occurrence Handle12241875

    Article  CAS  PubMed  Google Scholar 

  5. LA Loeb CF Springgate N Battula (1974) ArticleTitleErrors in DNA replication as a basis of malignant changes Cancer Res 34 IssueID9 2311–21 Occurrence Handle1:CAS:528:DyaE2cXls1Ohs7g%3D Occurrence Handle4136142

    CAS  PubMed  Google Scholar 

  6. LA Loeb (2001) ArticleTitleA mutator phenotype in cancer Cancer Res 61 IssueID8 3230–39 Occurrence Handle1:CAS:528:DC%2BD3MXjtFSjt7k%3D Occurrence Handle11309271

    CAS  PubMed  Google Scholar 

  7. SN Thibodeau G Bren D Schaid (1993) ArticleTitleMicrosatellite instability in cancer of the proximal colon Science 260 816–19 Occurrence Handle1:CAS:528:DyaK3sXkt1GlsLs%3D Occurrence Handle8484122

    CAS  PubMed  Google Scholar 

  8. JR Eshleman G Casey ME Kochera et al. (1998) ArticleTitleChromosome number and structure both are markedly stable in RER colorectal cancers and are not destabilized by mutation of p53 Oncogene 17 719–25 Occurrence Handle10.1038/sj.onc.1201986 Occurrence Handle1:CAS:528:DyaK1cXls1SmsLc%3D Occurrence Handle9715273

    Article  CAS  PubMed  Google Scholar 

  9. P Peltomaki A Chapelle Particlede la (1997) ArticleTitleMutations predisposing to hereditary nonpolyposis colorectal cancer Adv Cancer Res 71 93–119 Occurrence Handle1:CAS:528:DyaK2sXjvVOkurw%3D Occurrence Handle9111864

    CAS  PubMed  Google Scholar 

  10. WS Saunders M Shuster X Huang et al. (2000) ArticleTitleChromosomal instability and cytoskeletal defects in oral cancer cells Proc Natl Acad Sci USA 97 303–8 Occurrence Handle1:CAS:528:DC%2BD3cXjvVGisA%3D%3D Occurrence Handle10618413

    CAS  PubMed  Google Scholar 

  11. B Beheshti PC Park JM Sweet et al. (2001) ArticleTitleEvidence of chromosomal instability in prostate cancer determined by spectral karyotyping (SKY) and interphase fish analysis Neoplasia 3 62–9 Occurrence Handle10.1038/sj.neo.7900125 Occurrence Handle1:CAS:528:DC%2BD3MXis1agu7k%3D Occurrence Handle11326317

    Article  CAS  PubMed  Google Scholar 

  12. C Lengauer KW Kinzler B Vogelstein (1998) ArticleTitleGenetic instabilities in human cancers Nature 396 643–49 Occurrence Handle10.1038/25292 Occurrence Handle1:CAS:528:DyaK1MXisVWqsQ%3D%3D Occurrence Handle9872311

    Article  CAS  PubMed  Google Scholar 

  13. C Lengauer KW Kinzler B Vogelstein (1997) ArticleTitleGenetic instability in colorectal cancers Nature 386 623–7 Occurrence Handle10.1038/386623a0 Occurrence Handle1:CAS:528:DyaK2sXisFCntrk%3D Occurrence Handle9121588

    Article  CAS  PubMed  Google Scholar 

  14. LA Loeb (1991) ArticleTitleMutator phenotype may be required for multistage carcinogenesis Cancer Res 51 IssueID12 3075–9 Occurrence Handle1:CAS:528:DyaK3MXksVKqsb8%3D Occurrence Handle2039987

    CAS  PubMed  Google Scholar 

  15. DP Cahill C Lengauer J Yu et al. (1998) ArticleTitleMutations of mitotic checkpoint genes in human cancers Nature 392 IssueID6673 300–3 Occurrence Handle1:CAS:528:DyaK1cXitFahsro%3D Occurrence Handle9521327

    CAS  PubMed  Google Scholar 

  16. JR Teyssier D Ferre (1989) ArticleTitleFrequent clonal chromosomal changes in human non-malignant tumors Int J Cancer 44 828–32 Occurrence Handle1:STN:280:By%2BD287ksFA%3D Occurrence Handle2583864

    CAS  PubMed  Google Scholar 

  17. S Anand S Penrhyn-Lowe AR Venkitaraman (2003) ArticleTitleAURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol Cancer Cell 3 51–2 Occurrence Handle10.1016/S1535-6108(02)00235-0 Occurrence Handle1:CAS:528:DC%2BD3sXhtFamt7Y%3D Occurrence Handle12559175

    Article  CAS  PubMed  Google Scholar 

  18. HT Lynch T Smyrk JF Lynch (1996) ArticleTitleOverview of natural history, pathology, molecular genetics and management of HNPCC (Lynch syndrome) Int J Cancer 69 38–43 Occurrence Handle10.1002/(SICI)1097-0215(19960220)69:1<38::AID-IJC9>3.0.CO;2-X Occurrence Handle1:STN:280:BymC1c%2FjtlU%3D Occurrence Handle8600057

    Article  CAS  PubMed  Google Scholar 

  19. P Modrich (1997) ArticleTitleStrand-specific mismatch repair in mammalian cells J Biol Chem 272 24727–30 Occurrence Handle10.1074/jbc.272.40.24727 Occurrence Handle1:CAS:528:DyaK2sXms1eitLo%3D Occurrence Handle9312062

    Article  CAS  PubMed  Google Scholar 

  20. N Papadopoulos A Lindblom (1997) ArticleTitleMolecular basis of HNPCC: Mutations of MMR Genes Hum Mutat 10 89–99 Occurrence Handle10.1002/(SICI)1098-1004(1997)10:2<89::AID-HUMU1>3.0.CO;2-H Occurrence Handle1:CAS:528:DyaK2sXls1Srsb0%3D Occurrence Handle9259192

    Article  CAS  PubMed  Google Scholar 

  21. LA Loeb (1994) ArticleTitleMicrosatellite instability: marker of a mutator phenotype in cancer Cancer Res 54 5059–63 Occurrence Handle1:STN:280:ByqD3cjltVA%3D Occurrence Handle7923117

    CAS  PubMed  Google Scholar 

  22. JR Eshleman EZ Lang GK Bowerfind et al. (1995) ArticleTitleIncreased mutation rate at the hprt locus accompanies microsatellite instability in colon cancer Oncogene 10 IssueID1 33–7 Occurrence Handle1:CAS:528:DyaK2MXjtVOru7Y%3D Occurrence Handle7824277

    CAS  PubMed  Google Scholar 

  23. MA Peinado S Malkhosyan A Velazquez et al. (1992) ArticleTitleIsolation and characterization of allelic losses and gains in colorectal tumors by arbitrarily primed polymerase chain reaction Proc Natl Acad Sci USA 89 IssueID21 10065–9 Occurrence Handle1:CAS:528:DyaK3sXitVWntw%3D%3D Occurrence Handle1359533

    CAS  PubMed  Google Scholar 

  24. N Ohmiya S Matsumoto H Yamamoto et al. (2001) ArticleTitleGermline and somatic mutations in hMSH6 and hMSH3 in gastrointestinal cancers of the microsatellite mutator phenotype Gene 272 301–13 Occurrence Handle10.1016/S0378-1119(01)00517-0 Occurrence Handle1:CAS:528:DC%2BD3MXltlGqsb0%3D Occurrence Handle11470537

    Article  CAS  PubMed  Google Scholar 

  25. SD Markowitz J Wang L Myeroff et al. (1995) ArticleTitleInactivation of the type II TGF-ß receptor in colon cancer cells with microsatellite Science 268 1336–8 Occurrence Handle1:CAS:528:DyaK2MXmtVartrk%3D Occurrence Handle7761852

    CAS  PubMed  Google Scholar 

  26. R Parsons LL Myeroff B Liu et al. (1995) ArticleTitleMicrosatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer Cancer Res 55 5548–50 Occurrence Handle1:CAS:528:DyaK2MXps1KrtLs%3D Occurrence Handle7585632

    CAS  PubMed  Google Scholar 

  27. S Malkhosyan N Rampino H Yamamoto et al. (1996) ArticleTitleFrameshift mutator mutations Nature 382 499–500 Occurrence Handle10.1038/382499a0 Occurrence Handle1:CAS:528:DyaK28XkvFGjsbg%3D Occurrence Handle8700220

    Article  CAS  PubMed  Google Scholar 

  28. N Rampino H Yamamoto Y Ionov et al. (1997) ArticleTitleSomatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype Science 275 967–9 Occurrence Handle10.1126/science.275.5302.967 Occurrence Handle1:CAS:528:DyaK2sXht1Cksrk%3D Occurrence Handle9020077

    Article  CAS  PubMed  Google Scholar 

  29. H Yamamoto H Sawai M Perucho (1997) ArticleTitleFrameshift somatic mutations in gastrointestinal cancer of the microsatellite mutator phenotype Cancer Res 57 4420–26 Occurrence Handle1:CAS:528:DyaK2sXmsFCgs7w%3D Occurrence Handle9331106

    CAS  PubMed  Google Scholar 

  30. H Ouyang T Furukawa T Abe Y Kato A Horii (1998) ArticleTitleThe BAX gene, the promoter of apoptosis, is mutated in genetically unstable cancers of the colorectum, stomach, and endometrium Clin Cancer Res 4 1071–1074 Occurrence Handle1:CAS:528:DyaK1cXisFeqsrg%3D Occurrence Handle9563904

    CAS  PubMed  Google Scholar 

  31. H Yamamoto H Sawai TK Weber et al. (1998) ArticleTitleSomatic frameshift mutations in DNA mismatch repair and proapoptosis genes in hereditary nonpolyposis colorectal cancer Cancer Res 58 997–1003 Occurrence Handle1:CAS:528:DyaK1cXhsFers7k%3D Occurrence Handle9500462

    CAS  PubMed  Google Scholar 

  32. M Konishi R Kikuchi-Yanoshita K Tanaka et al. (1996) ArticleTitleMolecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer Gastroenterology 111 IssueID2 307–17 Occurrence Handle10.1053/gast.1996.v111.pm8690195 Occurrence Handle1:CAS:528:DyaK28XkvFOnsLo%3D Occurrence Handle8690195

    Article  CAS  PubMed  Google Scholar 

  33. Q Wang C Lasset F Desseigne et al. (1999) ArticleTitleNeurofibromatosis and early onset of cancers in hMLH1-deficient children Cancer Res 59 294–7 Occurrence Handle1:CAS:528:DyaK1MXntFKrsA%3D%3D Occurrence Handle9927034

    CAS  PubMed  Google Scholar 

  34. MD Ricciardone T Ozcelik B Cevher et al. (1999) ArticleTitleHuman MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1 Cancer Res 59 290–3 Occurrence Handle1:CAS:528:DyaK1MXntFKrsw%3D%3D Occurrence Handle9927033

    CAS  PubMed  Google Scholar 

  35. S Vilkki JL Tsao A Loukola et al. (2001) ArticleTitleExtensive somatic microsatellite mutations in normal human tissue Cancer Res 61 4541–44 Occurrence Handle1:STN:280:DC%2BD3Mzhs1ejsw%3D%3D Occurrence Handle11389087

    CAS  PubMed  Google Scholar 

  36. D Whiteside R McLeod G Graham et al. (2002) ArticleTitleA homozygous germ-line mutation in human MSH2 gene predisposes to hematological malignancy and multiple café-au-lait spots Cancer Res 62 359–62 Occurrence Handle1:CAS:528:DC%2BD38XhtVyhsbo%3D Occurrence Handle11809679

    CAS  PubMed  Google Scholar 

  37. TE Raevaara AM Gerdes KE Lonnqvist et al. (2004) ArticleTitleHNPCC mutation MLH1 P648S makes the functional protein unstable, and homozygosity predisposes to mild neurofibromatosis type 1 Genes Chromosomes Cancer 40 IssueID3 261–5 Occurrence Handle10.1002/gcc.20040 Occurrence Handle1:CAS:528:DC%2BD2cXlsFWhtL8%3D Occurrence Handle15139004

    Article  CAS  PubMed  Google Scholar 

  38. GF Xu P O’Connell D Viskochil et al. (1990) ArticleTitleThe neurofibromatosis type 1 gene encodes a protein related to GAP Cell 62 599–608 Occurrence Handle10.1016/0092-8674(90)90024-9 Occurrence Handle1:CAS:528:DyaK3cXlt1Omt7w%3D Occurrence Handle2116237

    Article  CAS  PubMed  Google Scholar 

  39. SM Huson (1994) Neurofibromatosis: Historical perspective, classification and diagnostic criteria SM Huson RAC Hughes (Eds) The neurofibromatoses. A pathogenetic and clinical overview. Chapman & Hall Medical London 1–22

    Google Scholar 

  40. Upadhyaya M, Cooper DN. The mutational spectrum in neurofibromatosis type 1 and its underlying mechanisms. In Upadhyaya M. Cooper DN (eds): Neurofibromatosis Type 1, From Genotype to Phenotype. Oxford BIOS Scientific, 1998; 65–82

  41. Q Wang G Montmain E Ruano et al. (2003) ArticleTitleNeurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type Hum Genet 112 117–23 Occurrence Handle1:CAS:528:DC%2BD3sXisF2ntrc%3D Occurrence Handle12522551

    CAS  PubMed  Google Scholar 

  42. J Wang L Sun L Myeroff et al. (1995) ArticleTitleDemonstration that mutation of the type II transforming growth factor beta receptor inactivates its tumor suppressor activity in replication error-positive colon carcinoma cells J Biol Chem 270 IssueID37 22044–49 Occurrence Handle1:CAS:528:DyaK2MXotFait7g%3D Occurrence Handle7665626

    CAS  PubMed  Google Scholar 

  43. J Huang N Papadopoulos AJ McKinley et al. (1996) ArticleTitleAPC mutations in colorectal tumors with mismatch repair deficiency Proc Natl Acad Sci USA 93 IssueID17 9049–54 Occurrence Handle10.1073/pnas.93.17.9049 Occurrence Handle1:CAS:528:DyaK28Xlt1Chsrs%3D Occurrence Handle8799152

    Article  CAS  PubMed  Google Scholar 

  44. TF Homfray SE Cottrell M Ilyas et al. (1998) ArticleTitleDefects in mismatch repair occur after APC mutations in the pathogenesis of sporadic colorectal tumors Hum Mutat 11 IssueID2 114–20 Occurrence Handle10.1002/(SICI)1098-1004(1998)11:2<114::AID-HUMU3>3.0.CO;2-J Occurrence Handle1:CAS:528:DyaK1cXhtVGjtbo%3D Occurrence Handle9482574

    Article  CAS  PubMed  Google Scholar 

  45. OM Sieber K Heinimann IP Tomlinson (2003) ArticleTitleGenomic instability-the engine of tumorigenesis? Nat Rev Cancer 3 IssueID9 701–8 Occurrence Handle10.1038/nrc1170 Occurrence Handle1:CAS:528:DC%2BD3sXmvVWksr8%3D Occurrence Handle12951589

    Article  CAS  PubMed  Google Scholar 

  46. NJ Hawkins I Tomlinson A Meagher et al. (2001) ArticleTitleMicrosatellite-stable diploid carcinoma: a biologically distinct and aggressive subset of sporadic colorectal cancer Br J Cancer 84 232–6 Occurrence Handle10.1054/bjoc.2000.1554 Occurrence Handle1:STN:280:DC%2BD3M7ktFyhuw%3D%3D Occurrence Handle11161382

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Unité d’Oncologie Moléculaire and Unité INSERM U590, Centre Léon Bérard, 28 rue Laënnec, 69008, Lyon, France

    Jacques Bertholon, Qing Wang, Carlos Maria Galmarini & Alain Puisieux

  2. Faculté de Pharmacie (ISPB), Université Claude Bernard Lyon I, 8 avenue Rockefeller, 69008, Lyon, France

    Jacques Bertholon & Alain Puisieux

Authors
  1. Jacques Bertholon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carlos Maria Galmarini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alain Puisieux
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alain Puisieux.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bertholon, J., Wang, Q., Galmarini, C.M. et al. Mutational Targets in Colorectal Cancer Cells with Microsatellite Instability. Familial Cancer 5, 29–34 (2006). https://doi.org/10.1007/s10689-005-2573-5

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10689-005-2573-5

Keywords

Search

Navigation