Due to major developments in genetics over the past decade, molecular biology tests are serving promising tools in early diagnosis and follow-up of cancer patients. Recent epidemiological studies revealed that the risk for each individual to develop cancer is closely linked to his/her own genetic potentialities. Some populations that are defective in DNA repair processes, for example in Xeroderma pigmentosum or in the Lynch syndrome, are particularly prone to cancer due to the accumulation of mutations within the genome. Such populations would benefit from the development of tests aimed at identifying people who are particularly at risk. Here, we review some data suggesting that the inactivation of mismatch repair is often found in endometrial cancer and we discuss molecular-based strategies that would help to identify the affected individuals in families with cases of glandular malignancies.
SidranskyD.Nucleic acid based methods for the detection of cancer. Science278: 1054–1058, 1997.
2.
TonioloP, BoffetaP, ShukerDEG, RothmanN, HulkaB, PearceN.Application of Biomarkers in Cancer Epidemiology. Lyon, France: IARC Scientific Publications, no. 142, 1998.
3.
ParsonsBL, HefflichRH. Genotypic selection method for the direct analysis of point mutations. Mutat Res387: 97–121, 1997.
4.
BurnoufDY, MiturskiR, NagaoM, NakagamaH, NothisenM, WagnerJ, FuchsRPP. Early detection of 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP)-induced mutations within the APC gene of rat colon. Carcinogenesis22: 329–335, 2001.
5.
KirkwoodTB. DNA, mutations and aging. Mutat Res219: 1–7, 1989.
6.
JacksonAL, LoebLA. The mutation rate and cancer. Genetics148: 1483–1490, 1998.
7.
CooperDN, KrawczakM.The mutational spectrum of single base-pair substitutions causing human genetic disease: pattern and predictions. Hum Genet85: 55–74, 1990.
8.
LindahlT.Instability and decay of the primary structure of DNA. Nature362: 709–714, 1993.
9.
LindahlT, WoodR.Quality control by DNA Repair. Science286: 1897–1905, 1999.
10.
LivnehZ, Cohen-FixO, SkaliterR, ElizurT.Replication of damaged DNA and the molecular mechanisms of UV light mutagenesis. Crit Rev Biochem Mol Biol28: 465–513, 1993.
11.
RuppWD, Howard-FlandersP.Discontinuities in the DNA synthesized in an excision-defective strain of Escherichia coli following ultraviolet radiation. J Mol Biol31: 291–304, 1968.
12.
HigginsNP, KatoK, StraussB.A model for replication repair in mammalian cells. J Mol Biol101: 417–425, 1976.
BridgesBA, WoodgateR.The two step model of bacterial UV mutagenesis. Mutat Res150: 133–139, 1985.
15.
WoodgateR.A plethora of lesion-replicating DNA polymerases. Genes Dev13: 2191–2195, 1999.
16.
NapolitanoR, Janel-BintzR, WagnerJ, FuchsRPP. All three SOS-inducible DNA polymerases (Pol II, Pol IV and Pol V) are involved in induced mutagenesis. EMBO J19: 1–7, 2000.
17.
ModrichP.Mechanisms and biological effect of mismatch repair. Annu Rev Genet25: 229–253, 1991.
18.
ModrichP.Strand specific mismatch repair in mammalian cells. J Biol Chem272: 24727–24730, 1997.
19.
JiricnyJ.Replication errors: cha(lle)nging the genome. EMBO J17: 6427–6436, 1998.
20.
DrummondJT, LiGM, LongleyJ, ModrichP.Isolation of an hMSH2-p160 heterodimer that restore DNA mismatch repair to tumor cells. Science268: 1909–1912, 1995.
21.
PalomboF, GallinariP, IaccarinoI, LettieriT, HughesM, D'arrigoA, TruongO, HsuanJJ, JiricnyJ.GTBP, a 160-kilodalton protein essential for mismatch-binding activity in human cells. Science268: 1912–1914, 1995.
22.
AlaniE.The Saccharomyces cerevisiae Msh2 and Msh6 proteins form a complex that specifically binds to duplex oligonucleotides containing mismatched DNA base pairs. Mol Cell Biol16: 5604–5615, 1996.
23.
PalomboF, IaccarinoI, NakajimaE, IkejimaM, ShimadaT, JiricnyJ.hMutSβ, a heterodimer of hMSH2 and hMSH3, binds to insertion/deletion loops in DNA. Curr Biol6: 1181–1184, 1996.
24.
GenschelJ, LittmanSJ, DrummondJT, ModrichP.Isolation of MutSβ from human cells and comparison of the mismatch repair specificities of MutSβ and MutSα. J Biol Chem273: 19895–19901, 1998.
25.
HabrakenY, SungP, PrahashL, PrakshS.Binding of insertion/deletion DNA mismatches by the heterodimer of yeast mismatch repair proteins MSH2 and MSH3. Curr Biol6: 1185–1187, 1996.
26.
BlackwellLJ, MartikD, BjornsonKP, BjornsonES, ModrichP.Nucleotide-promoted release of hMutS from heteroduplex DNA is consistent with an ATP-dependent translocation mechanism. J Biol Chem273: 32055–32062, 1998.
27.
GradiaS, SubramanianD, WilsonT, AcharyaS, MakhovA, GriffithJ, FishelR.hMSH2-hMSH6 forms a hydrolysis independant sliding clamp on mismatched DNA. Mol Cell3: 25–261, 1999.
28.
IaccarinoI, MarraG, DufnerP, JiricnyJ.Mutation of the magnesium binding site of hMSH6 disables the hMutSα sliding clamp from translocating along DNA. J Biol Chem275: 2080–2086, 2000.
29.
LiGM, ModrichP.Restoration of mismatch repair to nuclear extracts of H6 colorectal tumor cells by a heterodimer of human MutL homologs. Proc Natl Acad Science U S A92: 1950–1954, 1995.
30.
SchmutteC, MarinescuRC, SadoffMM, GueretteS, OverhauserJ, FishelR.Human exonuclease I interact with the mismatch repair protein hMSH2. Cancer Res58: 4537–4542, 1998.
31.
TishkoffDX, FilosiN, GaidaGM, KolodnerRD. A novel mutation avoidance mechanism dependent on S. cerevisiae RAD27 is distinct from DNA mismatch repair. Cell88: 253–263, 1997.
32.
LongleyMJ, PierceA, ModrichP.DNA polymerase δ is required for human mismatch repair in vitro. J Biol Chem272: 10917–10921, 1997.
33.
GuL, HongY, McCullochS, WatanabeH, LiGM. ATP-dependent interaction of human mismatch repair proteins and dual role of PCNA in mismatch repair. Nucleic Acids Res26: 1173–1178, 1998.
34.
UmarA, BuermeyerAB, SimonJA, ThomasDC, ClarkAB, LiskayRM, KunkelTA. Requirement for PCNA in DNA mismatch repair at a step preceding DNA resynthesis. Cell87: 65–73, 1996.
35.
LinYL, ShivjiMK, ChenC, KolodnerR, WoodRD, DuttaA.The evolutionary conserved zinc finger motif in the largest protein of human replication protein A is required for DNA replication and mismatch repair but not for nucleotide excision repair. J Biol Chem273: 1453–1461, 1998.
36.
KolodnerR, MarsischkyGT. Eukariotic DNA mismatch repair. Curr Opin Cancer Dev9: 89–96, 1999.
37.
KarranP.Appropriate partners make good matches. Science268: 1857–1858, 1995.
38.
ParsonsR, LiGM, LongleyMJ, FangWH, PapadopoulosN, JenJ, de la ChapelleA, KinzlerKW, VogelsteinB, ModrichP.Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell75: 1227–1236, 1993.
39.
EshlemanJR, LangEZ, BowerfindGK, ParsonsR, VogelsteinB, WillsonJK, VeiglML, SedwickWD, MarkowitzSD. Increased mutation rate at the hprt locus accompanies microsatellite instability in colon cancer. Oncogen10: 33–37, 1995.
PapadopoulosN, LindblomA.Molecular basis of HNPCC: mutations of MMR genes. Hum Mutat10: 89–99, 1997.
42.
PeltomakiP, VasenHFA. International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer: mutation predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. Gastroenterology113: 1148–1158, 1997.
43.
LynchHT, SmyrkT, LynchJF. An update on Lynch Syndrome. Curr Opin Oncol10: 349–356, 1998.
44.
LynchHT, SmyrkT, LynchJF. Molecular genetics and clinical-pathology features of hereditary nonpolyposis colorectal carcinoma (Lynch syndrome): historical journey from pedigree anecdote to molecular genetic confirmation. Oncology55: 103–108, 1998.
IonovY, PenadoMA, MalkhosyanS, ShibataD, PeruchoM.Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature363: 558–561, 1993.
47.
AaltonenLA, PeltomakiP, LeachFS, SistonenP, PylkannenL, MecklinJP, JarvinenH, PowellSM, JenJ, HamiltonSR, PetersenGM, KinzlerKW, VogelsteinB, de la ChapelleA.Clues to the pathogenesis of familial colorectal cancer. Science260: 812–816, 1993.
48.
LindblomA, TannergardP, WereliousB, NordenskjoldM.Genetic mapping of a second locus predisposing to hereditary non-polyposis colon cancer. Nat Genet5: 279–282, 1993.
49.
LiuB, ParsonsR, PapadopoulosN, NicolaidesNC, LynchHT, WatsonP, JassJR, DunlopM, WyllieA, PeltomakiP, de la ChapelleA, HamiltonSR, VogelsteinB, KinzlerKW. Analysis of mismatch repair gene in hereditary non polyposis colon cancer patients. Nat Med21: 169–174, 1996.
50.
BockerD, DiermanJ, FriedlW, GebertJ, Holinsky-FederE, Karner-HanushJ, von Knebel-Doeberitz, KoelbleK, SchackertHK, WirtzHC, FishelR, RuschoffJ.Microsattelite instability analysis: a multicenter study for reliability and quality control. Cancer Res57: 4739–4743, 1997.
51.
BolandCR, ThibodeauSN, HamiltonSR, SidranskyD, EshelmanJR, BurtRW, MeltzerSJ, Rodriguez-BigasMA, FoddeR, RanzaniGN, SrivastavaS.A National Cancer Institute Workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res58: 5248–5257, 1998.
52.
KunkelTA. Nucleotide repeats: slippery DNA and diseases. Nature365: 207–208, 1993.
53.
BoyerJC, UmarA, RisingerJI, LipfordJR, KaneM, YinS, BarettJC, KolodnerRD, KunkelTA. Microsatellite instability, mismatch repair and genetic defects in human cancer cell lines. Cancer Res55: 6063–6070, 1995.
54.
ParsonsR, Guo-MinL, LongleyM, ModrichP, LiuB, BerkT, HamiltonSR, KinzlerKW, VogelsteinB.Mismatch repair deficiency in phenotypically normal human cells. Science268: 738–740, 1995.
55.
BhattacharryaNP, SkandalisA, GaneshA, GrodenJ, MeuthM.Mutator phenotypes in human colorectal carcinoma cell lines. Proc Natl Acad Sci U S A91: 6319–6323, 1994.
56.
HermanJG, UmarA, PolyakK, GraffJR, AhujaN, IssaJPJ, MarkowitzS, WillsonJKV, HamiltonSR, KinzlerKW, KaneMF, KolodnerRD, VogelsteinB, KunkelTA, BaylinSB. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A95: 6870–6875, 1998.
57.
VeiglML, KasturiL, OlechnowiczJ, MaAH, LutterbaughJD, PeriyasamyS, LiGM, DrummondJ, ModrichPL, SedwickWD, MarkowitzSD. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human cancer. Proc Natl Acad Sci U S A95: 8698–8702, 1998.
58.
CunninghamJM, ChristensenER, TesterDJ, KimCY, RochePC, BurgartLJ, ThibodeauSN. Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res. 58: 3455–3460, 1998.
59.
AarnioM, SankilaR, PukkalaE, SalovaaraR, AaltonenLA, de la ChapelleA, PeltomakiP, MecklinJP, JarvinenHJ. Cancer risk in mutation carriers of DNA mismatch repair genes. Int J Cancer81: 214–218, 1999.
60.
VogelsteinB, KinzlerKW. The multistep nature of cancer. Trends Genet9: 138–141, 1993.
61.
VasenHFA, WijnenJT, MenkoFH. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology110: 1020–1027, 1996.
62.
RisingerJL, BerchuckA, KohlerM, WatsonP, LynchHT, BoydJ.Genetic instability of microsatellites in endometrial carcinoma. Cancer Res53: 5100–5103, 1993.
63.
IchikawaY, LemonSJ, WangS, FranklinB, WatsonP, KnezeticJA, BewtraC, LynchHT. Microsatellites instability and expression of hMSH2 or hMLH1 in normal and malignant endometrial and ovarian epithelium in hereditary nonpolyposis colorectal cancer family members. Cancer Genet Cytogenet112: 2–8, 1999.
DugganBD, FelixJC, MuderspachLI, TourgemanD, ZhengJ, ShibataD.Microsatellite instability in sporadic endometrial carcinoma. J Natl Cancer Inst86: 1216–1221, 1994.
66.
LimPC, TesteD, CilbyW, ZiesmerSC, RochePC, HartmanL, ThibodeauSN, PodratzKC, JenkinsRB. Absence of mutation in DNA mismatch repair genes in sporadic endometrial tumors with microsatellite instability. Clin Cancer Res2: 197–1911, 1996.
67.
KatabuchiH, van ReesB, LambersAR, RonnetBM, BlazersMS, LeachFS, ChoKR, HedrickL.Mutations in DNA mismatch repair genes are not responsible for microsatellite instability in most sporadic endometrial carcinomas. Cancer Res55: 5556–5560, 1995.
68.
KobayashiK, MatsushimaM, KoiS, SaitoH, SagaeS, KudoR, NakamuraY.Mutational analysis of mismatch repair genes hMLH1 and hMSH2 in sporadic endometrial carcinomas with microsatellite instability. Jpn J Cancer Res87: 141–145, 1996.
69.
KowalskiLD, MutchDG, HerzogTJ, RaderJS, GoodfellowPJ. Mutational analysis of MLH1 and MSH2 in 25 prospectively-acquired RER+ endometrial cancers. Genes Chromosomes Cancer18: 219–227, 1997.
70.
RisingerJ, UmarA, BoydJ, BrchuckA, KunkelTA, BarettJC. Mutation of MSH3 in endometrial cancer and evidence for its functional role in heteroduplex repair. Nat Genet14: 102–105, 1996.
71.
SchwartzSJr., YamamotoH, NavarroM, MaestroM, RaventosJ, PeruchoM.Frameshift mutations of mononucleotide repeats in caspase-5 and other target genes in endometrial and gastrointestinal cancer of microsatellite mutator genotype. Cancer Res59: 2995–3002, 1999.
72.
SimpkinsSB, BockerT, SwisherEM, MutchDG, GersellDJ, KovatichAJ, PalazzoJP, FishelR, GoodfellowPJ. hMLH1 promoter methylation and gene silencing is the primary cause of microsatellite instability in sporadic endometrial cancer. Hum Mol Genet8: 661–666, 1999.
73.
GurinCC, FedericiMG, KangL, BoydJ.Causes and consequences of microsatellite instability in endometrial carcinoma. Cancer Res59: 462–466, 1999.
74.
EstellerM, LevineR, BaylinSB, EllensonLH, HermanJG. MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinomas. Oncogene17: 2413–2417, 1998.
75.
ArzimanglouIL, LallasT, OsborneM, BarberH, GilbertF.Microsatellite instability differences between familial and sporadic ovarian cancer. Carcinogenesis17: 1799–1804, 1996.
OrthK, HungJ, GazdarA, BowcockA, MathiJM, SambrookJ.Genetic instability in human ovarian cell lines. Proc Natl Acad Sci U S A91: 9495–9499, 1994.
78.
CreasmanWT. Prognostic significance of hormone receptors in endometrial cancer. Cancer71: 1467–1470, 1993.
79.
MurphyLC, DotzlawH, AlkhahefM, CouttsA, MillerT, WongMS, GongY, MurphyLJ. Mechanisms of growth inhibition by antioestrogenes and progestins in human breast and endometrial cancer cell lines. Steroid Biochem Mol Biol43: 117–121, 1992.
80.
MiturskiR, SemczukA, JakowickiJ.Simultaneous expression of the ras p21 and p53 proteins in human endometrial carcinomas. Acta Histochem98: 411–418, 1996.
81.
SemczukA, MiturskiR, BaranowskiW, JakowickiJ.Ras p21 immunohistochemical detection in human endometrial carcinomas. Gynecol Obstet Invest44: 132–135, 1997.
82.
MiturskiR, SemczukA, JakowickiJ.Expression of p21 in the stromal cells of human neoplastic endometrium. Eur J Gynaecol Oncol19: 308–311, 1998.
83.
EnomotoT, FujitaM, InoueM, NomuraT, ShroyerKR. Alteration of the p53 tumor suppressor gene and activation of c-K-ras-2 protooncogene in endometrial adenocarcinoma from Colorado. Am J Clin Pathol103: 224–230, 1995.
84.
SaegusaM, HashimuraM, YoshidaT, OkayasuI.β-Catenin mutations and aberrant nuclear expression during endometrial tumorigenesis. Br J Cancer84: 209–217, 2001.
85.
FukuchiT, SakamotoM, TosudaH, MaruyamaK, NozawaS, HirhashiS.β-Catenin mutation in carcinoma of the uterine endometrium. Cancer Res15: 3526–3528, 1998.
86.
JeyarajahA, OramD, JacobsI.Molecular events in endometrial carcinogenesis. Int J Gynecol Cancer6: 425–438, 1996.
87.
MutterGL, LinM-C, FitzgeraldJT, KumJB, BaakJPA, LeesJA, WengL-P, EngH.Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst92: 924–931, 2000.
88.
BussagliaE, del RioE, Matias-GuiuX, PratJ.PTEN mutations in endometrial carcinomas: a molecular and clinicopathologic analysis of 38 cases. Hum Pathol31: 312–317, 2000.
89.
MiturskiR, BurnoufD, NothisenM, TomaszewskiJ, JakowickiJ, FuchsR.Endometrial cancer and APC gene mutations (abstract). FASEB J12: 1864, 1998.
90.
McEachernMJ, KrauskopfA, BlackburnEH. Telomeres and their control. Annu Rev Genet34: 331–358, 2000.
91.
BreslowRA, ShayJW, GazdarAF, SrivastavaS.Telomerase and early detection of cancer: a National Cancer Institute workshop. J Natl Cancer Inst89: 618–623, 1997.
92.
KramerBS, BrawleyOW. Cancer screening. Hematol Oncol Clin North Am14: 831–848, 2000.
93.
PereraFP, WeinsteinIB. Molecular epidemiology and carcinogen-DNA adduct detection: new approaches to studies of human cancer causation. J Chron Dis35: 581–600, 1982.
94.
PereraFP. Molecular epidemiology: on the path to prevention?J Natl Cancer Inst92: 602–612, 2000.
EisenbergerCF, SchoenbergM, EngerC, HortopanS, ShahS, ChowNH, MarshallFF, SidranskyD.Diagnosis of renal cancer by molecular urinalysis. J Natl Cancer Inst91: 2028–2032, 1999.
SalbeC, TrevisiolC, FerruzziE, MancusoT, NascimbeniR, Di FabioF, SalerniB, DittadiR.Molecular detection of codon 12 K-ras mutations in circulating DNA from serum of colorectal cancer patients. Int J Biol Markers15: 300–307, 2000.
99.
LiloglouT, MaloneyP, XinarianosG, HulbertM, WalshawMJ, GosneyJR, TurnbullL, FieldJK. Cancer-specific genomic instability in bronchial lavage: a molecular tool for lung cancer detection. Cancer Res61: 1624–1628, 2001.
100.
HemstreetGPIII, YinS, MaZ, BonnerRB, BiW, RaoJY, ZangM, ZhengQ, BaneB, AsalN, LiG, FengP, HurstRE, WangW.Biomarker risk assessment and bladder cancer detection in a cohort exposed to benzidine. J Natl Cancer Inst93: 427–436, 2001.
101.
FinkD, AebiS, HowellSB. The role of DNA mismatch repair in drug resistance. Clin Cancer Res4: 1–6, 1998.
102.
FinkD, NebelS, NorrisPS, BaergenRN, WiczynskiSP, CostaMJ, HaasM, CannistraSA, HowellSB. Enrichment of DNA mismatch repair-deficient cells during treatment with cisplatin. Int J Cancer77: 741–746, 1998.
103.
StrathdeeG, McKeanMJ, IllandM, BrownR.A role for methylation of the hMLH1 promoter in loss of hMLH1 expression and drug resistance in ovarian cancer. Oncogene18: 2335–2341, 1999.
104.
ParsonsR, Guo-MinL, LongleyM, ModrichP, LiuB, BerkT, HamiltonSR, KinzlerKW, VogelsteinB.Mismatch repair deficiency in phenotypically normal human cells. Science268: 738–740, 1995.
105.
TomlinsonIP, HampsonR, KarranP, BodmerWF. DNA mismatch repair in lymphoblastoid cells from hereditary non-polyposis colorectal cancer (HNPCC) patients is normal under conditions of rapid cell division and increased mutational load. Mutat Res383: 177–182, 1997.
106.
ChaRS, ZarblH, KeohavongP, ThillyWG. Mismatch amplification mutation assay (MAMA): application to the c-H-ras gene. PCR Methods Applications2: 14–20, 1992.
