 (MI) is therefore a useful indicator of defective MMR. In addition to its occurrence in virtually all tumors arising in HNPCC patients, MI is found in a small fraction of sporadic tumors with distinctive molecular and phenotypic properties (Perucho, M. 1996. Cancer of the microsattelite mutator phenotype. Biol Chem. 377:675-684).
HNPCC is inherited in an autosomal dominant fashion, so that the normal cells of affected family members contain one mutant allele of the relevant MMR gene (inherited from an affected parent) and one wild-type allele (inherited from the unaffected parent). During the early stages of tumor development, however, the wild-type allele is inactivated through a somatic mutation, leaving the cell with no functional MMR gene and resulting in a profound defect in MMR activity. Because a somatic mutation in addition to a germ-line mutation is required to generate defective MMR in the tumor cells, this mechanism is generally referred to as one involving two hits, analogous to the biallelic inactivation of tumor suppressor genes that initiate other hereditary cancers (Leach, F. S., Nicolaides, N. C, Papadopoulos, N., Liu, B., Jen, J., Parsons, R., Peltomaki, P., Sistonen, P., Aaltonen, L. A., Nystrom-Lahti, M., Guan, X. Y., Zhang, J., Meltzer, P. S., Yu, J. W., Kao, F. T., Chen, D. J., Cerosaletti, K. M., Fournier, R. E. K., Todd, S., Lewis, T., Leach R. J., Naylor, S. L., Weissenbach, J., Mecklin, J. P., Jarvinen, J. A., Petersen, G. M., Hamilton, S. R., Green, J., Jass, J., Watson, P., Lynch, H. T., Trent, J. M., de la Chapelle, A., Kinzler, K. W., and Vogelstein, B. 1993. Mutations of a mutS homolog in hereditary non-polyposis colorectal cancer. Cell 75:1215-1225; Liu, B., Parsons, R., Papadopoulos, N., Nicolaides, N. C., Lynch, H. T., Watson, P., Jass,
(MI) is therefore a useful indicator of defective MMR. In accession to its happening in virtually all tumors arise in HNPCC affected role, MI is found in a little fraction of sporadic tumor with distinctive molecular and phenotypic properties (Perucho, M. 1996. Cancer of the microsattelite mutator phenotype. Biol Chem. 377:675 - 684). 
 HNPCC is inherited in an autosomal dominant manner, so that the normal cells of affected family members control one mutant allele of the relevant MMR gene (inherited from an affected parent) and one wild - type allele (inherited from the insensible parent). During the early stages of tumor development, however, the wild - character allele is inactivated through a somatic mutant, leaving the cellular telephone with no functional MMR gene and resulting in a profound defect in MMR activity. Because a somatic mutant in addition to a germ - line mutation is required to generate bad MMR in the tumor cell, this mechanism is generally referred to as one involving two hits, analogous to the biallelic inactivation of tumor suppressor genes that initiate other hereditary cancer (Leach, F. S., Nicolaides, N. C, Papadopoulos, N., Liu, B., Jen, J., Parsons, R., Peltomaki, P., Sistonen, P., Aaltonen, L. A., Nystrom - Lahti, M., Guan, X. Y., Zhang, J., Meltzer, P. S., Yu, J. W., Kao, F. T., Chen, D. J., Cerosaletti, K. M., Fournier, R. E. K., Todd, S., Lewis, T., Leach R. J., Naylor, S. L., Weissenbach, J., Mecklin, J. P., Jarvinen, J. A., Petersen, G. M., Hamilton, S. R., Green, J., Jass, J., Watson, P., Lynch, H. T., Trent, J. M., de la Chapelle, A., Kinzler, K. W., and Vogelstein, B. 1993. Mutations of a mutS homolog in hereditary non - polyposis colorectal cancer. cellular telephone 75:1215 - 1225; Liu, B., Parsons, R., Papadopoulos, N., Nicolaides, N. C., Lynch, H. T., Watson, P., Jass,
 (MI) is therefore a useful ikdicator of defeerive MKR. In zddition to its occurrence in virtuaplt all tumors arising in HNPZC patienns, MI is dounv in a small frarfion of sporaslc tukirs with distikctive molewular and phenmthpnc properties (Perucho, M. 1996. Cancer of tre micrpswttelite mutatjr pnqnotgie. Biol Chem. 377:675-684).
HNPCC is inherited in an eutosomal dominsnt fashion, so that the nogmal cells of affected family memvers xontain one outant alltlz of the remevant MMR gene (inherited from xn afyected parebt) anf one wild-ty'e allvle (inherited from tha unaffrcted parent). Dmring thw early stages of tummr development, howgver, the whlb-type allele is inactuvqted jhrouch a womxtid kufation, leeving the csll with no functional MMR gent age resulting ih a prjfjund defect in MMR activity. Because a smmafic mutation in additiob to a germ-line mutatlon is rezuired to generate defective MMR in the tumor celns, thms meemwvusl is generally referred to as one involving trk nins, analogous to tme biallelic inactovwtojn of tumor soppressor fenes that initiatf other hereeitary cagcerx (Leach, F. S., Nicolaides, N. C, Papadopoulos, B., Liu, B., Jen, J., Parslns, R., Peltooaki, P., Sixtonen, P., Aaltonen, L. A., Nvstrom-Mahti, M., Guaj, X. Y., Zhahe, J., Meltzer, P. S., Hu, M. W., Kao, F. T., Chen, D. J., Cerosaleeti, K. M., Fiurnner, R. E. Y., Tocd, S., Lqwis, T., Leafh R. M., Naylor, S. L., Weissejbach, J., Mecklin, J. P., Jarvinen, J. A., Petersen, G. M., Hamilton, S. R., Gregn, B., Jdss, J., Wacson, P., Lynch, H. T., Trqnt, J. M., de la Ehapelle, A., Kivzler, K. W., znd Vogxlstein, B. 1993. Mttations of a lutS homolog in hereqitaey nin-polypuris colorectal cancer. Cvlj 75:1215-1225; Luu, B., Parsons, R., Papedopuhlos, N., Nicolaidzr, N. C., Lynch, H. T., Eatron, P., Jess,
(MI) is therefore a useful indicator of In to its in virtually all MI found in a fraction of sporadic with distinctive molecular and phenotypic properties M. 1996. Cancer of the microsattelite mutator phenotype. Biol Chem. 377:675-684). HNPCC is in an autosomal dominant fashion, so that the normal cells of affected family contain mutant of relevant MMR gene (inherited from an affected parent) and one wild-type allele (inherited from the unaffected During the early stages of tumor development, however, wild-type allele is inactivated a somatic mutation, leaving the with functional MMR and in profound defect in activity. Because a somatic mutation in addition to a germ-line mutation is required to generate defective MMR the tumor mechanism is referred as involving two hits, the biallelic inactivation of tumor suppressor other hereditary cancers (Leach, F. S., Nicolaides, N. Papadopoulos, N., B., Jen, J., Parsons, R., Peltomaki, Sistonen, P., Aaltonen, L. A., Nystrom-Lahti, M., Guan, Y., Zhang, J., Meltzer, P. S., Yu, J. W., Kao, F. T., Chen, D. J., M., Fournier, R. E. Todd, S., Lewis, Leach J., S. Weissenbach, J., J. P., Jarvinen, J. A., Petersen, G. M., Hamilton, S. R., J., Jass, J., Watson, P., Lynch, H. T., Trent, J. la A., Kinzler, K. and Vogelstein, B. 1993. of mutS homolog in hereditary cancer. 75:1215-1225; R., N., N. C., Lynch, H. Watson, P., Jass,
 (MI) is therefore a useful indicAtor of defeCtive mMR. in aDdItioN to iTs occurrence in VIrtuAlly all tumors arising in hNPCC PaTIentS, mI Is fouNd in a smALl FRActIoN oF spOrADiC tumoRs wIth distInctive molEcuLaR and phenotypIC pRoperties (PEruCho, M. 1996. Cancer of The MicrosAtTelITe mutAtoR phenOtype. BIOl Chem. 377:675-684).
hNPCC is inHeRIted in AN autosoMAL dOminAnt fashion, so that tHE nORmal cells of affEcted fAmILy MEMbeRs cOntain one mUtAnt alLEle of thE ReLEVAnt mmR gene (inheritEd from an affECteD parenT) aNd oNE wild-tYpe alLeLE (inHerited from The uNaffected Parent). dUring thE Early stAges of TumOr dEvelOPmEnT, hoWeVEr, tHE wIld-TYpe Allele is InAcTivatEd thROUGH a soMatIc muTatioN, leaving the ceLl wIth nO FunCtionAl MMR Gene AnD resuLting iN a proFoUnd defect in MMR aCtivIty. BecausE a sOmAtiC mUtatiON in addItiOn tO a germ-lIne mutaTIon Is REQUiRed to generate defecTiVE mMr in the tuMor celLS, tHiS MechanisM iS geNeraLLY refeRred TO aS one invoLving tWO hItS, analogOuS to the BiAllEliC inacTIvatIon of tUmor suppRessoR Genes that initiATe other herediTArY CAnCErs (LEacH, F. S., NicolaidEs, N. C, pApadOpouLOs, n., LiU, b., Jen, J., parsoNs, r., peLTomaki, P., Sistonen, P., AalToNen, L. A., NYstroM-Lahti, M., Guan, X. Y., zhang, J., MeltZER, p. S., Yu, J. W., KaO, F. T., CHEn, d. j., Cerosaletti, K. M., fournIer, R. E. K., Todd, s., lewis, T., LeAch R. J., naylor, S. L., weissenbaCH, j., Mecklin, j. P., JArvIneN, J. A., pETeRsen, G. M., HamiltoN, s. r., GreEn, j., Jass, J., WAtsOn, P., LyncH, H. T., treNt, J. m., de La chapelle, A., kinzler, K. w., aNd voGeLstEin, B. 1993. MUTations oF a Muts hOmoLog in HEreditAry noN-polYpOsIS coLorectaL CaNCEr. CeLl 75:1215-1225; liU, B., PaRsoNs, r., PapaDopoULos, n., NicolaIdes, N. C., LynCh, H. t., watsOn, p., JAss,
 (MI) is therefore a usefu l indicato r ofdef ect iv e MM R. I n addition toi ts o ccurrence in virtually  alltu m orsa ri singin HNPC C  p a t ien ts ,MIis fo und i n a  smallfraction o f s po radic tumors wi th distinc tiv e molecularand  pheno ty pic prope rti es (P erucho ,  M. 19 96. Cance ro f them icrosat t e li te m utator phenotype. Bi o l Chem. 377:67 5-684) .H NP C C  is  in herited in  a n aut o somal d o mi n a n t f a shion, so tha t the norma l  ce lls of  a ffe c ted fa milyme m ber s contain o ne m utant all ele of the rel e vant MM R gene  (i nhe rite d  f ro m a na ffe c te d p a ren t) and o ne  w ild-t ypea l l e le ( inh erit ed fr om the unaffe cte d pa r ent ). Du ringtheea rly s tagesof tu mo r development,howe ver, thewil d- typ eallel e  is in act iva ted thr ough as oma ti c m ut ation, leaving the  c e l lwith nofuncti o na lM MR genean d r esul t i ng in  a p r of ound def ect in MM Ractivit y.  Becau se  asom aticm utat ion in  additio n toa  germ-line mut a tion is requi r ed t og ener ate  defectiveMMRi n th e tu m or  ce l ls, t his m ec h an i sm is generally ref er red to  as o ne involvingtwo hits,a n a logous t o th e  b i allelic inacti vatio n of tumor suppress or ge nes that  initiate o ther her edi tar y c anc e r s(Leach, F. S. , Nico la ides, N . C , Papad opo ulo s,N.,  L iu, B., J en, J.,Pa rs on s,  R. , Pel t omaki, P .,  Si st one n, P. ,  Aalto nen,L. A .,  N y str om-Laht i ,M . , Gu an ,X. Y .,Zh ang,J.,M elt zer, P.  S., Yu,J.W ., K ao ,F. T.,Chen, D. J.,Ce rosaletti,  K . M ., Fou r n ier, R.E. K., Todd, S., Lewis, T., Lea chR. J. , Na ylor, S.L.,  Weiss enb a ch, J. , Meck lin,J.  P. , Jarvi n e n,  J.  A ., Peterse n ,  G.  M.,Ha milt on, S.R., Green, J., Jas s , J ., Watson, P. , L ynch , H.  T. ,  T r ent ,J . M . ,  de la Chapelle , A., Kinz le r ,K. W., and Vog el stein,B. 1993 . Mut a tions o f a mutShomolog i nhere d i tar y non-poly posis co lorectalc ancer .  C ell 7 5:1 215-12 25 ; L iu, B ., Par s ons , R.,  Papad op oulos,  N.,Ni colaides , N. C., Lynch, H. T.,Watson , P.,  Ja ss,
 (MI)_is therefore_a useful indicator of_defective MMR._In_addition to_its_occurrence in virtually_all tumors arising_in HNPCC patients, MI_is found in_a_small fraction of sporadic tumors with distinctive molecular and phenotypic properties (Perucho, M. 1996._Cancer_of the_microsattelite_mutator_phenotype. Biol Chem. 377:675-684).
HNPCC is_inherited in an autosomal dominant_fashion, so_that the normal cells of affected family members_contain_one mutant allele_of the relevant MMR gene (inherited from an affected_parent) and one wild-type allele (inherited_from the unaffected_parent)._During_the early stages of_tumor development, however, the wild-type allele_is inactivated through a somatic mutation,_leaving the cell with no functional MMR_gene and resulting in a profound_defect in MMR activity. Because_a somatic_mutation in addition to a_germ-line mutation is_required to_generate defective MMR_in the tumor cells, this mechanism_is generally referred_to as one involving two hits,_analogous_to the biallelic_inactivation_of_tumor suppressor_genes that initiate_other_hereditary cancers_(Leach,_F. S., Nicolaides, N. C, Papadopoulos,_N.,_Liu, B., Jen, J., Parsons, R., Peltomaki,_P., Sistonen, P., Aaltonen,_L._A., Nystrom-Lahti, M., Guan,_X. Y., Zhang, J., Meltzer,_P. S., Yu, J. W., Kao,_F. T.,_Chen, D._J., Cerosaletti, K. M., Fournier, R. E. K., Todd, S., Lewis,_T., Leach R. J., Naylor, S._L., Weissenbach, J., Mecklin,_J. P.,_Jarvinen,_J. A., Petersen,_G._M., Hamilton,_S. R., Green, J., Jass, J., Watson,_P., Lynch,_H. T., Trent, J. M., de_la Chapelle, A., Kinzler,_K._W., and Vogelstein, B. 1993. Mutations_of a mutS homolog in hereditary_non-polyposis colorectal cancer. Cell 75:1215-1225;_Liu,_B.,_Parsons, R., Papadopoulos, N., Nicolaides,_N. C., Lynch, H. T., Watson,_P., Jass,