Gliomas, the most frequent primary brain tumors in humans, form a heterogeneous group, encompassing many different histological types and malignancy grades. Within this group, the diffuse infiltrative gliomas are by far the most common in adults. The major representatives in this subgroup are the diffuse astrocytic, oligodendroglial, and mixed oligo-astrocytic tumors. Especially in these diffuse gliomas, the role of molecular diagnostics is rapidly increasing. After summarizing the most relevant genetic aberrations and pathways in these tumors detected up till now, this review will discuss the clinical relevance of this information. Several molecular markers have been identified in diffuse gliomas that carry diagnostic and prognostic information. In addition, some of these and other markers predict the response of these gliomas to particular (chemo)therapeutic approaches. The techniques used to obtain this molecular information, as well as the advantages and disadvantages of the different techniques will be discussed. Finally, future perspectives will be presented with regard to the contribution of molecular diagnostics to tailor-made therapy in glioma patients.
CBTRUS Statistical Report. Primary Brain Tumors in the United States, 1998–2002. (2006). Central Brain Tumor Registry Of The United States (www.cbtrus.org).
2.
KleihuesP. and CaveneeW. K.World Health Organization Classification of Tumours. Pathology and Genetics. Tumours of the Nervous System. IARC Press, Lyon France (2000).
3.
OhgakiH. and KleihuesP.Epidemiology and Etiology of Gliomas. Acta. Neuropathol. (Berl)109, 93–108 (2005).
4.
VogelsteinB. and KinzlerK. W.Cancer Genes and the Pathways They Control. Nat. Med.10, 789–799 (2004).
5.
KleihuesP. and OhgakiH.Primary and Secondary Glioblastomas: From Concept to Clinical Diagnosis. Neuro-Oncology1, 44–51 (2000).
6.
TsoC. L., FreijeW. A., DayA., ChenZ., MerrimanB., PerlinaA., LeeY., DiaE. Q., YoshimotoK., MischelP. S., LiauL. M., CloughesyT. F., and NelsonS. F.Distinct Transcription Profiles of Primary and Secondary Glioblastoma Subgroups. Cancer Res.66, 159–167 (2006).
7.
JeukenJ. W., Von DeimlingA., and WesselingP.Molecular Pathogenesis of Oligodendroglial Tumors. J. Neurooncol.70, 161–181 (2004).
8.
ReifenbergerG. and LouisD. N.Oligodendroglioma: Toward Molecular Definitions in Diagnostic Neuro-Oncology. J. Neuropathol. Exp. Neurol.62, 111–126 (2003).
9.
JeukenJ. W. M., SprengerS. H. E., WesselingP., MacvilleM. V. E., Von DeimlingA., TeepenH. L. J. M., Van OverbeekeJ. J., and BoermanR. H.Identification of Subgroups of High-grade Oligodendroglial Tumors by Comparative Genomic Hybridization. J. Neuropathol. Exp. Neurol.58, 606–612 (1999).
10.
JeukenJ. W. M., SprengerS. H. E., VermeerH., KappelleA. C., BoermanR. H., and WesselingP.Chromosomal Imbalances in Primary Oligodendroglial Tumors and Their Recurrences; Clues for Malignant Progression as Detected by CGH. J. Neurosurg.96, 559–564 (2002).
11.
JeukenJ. W. M., Boots-SprengerS. H. E., and WesselingP.Chromosomal Imbalances in Oligodendroglial Tumors as Detected by Comparative Genomic Hybridization (CGH). In Genomic And Molecular Neuro-Oncology, pp. 185–198. Eds., ZhangW. and FullerG. N.. Jones and Bartlett Publishers (2004).
12.
KrosJ. M., Van RunP. R. W. A., AlersJ. C., BeverlooB., van den BentM., AvezaatC. J. J., and van DekkenH.Genetic Aberrations in Oligodendroglial Tumours: An Analysis Using Comparative Genomic Hybridization (CGH). J. Pathol.188, 282–288 (1999).
13.
BignerS. H., MatthewsM. R., RasheedB. K. A., WiltshireR. N., FriedmanH. S., FriedmanA. H., StenzelT. T., DawesD. M., McLendonR. E., and BignerD. D.Molecular Genetic Aspects of Oligodendrogliomas Including Analysis by Comparative Genomic Hybridization. Am. J. Pathol.155, 375–386 (1999).
14.
KrausJ. A., KoopmannJ., KaskelP., MaintzD., BrandnerS., SchrammJ., LouisD. N., WeistlerO. D., and von DeimlingA.Shared Allelic Losses on Chromosome 1p and 19q Suggest a Common Origin of Oligodendrogliomas and Oligoastrocytomas. J. Neuropathol. Exp. Neurol.54, 91–95 (1995).
15.
BelloM. J., VaqueroJ., de CamposJ. M., KusakM. E., SarasaJ. L., Saez-CastresanaJ., PestanaA., and ReyJ. A.Molecular Analysis of Chromosome 1 Abnormalities in Human Gliomas Reveals Frequent Loss of 1p in Oligodendroglial Tumors. Int. J. Cancer.57, 172–175 (1994).
16.
BelloM. J., LeoneP. E., VaqueroJ., de CamposJ. M., KusakM. E., and SarasaJ. L.Allelic Loss at 1p and 19q Frequently Occurs in Association and May Represent Early Oncogenic Events in Oligodendroglial Tumors. Int. J. Cancer64, 207–210 (1995).
17.
ReifenbergerJ., ReifenbergerG., LiuL., JamesC. D., WechslerW., and CollinsV. P.Molecular Genetic Analysis of Oligodendroglial Tumors Shows Preferential Allelic Deletions on 19q and 1p. Am. J. Pathol.145, 1175–1190 (1994).
18.
MaintzD., FiedlerK., KoopmannJ., RollbrockerB., NechevS., LenartzD., StanglA. P., LouisD. N., SchrammJ., WiestlerO. D., and von DeimlingA.Molecular Genetic Evidence for Subtypes of Oligoastrocytomas. J. Neuropathol. Exp. Neurol.56, 1098–1104 (1997).
19.
RosenbergJ. E., LisleD. K., BurwickA., UekiK., von DeimlingA., MohrenweiserH. W., and LouisD. N.Refined Deletion Mapping of 19q Glioma Tumor Suppressor Gene to the D19s412-std Interval. Oncogene13, 2483–2485 (1996).
20.
RitlandS. R., GanjuV., and JenkinsR. B.Region-specific Loss of Heterozygosity on Chromosome 19 is Related to the Morphologic Type of Human Glioma. Gen. Chrom. Cancer12, 277–282 (1995).
21.
von DeimlingA., NagelJ., BenderB., LenartzD., SchrammJ., LouisD. N., and WeistlerO. D.Deletion Mapping of Chromosome 19 in Human Gliomas. Int. J. Cancer57, 676–680 (1994).
22.
JeukenJ. W. M., SprengerS. H. E., BoermanR. H., von DeimlingA., TeepenH. L. J. M., van OverbeekeJ. J., and WesselingP.Subtyping of Oligo-astrocytic Tumours by Comparative Genomic Hybridisation. J. Pathol.194, 81–87 (2001).
23.
von DeimlingA.Neoplasia. Molecular Genetic Classification of Astrocytic and Oligodendroglial Tumors. Brain Pathol.7, 1311–1313 (1997).
24.
SinghS. K., ClarkeI. D., HideT., and DirksP. B.Cancer Stem Cells in Nervous System Tumors. Oncogene23, 7267–7273 (2004).
25.
SanaiN., Alvarez-BuyllaA., and BergerM. S.Neural Stem Cells and the Origin of Gliomas. N. Engl. J. Med.353, 811–822 (2005).
26.
RichJ. N. and BignerD. D.Development of Novel Targeted Therapies in the Treatment of Malignant Glioma. Nat. Rev. Drug Discov.3, 430–446 (2004).
27.
YardenY. and SliwkowskiM. X.Untangling the ErbB Signalling Network. Nat. Rev. Mol. Cell Biol.2, 127–137 (2001).
28.
KnobbeC. B., ReifenbergerJ., and ReifenbergerG.Mutation Analysis of the Ras Pathway Genes NRAS, HRAS, KRAS, and BRAF in Glioblastomas. Acta. Neuropathol. (Berl)108, 467–470 (2004).
29.
BastoD., TroviscoV., LopesJ. M., MartinsA., PardalF., SoaresP., and ReisR. M.Mutation Analysis of B-RAF Gene in Human Gliomas. Acta. Neuropathol. (Berl), 109, 207–210 (2005).
30.
FischerI., GagnerJ. P., LawM., NewcombE. W., and ZagzagD.Angiogenesis in Gliomas: Biology and Molecular Pathophysiology. Brain Pathol.15, 297–310 (2005).
31.
GagnerJ. P., LawM., FischerI., NewcombE. W., and ZagzagD.Angiogenesis in Gliomas: Imaging and Experimental Therapeutics. Brain Pathol.15, 342–363 (2005).
32.
FolkmanJ.Anti-angiogenesis: New Concept for Therapy of Solid Tumors. Ann. Surg, 175, 409–416 (1972).
33.
SchmidtE. E., IchimuraK., ReifenbergerG., and CollinsP.CDKN2(p16/MTS1) Gene Deletion or CDK4 Amplification Occurs in the Majority of Glioblastomas. Cancer Res.54, 6321–6324 (1994).
34.
HeJ., AllenR., CollinsP., Allalunis-TurnerJ., GodboutR., DayR. S., and JamesC. D.CDK4 Amplification is an Alternative Mechanism to p16 Gene Homozygeous Deletion in Glioma Cell Lines. Cancer Res.54, 5804–5807 (1994).
35.
UekiK., OnoY., HensonJ. W., EfirdJ. T., Von DeimlingA., and LouisD. N.CDKN2/p16 or RB Alterations Occur in the Majority of Glioblastomas and are Inversely Correlated. Cancer Res.56, 150–153 (1996).
36.
HeJ., OlsonJ., and JamesD.Lack of p16IKN4 or Retinablastoma Protein (pRB), or Amplification-associated Overexpression of cdk4 is Observed in Distinct Subsets of Malignant Glial Tumors and Cell Lines. Cancer Res.55, 4833–4836 (1995).
37.
WatanabeT., YokooH., YokooM., YonekawaY., KleihuesP., and OhgakiH.Concurrent Inactivation of RB1 and TP53 Pathways in Anaplastic Oligodendrogliomas. J. Neuropathol. Exp. Neurol.60, 1181–1189 (2001).
38.
BiernatW., KleihuesP., YonekawaY., and OhgakiH.Amplification and Overexpression of mdm2 in Primary (De Novo) Glioblastomas. J. Neuropathol. Exp. Neurol.56, 180–185 (1997).
39.
GersonS. L.Clinical Relevance of MGMT in the Treatment of Cancer. J. Clin. Oncol.20, 2388–2399 (2002).
40.
GonzalezJ. and GilbertM. R.Treatment of Astrocytomas. Curr. Opin. Neurol.18, 632–638 (2005).
41.
FineH. A., DearK. B., LoefflerJ. S., BlackP. M., and CanellosG. P.Meta-analysis of Radiation Therapy With and Without Adjuvant Chemotherapy for Malignant Gliomas in Adults. Cancer71, 2585–2597 (1993).
42.
StewartL. A.Chemotherapy in Adult High-grade Glioma: A Systematic Review and Meta-analysis of Individual Patient Data From 12 Randomised Trials. Lancet359, 1011–1018 (2002).
43.
StuppR., MasonW. P., van den BentM. J., WellerM., FisherB., TaphoornM. J., BelangerK., BrandesA. A., MarosiC., BogdahnU., CurschmannJ., JanzerR. C., LudwinS. K., GorliaT., AllgeierA., LacombeD., CairncrossJ. G., EisenhauerE., and MirimanoffR. O.Radiotherapy Plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N. Engl. J. Med.352, 987–996 (2005).
44.
HegiM. E., DiserensA. C., GorliaT., HamouM. F., DeT. N., WellerM., KrosJ. M., HainfellnerJ. A., MasonW., MarianiL., BrombergJ. E., HauP., MirimanoffR. O., CairncrossJ. G., JanzerR. C., and StuppR.MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma. N. Engl. J. Med.352, 997–1003 (2005).
45.
CairncrossJ. G. and MacdonaldD. R.Successful Chemotherapy for Recurrent Malignant Oligodendroglioma. Ann. Neurol.23, 360–364 (1988).
46.
CairncrossJ. G., UekiK., ZlatescuM. C., LisleD. K., FinkelsteinD., HammondR. R., SilverJ. S., StarkP. C., MacdonaldD. R., InoY., RamsayD. A., and LouisD. N.Specific Genetic Predictors of Chemotherapeutic Response and Survival in Patients with Anaplastic Oligodendrogliomas. J. Natl. Cancer Inst.90, 1473–1479 (1998).
47.
InoY., BetenskyR. A., ZlatescuM. C., SasakiH., MacdonaldD. R., Stemmer-RachamimovA. O., RamsayD. A., CairncrossJ. G., and LouisD. N.Molecular Subtypes of Anaplastic Oligodendroglioma: Implications for Patient Management at Diagnosis. Clin. Cancer Res.7, 839–845 (2001).
48.
Hoang-XuanK., HeJ., HuguetS., MokhtariK., MarieY., KujasM., LeuraudP., CapelleL., DelattreJ. Y., PoirierJ., BroetP., and SansonM.Molecular Heterogeneity of Oligodendrogliomas Suggests Alternative Pathways in Tumor Progression. Neurology57, 1278–1281 (2001).
49.
BissolaL., EoliM., PolloB., MerciaiB. M., SilvaniA., SalsanoE., MaccagnanoC., BruzzoneM. G., ContiA. M. Fuhrman, SoleroC. L., GiombiniS., BroggiG., BoiardiA., and FinocchiaroG.Association of Chromosome 10 Losses and Negative Prognosis in Oligoastrocytomas. Ann Neurol.52, 842–845 (2002).
50.
van den BentM. J., TaphoornM. J., BrandesA. A., MentenJ., StuppR., FrenayM., ChinotO., KrosJ. M., van der RijtC. C., VechtC., AllgeierA., and GorliaT.Phase II Study of First-line Chemotherapy with Temozolomide in Recurrent Oligodendroglial Tumors: The European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. J. Clin. Oncol.21, 2525–2528 (2003).
51.
Hoang-XuanK., CapelleL., KujasM., TaillibertS., DuffauH., LejeuneJ., PolivkaM., CriniereE., MarieY., MokhtariK., CarpentierA. F., LaigleF., SimonJ. M., CornuP., BroetP., SansonM., and DelattreJ. Y.Temozolomide as Initial Treatment for Adults with Low-grade Oligodendrogliomas or Oligoastrocytomas and Correlation with Chromosome 1p Deletions. J. Clin. Oncol.22, 3133–3138 (2004).
52.
LevinN., LavonI., ZelikovitshB., FuchsD., BoksteinF., FelligY., and SiegalT.Progressive Low-grade Oligodendrogliomas: Response to Temozolomide and Correlation Between Genetic Profile And O6-methylguanine DNA Methyltransferase Protein Expression. Cancer106, 1759–1765 (2006).
53.
FelsbergJ., ErkwohA., SabelM. C., KirschL., FimmersR., BlaschkeB., SchlegelU., SchrammJ., WiestlerO. D., and ReifenbergerG.Oligodendroglial Tumors: Refinement of Candidate Regions on Chromosome Arm 1p and Correlation of 1p/19q Status with Survival. Brain Pathol.14, 121–130 (2004).
54.
IdbaihA., MarieY., PierronG., BrennetotC., Hoang-XuanK., KujasM., MokhtariK., SansonM., LejeuneJ., AuriasA., DelattreO., and DelattreJ. Y.Two Types of Chromosome 1p Losses with Opposite Significance in Gliomas. Ann. Neurol.58, 483–487 (2005).
55.
McLendonR. E., HerndonJ. E., WestB., ReardonD., WiltshireR., RasheedB. K., QuinnJ., FriedmanH. S., FriedmanA. H., and BignerD. D.Survival Analysis of Presumptive Prognostic Markers Among Oligodendrogliomas. Cancer104, 1693–1699 (2005).
56.
TamuraK. and FukuokaM.Molecular Target-based Cancer Therapy: Tyrosine Kinase Inhibitors. Int. J. Clin. Oncol.8, 207–211 (2003).
57.
GschwindA., FischerO. M., and UllrichA.The Discovery of Receptor Tyrosine Kinases: Targets for Cancer Therapy. Nat. Rev. Cancer4, 361–370 (2004).
58.
MassR. D.The HER Receptor Family: A Rich Target for Therapeutic Development. Int. J. Radiat. Oncol. Biol. Phys.58, 932–940 (2004).
59.
HynesN. E. and LaneH. A.ERBB Receptors and Cancer: The Complexity of Targeted Inhibitors. Nat. Rev. Cancer5, 341–354 (2005).
60.
MellinghoffI. K., WangM. Y., VivancoI., Haas-KoganD. A., ZhuS., DiaE. Q., LuK. V., YoshimotoK., HuangJ. H., ChuteD. J., RiggsB. L., HorvathS., LiauL. M., CaveneeW. K., RaoP. N., BeroukhimR., PeckT. C., LeeJ. C., SellersW. R., StokoeD., PradosM., CloughesyT. F., SawyersC. L., and MischelP. S.Molecular Determinants of the Response of Glioblastomas to EGFR Kinase Inhibitors. N. Engl. J. Med.353, 2012–2024 (2005).
61.
RowinskyE. K.Targeting the Molecular Target of Rapamycin (mTOR). Curr. Opin. Oncol.16, 564–575 (2004).
62.
GalanisE., BucknerJ. C., MaurerM. J., KreisbergJ. I., BallmanK., BoniJ., PeralbaJ. M., JenkinsR. B., DakhilS. R., MortonR. F., JaeckleK. A., ScheithauerB. W., DanceyJ., HidalgoM., and WalshD. J.Phase II Trial of Temsirolimus (CCI-779) in Recurrent Glioblastoma Multiforme: A North Central Cancer Treatment Group Study. J. Clin. Oncol.23: 5294–5304 (2005).
63.
PenuelasS., AlemanyC., NoeV., and CiudadC. J.The Expression of Retinoblastoma and Sp1 is Increased by Low Concentrations of Cyclin-dependent Kinase Inhibitors. Eur. J. Biochem.270, 4809–4822 (2003).
64.
BensonC., KayeS., WorkmanP., GarrettM., WaltonM., and de BonoJ.Clinical Anticancer Drug Development: Targeting the Cyclin-dependent Kinases. Br. J. Cancer92, 7–12 (2005).
65.
CheneP.Inhibiting the p53-MDM2 Interaction: An Important Target for Cancer Therapy. Nat. Rev. Cancer3, 102–109 (2003).
66.
VassilevL. T., VuB. T., GravesB., CarvajalD., PodlaskiF., FilipovicZ., KongN., KammlottU., LukacsC., KleinC., FotouhiN., and LiuE. A.In Vivo Activation of the p53 Pathway by Small-molecule Antagonists of MDM2. Science303, 844–848 (2004).
67.
QuinnJ. A., DesjardinsA., WeingartJ., BremH., DolanM. E., DelaneyS. M., VredenburghJ., RichJ., FriedmanA. H., ReardonD. A., SampsonJ. H., PeggA. E., MoschelR. C., BirchR., McLendonR. E., ProvenzaleJ. M., GururanganS., DanceyJ. E., MaxwellJ., Tourt-UhligS., HerndonJ. E., BignerD. D., and FriedmanH. S.Phase I Trial of Temozolomide Plus O6-benzylguanine for Patients with Recurrent or Progressive Malignant Glioma. J. Clin. Oncol.23, 7178–7187 (2005).
68.
PlummerR., MiddletonM., and WilsonR.First in Human Phase I Trial of the PARP Inhibitor AG-014699 with Temozolomide in Patients with Advanced Solid Tumors. J. Clin. Oncol.23 (Suppl), 208s (2005).
69.
WesselingP., RuiterD. J., and BurgerP. C.Angiogenesis in Brain Tumors; Pathobiological and Clinical Aspects. J. Neurooncol.32, 253–265 (1997).
70.
KerbelR. and FolkmanJ.Clinical Translation of Angiogenesis Inhibitors. Nat. Rev. Cancer2: 727–739 (2002).
71.
TozerG. M., KanthouC., and BaguleyB. C.Disrupting Tumour Blood Vessels. Nat. Rev. Cancer5, 423–435 (2005).
72.
NeriD. and BicknellR.Tumour Vascular Targeting. Nat. Rev. Cancer5, 436–446 (2005).
73.
HatanpaaK. J., BurgerP. C., EshlemanJ. R., MurphyK. M., and BergK. D.Molecular Diagnosis of Oligodendroglioma in Paraffin Sections. Lab Invest.83, 419–428 (2003).
74.
SmithJ. S., AldereteB. E., MinnY., BorellT., PerryA., MohapatraG., SmithS. M., KimmelD., FallonJ. O., TatesA., FeuersteinB. G., BurgerP. C., and ScheithauerB. W.Localization of Common Deletion Regions on 1p and 19q in Human Gliomas and their Association with Histological Subtype. Oncogene18, 4144–4152 (1999).
75.
MercerK. E. and PritchardC. A.Raf Proteins and Cancer: B-RAF is Identified as a Mutational Target. Biochim. Biophys. Acta.1653, 25–40 (2003).
76.
NigroJ. M., TakahashiM. A., GinzingerD. G., LawM., PasseS., JenkinsR. B., and AldapeK. D.Detection of 1p and 19q Loss in Oligodendroglioma by Quantative Microsatellite Analysis, A Real-time Quantative Polymerase Chain Reaction Assay. Am. J. Pathol.158, 1253–1262 (2001).
77.
KitangeG., MisraA., LawM., PasseS., KollmeyerT. M., MaurerM., BallmanK., FeuersteinB. G., and JenkinsR. B.Chromosomal Imbalances Detected by Array Comparative Genomic Hybridization in Human Oligodendrogliomas and Mixed Oligoastrocytomas. Gen. Chrom. Cancer (2004).
78.
VissersL. E., VeltmanJ. A., van KesselA. G., and BrunnerH. G.Identification of Disease Genes by Whole Genome CGH Arrays. Hum. Mol. Genet.14 Spec No. 2, R215–r223 (2005).
79.
SchoutenJ. P., McElgunnC. J., WaaijerR., ZwijnenburgD., DiepvensF., and PalsG.Relative Quantification of 40 Nucleic Acid Sequences by Multiplex Ligation-dependent Probe Amplification. Nucleic Acid Res.30, E57 (2002).
80.
JeukenJ. W. M., CornelissenS., Boots-SprengerS. H. E., GijssenS., and WesselingP.Multiplex Ligation-dependent Probe Amplification (MLPA): A Diagnostic Tool for Simultaneous Identification of Different Genetic Markers in Glial Tumors. J. Mol. Diagn. In Press (2006).
81.
SmithJ. S., PerryA., BorellT. J., LeeH. K., FallonJ. O., HosekS. M., KimmelD., YatesA., BurgerP. C., ScheithauerB. W., and JenkinsR. B.Alterations of Chromosome Arms 1p and 19q as Predictors of Survival in Oligodendrogliomas, Astrocytomas, and Mixed Oligoastrocytomas. J. Clin. Oncol.18, 636–645 (2000).
82.
GersonS. L.MGMT: Its Role in Cancer Aetiology and Cancer Therapeutics. Nat. Rev. Cancer4, 296–307 (2004).
83.
FriedmanH. S., McLendonR. E., KerbyT., DuganM., BignerS. H., HenryA. J., AshleyD. M., KrischerJ., LovellS., RasheedK., MarchevF., SemanA. J., CokgorI., RichJ., StewartE., ColvinO. M., ProvenzaleJ. M., BignerD. D., HaglundM. M., FriedmanA. H., and ModrichP. L.DNA Mismatch Repair and O6-alkylguanine-DNA Alkyltransferase Analysis and Response to Temodal in Newly Diagnosed Malignant Glioma. J. Clin. Oncol.16, 3851–3857 (1998).
84.
NakasuS., FukamiT., BabaK., and MatsudaM.Immunohistochemical Study for O6-methylguanine-DNA Methyltransferase in the Non-neoplastic and Neoplastic Components of Gliomas. J. Neurooncol.70, 333–340 (2004).
85.
HegiM. E., DiserensA. C., GodardS., DietrichP. Y., RegliL., OstermannS., OttenP., van MelleG., de TriboletN., and StuppR.Clinical Trial Substantiates the Predictive Value of O-6-methylguanine-DNA Methyltransferase Promoter Methylation in Glioblastoma Patients Treated with Temozolomide. Clin. Cancer Res.10, 1871–1874 (2004).
86.
SmiragliaD. J. and PlassC.The Study of Aberrant Methylation in Cancer via Restriction Landmark Genomic Scanning. Oncogene21, 5414–5426 (2002).
87.
ClarkS. J., HarrisonJ., PaulC. L., and FrommerM.High Sensitivity Mapping of Methylated Cytosines. Nucleic Acids Res.22, 2990–2997 (1994).
88.
HermanJ. G., GraffJ. R., MyohanenS., NelkinB. D., and BaylinS. B.Methylation-specific PCR: A Novel PCR Assay for Methylation Status of CpG Islands. Proc. Natl. Acad. Sci. USA93, 9821–9826 (1996).
89.
HartmannC., MuellerW., LassU., StockhammerF., von EckardsteinK., VeelkenJ., JeukenJ., WickW., and von DeimlingA.No Preferential Loss of Paternal 19q Alleles in Oligodendroglial Tumors. Ann. Neurol.54, 256–258 (2003).
90.
PetricoinE. F.III, BichselV. E., CalvertV. S., EspinaV., WintersM., YoungL., BellucoC., TrockB. J., LippmanM., FishmanD. A., SgroiD. C., MunsonP. J., EssermanL. J., and LiottaL. A.Mapping Molecular Networks Using Proteomics: A Vision for Patient-tailored Combination Therapy. J. Clin. Oncol.23, 3614–3621 (2005).
91.
TateA. R., UnderwoodJ., AcostaD. M., Julià-SapéM., MajósC., Moreno-TorresA., HoweF., Van der GraafM., LefournierV., MurphyM. M., LoosemoreA., LadroueC., WesselingP., BossonJ. L., CabanasM. E., SimonettiA., GajewiczW., CalvarJ., CapdevillaA., WilkinsP. R., BellB. A., RémyC., HeerschapA., WatsonD., GriffithsJ. R., and ArúsC.Development of a Decision Support System for Diagnosis and Grading of Brain Tumours Using In Vivo Magnetic Resonance Single Voxel Spectra. NMR Biomed. In Press (2006).
92.
BaselgaJ.Anti-EGFR Therapy: A New Targeted Approach to Cancer Treatment. Oncol. Biotherapeutics2, 36 (2002).
93.
SansonM., LeuraudP., MarieY., DelattreJ. Y., and Hoang-XuanK.Preferential Loss of Paternal 19q, but not 1p, Alleles in Oligodendrogliomas. Ann. Neurol.52, 105–107 (2002).
94.
vonD. A., BenderB., LouisD. N., and WiestlerO. D.A Rapid and Non-radioactive PCR Based Assay for the Detection of Allelic Loss in Human Gliomas. Neuropathol. Appl. Neurobiol.19, 524–529 (1993).
