title: Chronic viral infection and primary central nervous system malignancy.
abstract: Primary central nervous system (CNS) tumors cause significant morbidity and mortality in both adults and children. While some of the genetic and molecular mechanisms of neuro-oncogenesis are known, much less is known about possible epigenetic contributions to disease pathophysiology. Over the last several decades, chronic viral infections have been associated with a number of human malignancies. In primary CNS malignancies, two families of viruses, namely polyomavirus and herpesvirus, have been detected with varied frequencies in a number of pediatric and adult histological tumor subtypes. However, establishing a link between chronic viral infection and primary CNS malignancy has been an area of considerable controversy, due in part to variations in detection frequencies and methodologies used among researchers. Since a latent viral neurotropism can be seen with a variety of viruses and a widespread seropositivity exists among the population, it has been difficult to establish an association between viral infection and CNS malignancy based on epidemiology alone. While direct evidence of a role of viruses in neuro-oncogenesis in humans is lacking, a more plausible hypothesis of neuro-oncomodulation has been proposed. The overall goals of this review are to summarize the many human investigations that have studied viral infection in primary CNS tumors, discuss potential neuro-oncomodulatory mechanisms of viral-associated CNS disease and propose future research directions to establish a more firm association between chronic viral infections and primary CNS malignancies.
authors.affiliation: School of Medicine, University of California, San Diego, CA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Saddawi-Konefka
authors.forename: John R
authors.initials: JR
authors.lastname: Crawford
mesh_terms: D000328:Adult; D016543:Central Nervous System Neoplasms / Q000209:etiology / Q000821:virology*; D020805:Central Nervous System Viral Diseases / Q000150:complications* / Q000821:virology; D002648:Child; D003586:Cytomegalovirus Infections / Q000150:complications / Q000821:virology; D006561:Herpes Simplex / Q000150:complications / Q000821:virology; D018259:Herpesvirus 1, Human / Q000502:physiology; D018258:Herpesvirus 2, Human / Q000502:physiology; D015654:Herpesvirus 6, Human / Q000502:physiology; D006801:Humans; D007577:JC Virus / Q000502:physiology; D027601:Polyomavirus Infections / Q000150:complications / Q000821:virology; D019349:Roseolovirus Infections / Q000150:complications / Q000821:virology; D014412:Tumor Virus Infections / Q000150:complications / Q000821:virology
references.citation: Neuro Oncol. 2002 Oct;4(4):278-99
references.pmid: 12356358
references.citation: J Cell Biochem. 1990 Jan;42(1):13-31
references.pmid: 2153691
references.citation: Proc Natl Acad Sci U S A. 1987 Jan;84(1):16-20
references.pmid: 3025851
references.citation: Acta Neuropathol. 2006 Apr;111(4):388-96
references.pmid: 16557392
references.citation: J Med Virol. 2003 Sep;71(1):115-23
references.pmid: 12858417
references.citation: Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7352-7
references.pmid: 8692997
references.citation: Lancet. 1988 May 14;1(8594):1065-7
references.pmid: 2896909
references.citation: J Clin Microbiol. 1989 Apr;27(4):651-3
references.pmid: 2542358
references.citation: Brain Pathol. 1999 Jan;9(1):33-42
references.pmid: 9989448
references.citation: Pediatr Infect Dis J. 2006 Sep;25(9):841-2
references.pmid: 16940845
references.citation: J Neurosurg. 2005 Apr;102(3 Suppl):294-8
references.pmid: 15881753
references.citation: J Virol. 2003 Mar;77(5):2807-18
references.pmid: 12584304
references.citation: Pediatrics. 2008 Sep;122(3):513-20
references.pmid: 18762520
references.citation: Adv Cancer Res. 1991;57:47-85
references.pmid: 1835254
references.citation: J Natl Cancer Inst. 2009 Apr 1;101(7):488-97
references.pmid: 19318640
references.citation: Hum Pathol. 2000 Mar;31(3):394-5
references.pmid: 10746685
references.citation: J Virol. 2000 Feb;74(3):1158-67
references.pmid: 10627526
references.citation: Cancer Res. 1996 Oct 15;56(20):4820-5
references.pmid: 8841004
references.citation: Adv Exp Med Biol. 2006;577:1-18
references.pmid: 16626024
references.citation: Semin Cancer Biol. 2009 Aug;19(4):252-60
references.pmid: 19505653
references.citation: J Virol. 1995 Nov;69(11):6697-704
references.pmid: 7474079
references.citation: Trends Mol Med. 2004 Jan;10(1):19-23
references.pmid: 14720582
references.citation: Cancer Res. 2003 Jul 15;63(14):4181-7
references.pmid: 12874024
references.citation: Int J Cancer. 2002 Oct 1;101(4):348-52
references.pmid: 12209959
references.citation: Tissue Antigens. 2000 May;55(5):412-21
references.pmid: 10885561
references.citation: J Gen Virol. 1988 Jul;69 ( Pt 7):1531-74
references.pmid: 2839594
references.citation: J Mol Diagn. 2001 Feb;3(1):1-10
references.pmid: 11227065
references.citation: J Biol Chem. 2004 Sep 10;279(37):38325-30
references.pmid: 15247271
references.citation: Neuro Oncol. 2008 Feb;10(1):10-8
references.pmid: 17951512
references.citation: Neuro Oncol. 2002 Jul;4(3):165-70
references.pmid: 12084346
references.citation: Cancer Epidemiol Biomarkers Prev. 2003 May;12(5):460-3
references.pmid: 12750243
references.citation: J Natl Cancer Inst. 2002 Feb 20;94(4):267-73
references.pmid: 11854388
references.citation: J Med Virol. 1995 Sep;47(1):105-11
references.pmid: 8551252
references.citation: Intervirology. 1996;39(4):259-69
references.pmid: 9078467
references.citation: J Gen Virol. 1990 Nov;71 ( Pt 11):2731-6
references.pmid: 2174963
references.citation: J Cell Physiol. 2005 Aug;204(2):402-6
references.pmid: 15690396
references.citation: Oncogene. 1997 Jan 23;14(3):359-67
references.pmid: 9018122
references.citation: Curr Infect Dis Rep. 2004 Aug;6(4):316-321
references.pmid: 15265461
references.citation: Neuropathology. 2001 Jun;21(2):129-37
references.pmid: 11396678
references.citation: Virology. 2009 Feb 20;384(2):294-303
references.pmid: 19070883
references.citation: J Infect Dis. 2000 Sep;182(3):643-51
references.pmid: 10950755
references.citation: Mod Pathol. 2005 Jun;18(6):838-43
references.pmid: 15578071
references.citation: Science. 2009 Jan 2;323(5910):30-1
references.pmid: 19119195
references.citation: Brain Res Brain Res Rev. 2005 Dec 1;50(1):69-85
references.pmid: 15982744
references.citation: Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11519-24
references.pmid: 10500209
references.citation: Virology. 1998 Apr 10;243(2):492-6
references.pmid: 9568046
references.citation: Am J Pathol. 1999 Jul;155(1):285-92
references.pmid: 10393860
references.citation: Brain Res. 2008 Jul 24;1221:108-14
references.pmid: 18565499
references.citation: Nat Rev Cancer. 2002 Dec;2(12):957-64
references.pmid: 12459734
references.citation: N Engl J Med. 2005 Feb 24;352(8):768-76
references.pmid: 15728809
references.citation: J Neurovirol. 1997 May;3 Suppl 1:S78-9
references.pmid: 9179802
references.citation: J Virol. 2001 Jul;75(13):6022-32
references.pmid: 11390604
references.citation: J Clin Pathol. 1999 Aug;52(8):620-3
references.pmid: 10645234
references.citation: J Virol. 2002 Dec;76(24):12803-12
references.pmid: 12438605
references.citation: Am J Epidemiol. 2001 Jul 15;154(2):161-5
references.pmid: 11447050
references.citation: Int J Cancer. 1987 Jan 15;39(1):60-7
references.pmid: 3025111
references.citation: Clin Infect Dis. 1998 Jan;26(1):132-7
references.pmid: 9455521
references.citation: J Neurooncol. 1994;20(1):55-8
references.pmid: 7807184
references.citation: Indian J Pathol Microbiol. 2009 Jan-Mar;52(1):42-5
references.pmid: 19136778
references.citation: PLoS Pathog. 2009 Jul;5(7):e1000523
references.pmid: 19649277
references.citation: Semin Cancer Biol. 2009 Aug;19(4):270-5
references.pmid: 19416753
references.citation: J Med Virol. 2001 Jan;63(1):45-51
references.pmid: 11130886
references.citation: J Med Virol. 2002 Apr;66(4):497-505
references.pmid: 11857528
references.citation: FEMS Microbiol Rev. 2004 Feb;28(1):59-77
references.pmid: 14975530
references.citation: J Virol. 2002 Apr;76(8):3731-8
references.pmid: 11907212
references.citation: J Clin Virol. 2009 Sep;46(1):37-42
references.pmid: 19505845
references.citation: J Virol. 1994 Jun;68(6):3917-24
references.pmid: 8189528
references.citation: Int J Cancer. 2003 Aug 10;106(1):140-2; author reply 143-5
references.pmid: 12794770
references.citation: Science. 1978 Sep 29;201(4362):1246-9
references.pmid: 211583
references.citation: Nature. 2008 Sep 18;455(7211):391-5
references.pmid: 18701889
references.citation: J Virol. 1998 Mar;72(3):2010-21
references.pmid: 9499055
references.citation: J Neurooncol. 2007 Dec;85(3):271-80
references.pmid: 17589804
references.citation: Cell Div. 2009 Jan 15;4:1
references.pmid: 19146698
references.citation: Cell Mol Life Sci. 2004 Jun;61(11):1307-16
references.pmid: 15170509
references.citation: Cancer Res. 2008 Feb 1;68(3):724-30
references.pmid: 18245472
references.citation: Lancet. 1971 Jun 19;1(7712):1257-60
references.pmid: 4104715
references.citation: Int J Cancer. 1995 Jun 9;61(6):756-60
references.pmid: 7790107
references.citation: Pathology. 2003 Jun;35(3):248-53
references.pmid: 14506971
references.citation: Acta Neuropathol. 2008 Jul;116(1):79-86
references.pmid: 18351367
references.citation: J Virol. 2003 Jun;77(12):7007-16
references.pmid: 12768019
references.citation: Folia Microbiol (Praha). 2003;48(3):291-318
references.pmid: 12879740
references.citation: Science. 1973 Aug 17;181(4100):674-6
references.pmid: 4353360
references.citation: Cancer. 2008 Oct 1;113(7 Suppl):1953-68
references.pmid: 18798534
references.citation: J Neurovirol. 1998 Apr;4(2):242-5
references.pmid: 9584961
references.citation: Herpes. 2008 Nov;15(2):28-32
references.pmid: 19856545
references.citation: Acta Vet Hung. 2000;48(4):477-84
references.pmid: 11402664
references.citation: Virology. 2004 Jan 5;318(1):1-9
references.pmid: 15015494
references.citation: J Virol. 1996 Apr;70(4):2378-86
references.pmid: 8642665
references.citation: J Clin Oncol. 2005 Nov 1;23(31):7951-7
references.pmid: 16258095
references.citation: Curr Top Microbiol Immunol. 2004;273:215-44
references.pmid: 14674603
references.citation: Am J Epidemiol. 2005 May 15;161(10):929-38
references.pmid: 15870157
references.citation: Semin Cancer Biol. 2004 Oct;14(5):387-96
references.pmid: 15288264
references.citation: Virology. 2009 Feb 20;384(2):266-73
references.pmid: 18995875
references.citation: N Engl J Med. 1992 Apr 9;326(15):988-93
references.pmid: 1312224
references.citation: Mol Cell Biol. 1999 May;19(5):3607-13
references.pmid: 10207084
references.citation: Br J Cancer. 2005 Feb 28;92(4):747-50
references.pmid: 15700045
references.citation: Oncogene. 2003 Aug 11;22(33):5192-200
references.pmid: 12910256
references.citation: Adv Exp Med Biol. 2006;577:342-56
references.pmid: 16626047
references.citation: J Clin Invest. 1997 Oct 15;100(8):2054-61
references.pmid: 9329970
references.citation: J Clin Microbiol. 2008 Aug;46(8):2700-6
references.pmid: 18550745
references.citation: Neurology. 1979 Dec;29(12):1590-4
references.pmid: 228217
references.citation: Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2836-41
references.pmid: 11867723
references.citation: Adv Virus Res. 1998;50:69-99
references.pmid: 9520997
references.citation: J Virol. 2003 Jan;77(1):631-41
references.pmid: 12477866
references.citation: Rev Med Virol. 2009 Jul;19(4):185-99
references.pmid: 19530118
references.citation: Clin Diagn Virol. 1994 Jun;2(3):211-20
references.pmid: 15566767
references.citation: Proc Natl Acad Sci U S A. 1981 Oct;78(10):6446-50
references.pmid: 6273871
references.citation: Int J Cancer. 2008 Jul 15;123(2):247-250
references.pmid: 18449881
references.citation: Mol Pathol. 2001 Oct;54(5):331-7
references.pmid: 11577176
references.citation: Adv Exp Med Biol. 2006;577:319-41
references.pmid: 16626046
references.citation: Proc Natl Acad Sci U S A. 2001 Jul 3;98(14):7829-34
references.pmid: 11427719
references.citation: Virology. 1984 Jul 30;136(2):359-67
references.pmid: 6087549
references.citation: Herpes. 2004 Jun;11 Suppl 2:120A-127A
references.pmid: 15319099
references.citation: Med Microbiol Immunol. 2009 May;198(2):79-81
references.pmid: 19198878
references.citation: J Virol. 2003 May;77(9):5039-45
references.pmid: 12692206
references.citation: J Virol. 1997 Jul;71(7):5620-3
references.pmid: 9188637
references.citation: Virology. 1995 Oct 1;212(2):710-7
references.pmid: 7571441
references.citation: Semin Cancer Biol. 2001 Feb;11(1):49-61
references.pmid: 11243899
references.citation: J Gen Virol. 2001 Mar;82(Pt 3):493-497
references.pmid: 11172089
references.citation: Nature. 2003 Jul 24;424(6947):456-61
references.pmid: 12879076
references.citation: Semin Cancer Biol. 2009 Aug;19(4):261-9
references.pmid: 19505654
references.citation: Acta Neurochir (Wien). 1978;43(3-4):239-49
references.pmid: 212932
references.citation: Cancer Res. 2001 May 15;61(10):4287-93
references.pmid: 11358858
references.citation: N Engl J Med. 1994 Aug 18;331(7):432-8
references.pmid: 8035839
references.citation: J Neurosurg. 2001 Jul;95(1):96-101
references.pmid: 11453404
references.citation: J Neurovirol. 2007;13(1):85; author reply 86-7
references.pmid: 17454453
references.citation: J Gen Virol. 1997 Dec;78 ( Pt 12):3341-8
references.pmid: 9400986
references.citation: Sci STKE. 2006 May 16;2006(335):re4
references.pmid: 16705130
references.citation: Cancer Res. 2002 Jun 15;62(12):3347-50
references.pmid: 12067971
references.citation: J Neurooncol. 2009 Oct;95(1):49-60
references.pmid: 19424665
references.citation: Am J Epidemiol. 1997 Apr 1;145(7):594-7
references.pmid: 9098175
references.citation: Int J Cancer. 1978 Jan 15;21(1):12-7
references.pmid: 203540
references.citation: Ann Neurol. 2008 Oct;64(4):379-87
references.pmid: 18688812
references.citation: Mol Cell Biol. 1990 Jan;10(1):120-30
references.pmid: 2136765
references.citation: Clin Microbiol Rev. 2005 Jan;18(1):217-45
references.pmid: 15653828
references.citation: Virology. 1991 Jan;180(1):49-57
references.pmid: 1845837
references.citation: J Neurovirol. 2006 Apr;12(2):90-9
references.pmid: 16798670
references.citation: Yale J Biol Med. 2006 Dec;79(3-4):115-22
references.pmid: 17940621
references.citation: Apoptosis. 2005 Mar;10(2):251-65
references.pmid: 15843887
references.citation: Prog Clin Biol Res. 1983;105:227-37
references.pmid: 6304760
references.citation: BMC Med Genomics. 2009 May 08;2:22
references.pmid: 19426505
references.citation: Neurology. 2002 Mar 26;58(6):895-900
references.pmid: 11914404
references.citation: Virology. 1987 Sep;160(1):268-70
references.pmid: 2820135
references.citation: J Virol. 2007 Jul;81(14):7629-35
references.pmid: 17494079
references.citation: Lancet. 1971 Jun 19;1(7712):1253-7
references.pmid: 4104714
references.citation: N Engl J Med. 2008 Jul 31;359(5):539-41
references.pmid: 18669440
references.citation: Oncogene. 2002 Feb 14;21(8):1141-9
references.pmid: 11850833
references.citation: Adv Exp Med Biol. 2006;577:310-8
references.pmid: 16626045
references.citation: J Virol. 1984 Mar;49(3):848-56
references.pmid: 6321769
references.citation: J Gen Virol. 1986 Sep;67 ( Pt 9):1759-816
references.pmid: 3018124
references.citation: Proc Soc Exp Biol Med. 1962 Nov;111:343-4
references.pmid: 14002172
references.citation: Virology. 1996 Aug 15;222(2):365-74
references.pmid: 8806520
references.citation: J Neurovirol. 2003 Apr;9(2):173-82
references.pmid: 12707848
references.citation: Brain Pathol. 2000 Jan;10(1):85-92
references.pmid: 10668898
references.citation: Dis Markers. 2001;17(3):149-51
references.pmid: 11790879
references.citation: Br J Cancer. 2009 Apr 21;100(8):1292-302
references.pmid: 19293793
references.citation: Ann Neurol. 2000 Dec;48(6):932-6
references.pmid: 11117551