title: LOH in the HLA class I region at 6p21 is associated with shorter survival in newly diagnosed adult glioblastoma.
abstract: OBJECTIVE
  Glioblastoma (GBM) shows downregulated expression of human leukocyte antigen (HLA) class I, thereby escaping from cytotoxic T cells and limiting the efficacy of immunotherapy. Loss of heterozygosity (LOH) of HLA class I (6p21) and/or β-2 microglobulin (B2m) (15q21) regions represents irreversible downregulation. In this study, we examined the prevalence of these LOH events and their relations with overall survival in GBM.
  
  
  METHODS
  In a cross-sectional analysis on 60 adult patients with GBM, DNA from formalin-fixed, paraffin-embedded specimens were evaluated for 10 microsatellite regions of HLA class I, B2m, HLA class II, HLA class III, and 6q by PCR as well as immunohistochemical evaluation of HLA class I expression and CD8(+) T-cell infiltration.
  
  
  RESULTS
  LOH in HLA class I, B2m, HLA class II, HLA class III, and 6q regions was present in 41.4%, 18.2%, 9.4%, 77.8%, and 36.0% of informative cases, respectively. LOH of HLA class I was associated with shorter overall survival (HR = 4.89, P = 0.0078). HLA class I was downregulated in 22% to 43% of cases based on immunohistochemistry. Cases that displayed negative staining were significantly younger. HLA class I expression correlated with intratumoral CD8(+) T-cell infiltration.
  
  
  CONCLUSIONS
  LOH in the HLA class I region is frequent in adult GBMs. The association of shorter survival with LOH in this region suggests a crucial role for these genes in immunosurveillance.
authors: Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: Jacky T
authors: JT
authors: Yeung
authors: Ronald L
authors: RL
authors: Hamilton
authors: Koji
authors: K
authors: Ohnishi
authors: Maki
authors: M
authors: Ikeura
authors: Douglas M
authors: DM
authors: Potter
authors: Marina N
authors: MN
authors: Nikiforova
authors: Soldano
authors: S
authors: Ferrone
authors: Regina I
authors: RI
authors: Jakacki
authors: Ian F
authors: IF
authors: Pollack
authors: Hideho
authors: H
authors: Okada
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D002884:Chromosomes, Human, Pair 15; D002896:Chromosomes, Human, Pair 6; D016000:Cluster Analysis; D005260:Female; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality*; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D019656:Loss of Heterozygosity; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D011379:Prognosis
chemical_list: D015395:Histocompatibility Antigens Class I
references: Hum Immunol. 1996 Apr 15-May;47(1-2):1-184
references: 8909580
references: J Neuroinflammation. 2010 Mar 06;7:16
references: 20205746
references: J Neurosurg. 2006 Feb;104(2):264-71
references: 16509500
references: Am J Surg Pathol. 2012 Aug;36(8):1186-93
references: 22472960
references: Immunogenetics. 2004 Jul;56(4):244-53
references: 15258706
references: Cancer Immunol Immunother. 2012 Jun;61(6):789-801
references: 22065046
references: Carcinogenesis. 2012 Mar;33(3):687-93
references: 22219178
references: Cancer Immunol Immunother. 2010 Jan;59(1):13-26
references: 19430787
references: Cancer Immunol Immunother. 2002 Sep;51(7):389-96
references: 12192539
references: Oncogene. 1998 Apr 30;16(17):2213-8
references: 9619830
references: Gynecol Oncol. 2001 Mar;80(3):364-71
references: 11263933
references: N Engl J Med. 2005 Mar 10;352(10):987-96
references: 15758009
references: Lab Invest. 2004 May;84(5):649-57
references: 15048133
references: Cancer Immunol Immunother. 2010 Oct;59(10):1601-6
references: 20625726
references: Br J Cancer. 2000 Feb;82(3):543-9
references: 10682663
references: Genes Chromosomes Cancer. 1995 Jun;13(2):86-93
references: 7542911
references: Clin Cancer Res. 2011 Jul 1;17(13):4296-308
references: 21478334
references: Biochim Biophys Acta. 2004 Nov 29;1695(1-3):225-33
references: 15571818
references: Cancer Res. 2007 Jun 1;67(11):5471-8
references: 17545629
references: J Clin Neurosci. 2010 Nov;17(11):1381-5
references: 20727764
references: Tissue Antigens. 1999 Sep;54(3):235-45
references: 10519360
references: Neuro Oncol. 2004 Jul;6(3):227-35
references: 15279715
references: J Cancer Res Clin Oncol. 2012 May;138(5):723-8
references: 22426959
references: Arch Pathol Lab Med. 2011 May;135(5):558-68
references: 21526954
references: Lab Invest. 2003 Mar;83(3):419-28
references: 12649342
references: Neuro Oncol. 2012 Jun;14(6):777-89
references: 22492957
references: Oncogene. 1996 Sep 5;13(5):983-94
references: 8806688
references: Cancer Res. 2012 Mar 1;72(5):1070-80
references: 22266112
references: J Neurosurg. 2001 Aug;95(2):190-8
references: 11780887
references: Int J Cancer. 2003 Mar 1;103(6):759-67
references: 12516095
references: Oncology. 2004;66(5):395-403
references: 15331927
references: Proc Natl Acad Sci U S A. 1971 Apr;68(4):820-3
references: 5279523
references: Immunogenetics. 2006 Jul;58(7):503-10
references: 16705407
references: Pathol Int. 2009 Apr;59(4):205-17
references: 19351363
references: Adv Immunol. 2000;74:181-273
references: 10605607
references: Int J Cancer. 2002 Apr 1;98(4):609-15
references: 11920623
references: J Natl Cancer Inst. 2012 Aug 22;104(16):1251-9
references: 22855780
references: Cell Mol Life Sci. 1999 Oct 30;56(5-6):481-506
references: 11212300
references: Immunology. 1992 Feb;75(2):269-74
references: 1551690
references: Acta Neuropathol. 2010 May;119(5):641-9
references: 20044755
references: Brain Pathol. 1996 Jul;6(3):217-23; discussion 23-4
references: 8864278
references: Immunogenetics. 2011 Feb;63(2):65-71
references: 21086121
references: Acta Neurol Scand. 2010 Sep;122(3):159-67
references: 20298491
references: Clin Cancer Res. 2005 Dec 1;11(23):8304-11
references: 16322289
references: J Hum Genet. 2009 Jan;54(1):15-39
references: 19158813
references: Cancer Res. 1995 May 15;55(10):2169-72
references: 7743519