O6-Methylguanine-DNA methyltransferase protein expression by immunohistochemistry in brain and non-brain systemic tumours: systematic review and meta-analysis of correlation with methylation-specific polymerase chain reaction.
BACKGROUND
The DNA repair protein O6-Methylguanine-DNA methyltransferase (MGMT) confers resistance to alkylating agents. Several methods have been applied to its analysis, with methylation-specific polymerase chain reaction (MSP) the most commonly used for promoter methylation study, while immunohistochemistry (IHC) has become the most frequently used for the detection of MGMT protein expression. Agreement on the best and most reliable technique for evaluating MGMT status remains unsettled. The aim of this study was to perform a systematic review and meta-analysis of the correlation between IHC and MSP.


METHODS
A computer-aided search of MEDLINE (1950-October 2009), EBSCO (1966-October 2009) and EMBASE (1974-October 2009) was performed for relevant publications. Studies meeting inclusion criteria were those comparing MGMT protein expression by IHC with MGMT promoter methylation by MSP in the same cohort of patients. Methodological quality was assessed by using the QUADAS and STARD instruments. Previously published guidelines were followed for meta-analysis performance.


RESULTS
Of 254 studies identified as eligible for full-text review, 52 (20.5%) met the inclusion criteria. The review showed that results of MGMT protein expression by IHC are not in close agreement with those obtained with MSP. Moreover, type of tumour (primary brain tumour vs others) was an independent covariate of accuracy estimates in the meta-regression analysis beyond the cut-off value.


CONCLUSIONS
Protein expression assessed by IHC alone fails to reflect the promoter methylation status of MGMT. Thus, in attempts at clinical diagnosis the two methods seem to select different groups of patients and should not be used interchangeably.
Department of Neurosurgery, Son Dureta University Hospital, Palma de Mallorca, Spain. m.brell@telefonica.net
Marta
M
Brell
Javier
J
Ibáñez
Avelina
A
Tortosa
D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019175:DNA Methylation; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction / Q000379:methods; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics
D019853:O(6)-Methylguanine-DNA Methyltransferase
Clin Cancer Res. 2007 Mar 1;13(5):1429-37
17332285
Int J Cancer. 2005 Jan 20;113(3):379-85
15455350
Cancer Genet Cytogenet. 2007 Apr 1;174(1):1-8
17350460
Ann Intern Med. 1994 Apr 15;120(8):667-76
8135452
Intern Emerg Med. 2009 Jun;4(3):255-8
19357825
J Neurooncol. 2007 Jun;83(2):173-9
17219056
Neurol Res. 2003 Apr;25(3):241-8
12739231
J Clin Oncol. 1998 Oct;16(10):3310-5
9779706
Clin Cancer Res. 2003 Nov 1;9(14):5306-12
14614014
Cancer Res. 2001 Apr 15;61(8):3225-9
11309270
J Clin Oncol. 2008 May 10;26(14):2299-304
18467721
Brain Pathol. 2009 Apr;19(2):279-92
18616639
BMC Med Res Methodol. 2006 Jul 12;6:31
16836745
Neuropathology. 2009 Aug;29(4):379-88
19019175
Arch Otolaryngol Head Neck Surg. 2008 Mar;134(3):251-6
18347248
Cancer Res. 1999 Feb 15;59(4):793-7
10029064
Br J Cancer. 2003 Feb 24;88(4):521-9
12592365
Int J Cancer. 2008 Jun 1;122(11):2429-36
18240147
Ann Intern Med. 2008 Dec 16;149(12):889-97
19075208
Lab Invest. 2007 Oct;87(10):1055-65
17700563
Lancet Oncol. 2008 Jan;9(1):29-38
18082451
J Chemother. 2008 Apr;20(2):263-8
18467255
Clin Cancer Res. 2007 May 1;13(9):2606-13
17473190
Clin Cancer Res. 2005 Jul 15;11(14):5167-74
16033832
Mol Carcinog. 2003 May;37(1):32-8
12720298
Oncol Rep. 2010 May;23(5):1269-76
20372840
Carcinogenesis. 2003 Jun;24(6):1039-44
12807758
J Neurooncol. 2010 May;97(3):311-22
19841865
Neuro Oncol. 2004 Jul;6(3):200-7
15279712
J Clin Oncol. 2006 Jul 20;24(21):3431-7
16849758
Cancer Res. 2001 Feb 1;61(3):827-30
11221863
Mol Cancer Ther. 2006 Oct;5(10):2531-9
17041097
Hum Pathol. 2009 Jul;40(7):934-41
19356788
BMJ. 2001 Jul 21;323(7305):157-62
11463691
Nat Genet. 1999 Feb;21(2):163-7
9988266
J Mol Diagn. 2006 Feb;8(1):68-75
16436636
Neuro Oncol. 2009 Aug;11(4):348-56
19224763
N Engl J Med. 2000 Nov 9;343(19):1350-4
11070098
Trends Genet. 2000 Apr;16(4):168-74
10729832
J Neuropathol Exp Neurol. 2008 Jan;67(1):1-15
18091559
J Pathol. 2004 Feb;202(2):233-40
14743506
Carcinogenesis. 2003 Aug;24(8):1337-45
12807730
J Clin Neurosci. 2008 Jan;15(1):1-8
18037296
J Korean Neurosurg Soc. 2009 Oct;46(4):385-8
19893731
Acta Neuropathol. 2008 Feb;115(2):249-59
17965865
Int J Cancer. 2008 Mar 15;122(6):1391-9
18000822
Int J Cancer. 2009 Jun 15;124(12):2872-9
19330828
Int J Cancer. 2006 Nov 15;119(10):2487-91
16858686
BMC Med Res Methodol. 2002 Aug 09;2:10
12171604
Am J Surg Pathol. 2008 Aug;32(8):1220-7
18580490
Acta Neurochir (Wien). 2009 Nov;151(11):1349-58
19730774
Clin Cancer Res. 2004 Mar 15;10(6):1871-4
15041700
N Engl J Med. 2005 Mar 10;352(10):997-1003
15758010
Cancer Genomics Proteomics. 2009 Jul-Aug;6(4):219-27
19656999
Hum Pathol. 2009 Nov;40(11):1534-42
19695681
Histol Histopathol. 2009 Apr;24(4):511-8
19224454
Neurosurgery. 2004 Feb;54(2):349-57; discussion 357
14744281
BMC Med Res Methodol. 2002 Jul 03;2:9
12097142
Ann Intern Med. 2003 Jan 7;138(1):40-4
12513043
Oncol Rep. 2007 Apr;17(4):817-22
17342321
Oncogene. 2002 Dec 12;21(57):8878-84
12483540
Nat Rev Cancer. 2004 Apr;4(4):296-307
15057289
Int J Cancer. 2008 Sep 1;123(5):1215-8
18546261
Clin Neuropathol. 2008 Nov-Dec;27(6):388-90
19130735
Hum Pathol. 2006 Aug;37(8):989-99
16867861
Int J Cancer. 2003 Feb 10;103(4):440-4
12478658
Clin Cancer Res. 2003 Aug 1;9(8):2912-9
12912936
J Mol Diagn. 2007 Jul;9(3):368-81
17591937
Cancer Lett. 2009 Mar 8;275(1):117-26
19027227
J Clin Oncol. 2007 Apr 20;25(12):1459-60
17442986
Leuk Lymphoma. 2009 Dec;50(12):1992-8
19860620
Cancer Prev Res (Phila). 2009 Oct;2(10):862-7
19789298
Pathol Int. 2005 Jun;55(6):303-9
15943786
Neurosurgery. 2009 Nov;65(5):866-75; discussion 875
19834398
Invest Ophthalmol Vis Sci. 2002 May;43(5):1344-9
11980845
J Clin Oncol. 1998 Dec;16(12):3851-7
9850030
Exp Mol Pathol. 2008 Jun;84(3):256-61
18410922
Lab Invest. 2007 Apr;87(4):392-7
17260000
J Neurooncol. 2008 Mar;87(1):71-8
18004504
J Clin Oncol. 2002 May 1;20(9):2388-99
11981013
Clin Biochem. 2008 Jan;41(1-2):19-25
18028895
Int J Clin Oncol. 2010 Aug;15(4):352-8
20232102
BMJ. 1997 Sep 13;315(7109):629-34
9310563
Cochrane Database Syst Rev. 2008 Oct 08;(4):CD007394
18843747
Surg Neurol. 2007 Dec;68(6):603-608
17825378
J Natl Cancer Inst. 2002 Jan 2;94(1):26-32
11773279
Clin Neuropathol. 2004 Jan-Feb;23(1):21-7
14986930
Ann Neurol. 2006 Dec;60(6):740-3
17192931
N Engl J Med. 2003 Nov 20;349(21):2042-54
14627790
Am J Clin Pathol. 2007 Mar;127(3):366-73
17276933
Clin Cancer Res. 2009 Nov 1;15(21):6683-93
19861461
J Clin Pathol. 2009 Aug;62(8):715-23
19638543
Mod Pathol. 2006 Jul;19(7):914-21
16607377
Epigenetics Chromatin. 2008 Nov 03;1(1):7
19014416
J Cancer Res Clin Oncol. 2005 Jun;131(6):364-70
15785933
World J Gastroenterol. 2005 Apr 7;11(13):2022-5
15800999
Int J Oncol. 2008 Sep;33(3):469-75
18695875
Cancer Res. 2001 Nov 15;61(22):8113-7
11719438
J Clin Epidemiol. 2001 Oct;54(10):1046-55
11576817
Neuro Oncol. 2010 Mar;12(3):283-8
20167816
J Clin Oncol. 2007 Apr 20;25(12):1470-5
17442989
J Clin Epidemiol. 2003 Nov;56(11):1129-35
14615004
Eur J Cancer. 2009 Jan;45(1):146-53
18945611
Cancer. 2001 Dec 1;92(11):2760-8
11753949
Oncogene. 2004 Jan 8;23(1):1-8
14712205
Brain Pathol. 2008 Oct;18(4):520-32
18400046
Gynecol Oncol. 2009 Jan;112(1):224-8
18973931
J Neurooncol. 2004 Dec;70(3):333-40
15662974
Ann Surg Oncol. 2005 May;12(5):354-63
15915369
Appl Immunohistochem Mol Morphol. 2008 Jan;16(1):59-65
18091318
Haematologica. 2004 Feb;89(2):154-64
15003890
Jpn J Cancer Res. 2002 Feb;93(2):184-9
11856482
BMC Med Res Methodol. 2003 Nov 10;3:25
14606960
Mod Pathol. 2006 Jan;19(1):106-14
16258501
Mol Carcinog. 2003 Jan;36(1):23-31
12503076
Jpn J Clin Oncol. 2007 Dec;37(12):897-906
18156172
Lung Cancer. 2010 Jun;68(3):484-90
19740564
Curr Opin Oncol. 2007 Nov;19(6):606-11
17906460
Mol Cell Biol. 1991 Sep;11(9):4660-8
1875945
Br J Cancer. 2002 Jun 17;86(12):1888-92
12085181
Cancer Sci. 2006 Dec;97(12):1335-42
17032312
Lab Invest. 1998 May;78(5):643-4
9605190
Mol Carcinog. 1999 Feb;24(2):90-8
10078936
Int J Cancer. 2005 Feb 10;113(4):581-7
15455376
Clin Cancer Res. 2007 Apr 1;13(7):2038-45
17404084
J Mol Diagn. 2008 Jul;10(4):308-10
18556768
Acta Neuropathol. 2003 Nov;106(5):479-85
12904991
J Clin Oncol. 2005 Apr 1;23(10):2318-24
15800322
Int J Cancer. 2006 Jul 15;119(2):264-8
16477636
Int J Cancer. 2010 Nov 1;127(9):2106-18
20131314
Nat Rev Neurol. 2010 Jan;6(1):39-51
19997073
J Natl Cancer Inst. 2005 Sep 21;97(18):1330-8
16174854
Cancer. 2009 Oct 15;115(20):4783-94
19637364
Carcinogenesis. 2000 Mar;21(3):461-7
10688866
PLoS One. 2009;4(3):e4775
19274096
Int J Cancer. 2007 Dec 1;121(11):2458-64
17691113
Clin Endocrinol (Oxf). 2009 Aug;71(2):226-33
19067722
BMJ. 2003 Sep 6;327(7414):557-60
12958120