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

Lung squamous cell carcinoma associated with hypoparathyroidism with sensorineural deafness and renal dysplasia syndrome: a case report

Mariko Kojima,1 Tatsuya Nagano,1 Kyosuke Nakata,1 Shigeo Hara,2 Naoko Katsurada,1 Masatsugu Yamamoto,1 Motoko Tachihara,1 Hiroshi Kamiryo,1 Kazuyuki Kobayashi,1 Takeshi Usui,3 Yoshihiro Nishimura1 1Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan; 2Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan; 3Department of Medical Genetics, Shizuoka General Hospital, Shizuoka City, Shizuoka, Japan Abstract: Hypoparathyroidism with sensorineural deafness and renal dysplasia (HDR) syndrome is an autosomal dominant condition caused by mutations of the gene encoding the dual zinc-finger transcription factor, GATA3. A previous study identified some patients with GATA3 gene variants and breast cancer, suggesting that GATA3 variants may contribute to tumorigenesis in estrogen receptor 1-positive breast tumors; however, these patients did not have HDR syndrome. A 32-year-old nonsmoking Japanese woman was histologically diagnosed with lung squamous cell carcinoma associated with HDR syndrome and a c.C952T>C (p.C318R) germline mutation in GATA3. This is the first report describing cancer in a patient with HDR syndrome. Our data indicates that GATA3 mutations may be a potential therapeutic target for lung cancer. Keywords: lung cancer, GATA3, missense variant, hypoparathyroidism, sensorineural deafness, renal dysplasi