Digital PCR quantification of MGMT methylation refines prediction of clinical benefit from alkylating agents in glioblastoma and metastatic colorectal cancer

被引：95

作者：

Barault, L. ^{[1
]}

Amatu, A. ^{[2
]}

Bleeker, F. E. ^{[3
]}

Moutinho, C. ^{[4
]}

Falcomata, C. ^{[1
]}

Fiano, V. ^{[5
]}

Cassingena, A. ^{[2
]}

Siravegna, G. ^{[1
,6
,7
]}

Milione, M. ^{[8
]}

Cassoni, P. ^{[5
]}

De Braud, F. ^{[9
]}

Ruda, R. ^{[10
,11
]}

Soffietti, R. ^{[10
,11
]}

Venesio, T. ^{[1
]}

Bardelli, A. ^{[1
,6
]}

Wesseling, P. ^{[12
,13
]}

Hamer, P. de Witt ^{[14
]}

Pietrantonio, F. ^{[8
]}

Siena, S. ^{[2
]}

Esteller, M. ^{[4
,15
,16
]}

Sartore-Bianchi, A. ^{[2
]}

Di Nicolantonio, F. ^{[1
,6
]}

机构：

[1] IRCCS, Candiolo Canc Inst FPO, Expt Clin Mol Oncol, Candiolo, Turin, Italy

[2] Osped Niguarda Ca Granda, Niguarda Canc Ctr, Milan, Italy

[3] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, NL-1105 AZ Amsterdam, Netherlands

[4] Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Program PEBC, Barcelona, Spain

[5] Univ Turin, Citte Salute & Sci Hosp, Dept Med Sci, Turin, Italy

[6] Univ Torino, Dept Oncol, Candiolo, Turin, Italy

[7] FIRC Inst Mol Oncol IFOM, Milan, Italy

[8] Ist Nazl Tumori, Fdn IRCCS, Dept Pathol & Lab Med, I-20133 Milan, Italy

[9] Ist Nazl Tumori, Fdn IRCCS, Dept Med Oncol, I-20133 Milan, Italy

[10] Univ Turin, Dept Neurooncol, Turin, Italy

[11] Citte Salute & Sci Hosp, Turin, Italy

[12] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, Amsterdam, Netherlands

[13] Radboud Univ Nijmegen, Med Ctr, Dept Pathol, NL-6525 ED Nijmegen, Netherlands

[14] Vrije Univ Amsterdam, Med Ctr, Neurosurg Ctr Amsterdam, Dept Neurosurg, Amsterdam, Netherlands

[15] Univ Barcelona, Sch Med, Dept Physiol Sci 2, Catalonia, Spain

[16] ICREA, Barcelona, Spain

来源：

ANNALS OF ONCOLOGY | 2015年 / 26卷 / 09期

关键词：

MGMT; DNA methylation; digital PCR; metastatic colorectal cancer; alkylating agent; cell free circulating DNA; PROMOTER METHYLATION; PHASE-II; TEMOZOLOMIDE; DNA; HYPERMETHYLATION; IMMUNOHISTOCHEMISTRY; DACARBAZINE; EXPRESSION; SURVIVAL; ANALYZE;

D O I：

10.1093/annonc/mdv272

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

O-6-methyl-guanine-methyl-transferase (MGMT) silencing by promoter methylation may identify cancer patients responding to the alkylating agents dacarbazine or temozolomide. We evaluated the prognostic and predictive value of MGMT methylation testing both in tumor and cell-free circulating DNA (cfDNA) from plasma samples using an ultra-sensitive two-step digital PCR technique (methyl-BEAMing). Results were compared with two established techniques, methylation-specific PCR (MSP) and Bs-pyrosequencing. Thresholds for MGMT methylated status for each technique were established in a training set of 98 glioblastoma (GBM) patients. The prognostic and the predictive value of MGMT methylated status was validated in a second cohort of 66 GBM patients treated with temozolomide in which methyl-BEAMing displayed a better specificity than the other techniques. Cutoff values of MGMT methylation specific for metastatic colorectal cancer (mCRC) tissue samples were established in a cohort of 60 patients treated with dacarbazine. In mCRC, both quantitative assays methyl-BEAMing and Bs-pyrosequencing outperformed MSP, providing better prediction of treatment response and improvement in progression-free survival (PFS) (P < 0.001). Ability of methyl-BEAMing to identify responding patients was validated in a cohort of 23 mCRC patients treated with temozolomide and preselected for MGMT methylated status according to MSP. In mCRC patients treated with dacarbazine, exploratory analysis of cfDNA by methyl-BEAMing showed that MGMT methylation was associated with better response and improved median PFS (P = 0.008). Methyl-BEAMing showed high reproducibility, specificity and sensitivity and was applicable to formalin-fixed paraffin-embedded tissues and cfDNA. This study supports the quantitative assessment of MGMT methylation for clinical purposes since it could refine prediction of response to alkylating agents.

引用

页码：1994 / 1999

页数：6

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