Open AccessMGMT inactivation as a new biomarker in patients with advanced biliary tract cancers
Author(s) -
Niger Monica,
Nichetti Federico,
CasadeiGardini Andrea,
Morano Federica,
Pircher Chiara,
Tamborini Elena,
Perrone Federica,
Canale Matteo,
Lipka Daniel B.,
Vingiani Andrea,
Agnelli Luca,
Dobberkau Anna,
Hüllein Jennifer,
Korell Felix,
Heilig Christoph E.,
Pusceddu Sara,
Corti Francesca,
Droz Michele,
Ulivi Paola,
Prisciandaro Michele,
Antista Maria,
Bini Marta,
Cattaneo Laura,
Milione Massimo,
Glimm Hanno,
Köhler Bruno C.,
Pruneri Giancarlo,
Hübschmann Daniel,
Fröhling Stefan,
Mazzaferro Vincenzo,
Pietrantonio Filippo,
Di Bartolomeo Maria,
Braud Filippo
Publication year - 2022
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.13256
Subject(s) - medicine , oncology , cohort , methyltransferase , immunohistochemistry , biomarker , cancer , epigenetics , cancer research , biology , methylation , dna , gene , biochemistry , genetics
Biliary tract cancers (BTCs) have poor prognosis and limited therapeutic options. The impact of O 6 ‐methylguanine‐DNA methyltransferase ( MGMT ) inactivation in advanced BTC patients is not established. We investigated the prevalence, prognostic, and predictive impact of MGMT inactivation in two multicenter cohorts. MGMT inactivation was assessed through PCR and immunohistochemistry (IHC) in an Italian cohort; the results were then externally validated using RNA sequencing (RNA‐seq) data from the BTC subcohort of the Molecularly Aided Stratification for Tumor Eradication Research (MASTER) precision oncology program of the National Center for Tumor Diseases Heidelberg and the German Cancer Consortium. Among 164 Italian cases, 18% presented MGMT promoter hypermethylation (> 14%) and 73% had negative MGMT protein expression. Both were associated with worse overall survival (OS; HR 2.31; P < 0.001 and HR 1.99, P = 0.012, respectively). In the MASTER cohort, patients with lower MGMT mRNA expression showed significantly poorer OS (median OS [mOS] 20.4 vs 31.7 months, unadjusted HR 1.89; P = 0.043). Our results suggest that MGMT inactivation is a frequent epigenetic alteration in BTC, with a significant prognostic impact, and provide the rationale to explore DNA‐damaging agents in MGMT ‐inactivated BTCs.