Originally published as JCO Early Release 10.1200/JCO.2008.18.8623 on March 16 2009

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Microsatellite Instability, Mismatch Repair Deficiency, and BRAF Mutation in Treatment-Resistant Germ Cell Tumors

Friedemann Honecker, Hendrik Wermann, Frank Mayer, Ad J.M. Gillis, Hans Stoop, Ruud J.L.M. van Gurp, Karin Oechsle, Ewout Steyerberg, Jörg Th. Hartmann, Winand N.M. Dinjens, J. Wolter Oosterhuis, Carsten Bokemeyer, Leendert H.J. Looijenga

From the Departments of Oncology, Hematology, and Bone Marrow Transplantation with section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg; Departments of Oncology, Hematology, Immunology, Rheumatology, and Pneumology, South West German Comprehensive Cancer Center, University of Tuebingen Medical Center, Tuebingen, Germany; and Department of Pathology, Josephine Nefkens Institute, and Department of Public Health, Center for Clinical Decision Science, Erasmus Medical Center-University Medical Center, Daniel den Hoed Cancer Center, Rotterdam, the Netherlands.

Corresponding author: Leendert H.J. Looijenga, PhD, Department of Pathology, Erasmus Medical Center-University Medical Center Rotterdam, Daniel den Hoed Cancer Center, Josephine Nefkens Institute, Building Be, Room 430b, Dr Molewaterplein 50, 3015 GE Rotterdam, the Netherlands; e-mail: l.looijenga{at}erasmusmc.nl.

Purpose Mismatch repair (MMR) deficiency and microsatellite instability (MSI) are associated with cisplatin resistance in human germ cell tumors (GCTs). BRAF mutation (V600E) is found in MSI colorectal cancers. The role of RAS/RAF pathway mutations in GCT treatment response is unknown.

Patients and Methods Two patient cohorts were investigated: 100 control GCTs (50 seminomas and 50 nonseminomas) and 35 cisplatin-based chemotherapy-resistant GCTs. MMR proteins were analyzed by immunohistochemistry, and eight microsatellite loci were examined for MSI. Tumors were assessed for specific BRAF and KRAS mutations.

Results Resistant tumors showed a higher incidence of MSI than controls: 26% versus 0% in two or more loci (P < .0001). All resistant tumors were wild-type KRAS, and two controls (2%) contained a KRAS mutation. There was a significantly higher incidence of BRAF V600E mutation in resistant tumors compared with controls: 26% versus 1% (P < .0001). BRAF mutations were highly correlated with MSI (P = .006), and MSI and mutated BRAF were correlated with weak or absent staining for hMLH1 (P = .017 and P = .008). Low or absent staining of hMLH1 was correlated with promoter hypermethylation (P < .001). Tumors lacking expression of hMLH1 or MSH6 were significantly more frequent in resistant GCTs than in controls (P = .001 and 0.0036, respectively). Within the subgroup of resistant tumors, patients with MSI showed a trend to longer progression-free survival (P = .068).

Conclusion We report for the first time a correlation between a gene mutation—BRAF V600E—and cisplatin resistance in nonseminomatous GCTs. Furthermore, a correlation between MMR deficiency, MSI, and treatment failure is confirmed.

F.H., H.W., and F.M. contributed equally to this work.

Supported by the Dutch Cancer Society/KWF (A.J.M.G., H.S., J.W.O., L.H.J.L.), the Wilhelm Sander-Stiftung (F.H., F.M., C.B.), and the Werner Otto Stiftung (F.H.). H.W. was financially supported by the fellowship program of the European Society of Medical Oncology.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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