Absence of microsatellite instability andBRAF(V600E) mutation in testicular germ cell tumors

Abstract

SUMMARYTesticular germ cell tumors (TGCT) are the most common malignant neoplasm in young men. DNA mismatch repair deficiency can lead to microsatellite instability (MSI), an important mechanism of genetic instability. A mutation of the BRAF gene has been implicated in the pathogenesis of several solid tumors and has recently become an important therapeutic target. The role of MSI and BRAF gene mutation in TGCT, particularly in refractory disease, is poorly understood and reported findings are controversial. In this study, we aimed to determine the frequency and clinical impact of MSI status and BRAF mutations in TGCT. DNA was isolated from formalin-fixed paraffin embedded (FFPE) tissue from 150 TGCT cases. The MSI phenotype was evaluated using multiplex PCR for five quasimonomorphic mononucleotide repeat markers. Exon 15 of the BRAF oncogene (V600E) was analyzed by PCR, followed by direct sequencing. Sixteen percent of cases were considered to have refractory disease. In a small subset of cases (17 for MSI and 18 for BRAF), the quantity and quality of DNA recovery were poor and therefore, were unable to be analyzed. The remaining 133 TGCT cases showed a complete absence of MSI. Of the 132 cases successfully evaluated for BRAF mutations, all were V600E wild-type. In conclusion, despite a distinct response of testicular germ cell tumors to therapy, microsatellite instability, and the BRAF V600E mutation were absent in all testicular germ cell tumors tested in this study.

Brachyury oncogene is a prognostic factor in high‐risk testicular germ cell tumors

“…In our cohort of TGCT patients, we recently reported that well‐known hallmarks of cancer, as microsatellite instability (MSI), V600E BRAF , and TERT promoter mutations, are not present (Carcano et al ., ,b). Recently, Bagrodia et al .…”

Postchemotherapy changes in testicular germ cell tumours: biology and morphology

“…While this appears paradoxical, defective mismatch repair may cause cisplatin resistance through inducing the BRAF mutation V600E and other cisplatin resistance gene mutations. Although BRAF mutation V600E in testicular GCTs (TGCTs) has been confirmed in a separate study at a very low frequency (1%), it has not been confirmed by other two studies . A lack of functional hMLH1 or MSH6 may also lead to the bypassing of the apoptotic pathway outlined above.…”

Cisplatin Resistance in Testicular Germ Cell Tumors: Current Challenges from Various Perspectives

“…However, some controversy in literature persists and more studies are needed to better explore the exact mechanism of how MMR proficiency interferes with cisplatin resistance. One study on 133 chemo-naïve primary TGCTs, 16% of which developed refractory disease, reported absence of BRAF mutations and of MSI [ 81 ]; however, studies including cisplatin-treated patient samples are more likely to tackle this matter [ 34 ]. Another mechanism worth exploring in the future is the one related to activation of translesion synthesis (TLS) induced by the absence of MMR proteins, which, in turn, potentiates skipping or bypassing of DNA adducts, again avoiding apoptotic-triggering [ 82 ].…”