Germline MSH6 Mutation in a Patient With Two Independent Primary Glioblastomas

We previously reported a patient who had developed 2 glioblastomas at the age of 54 and 64 years, respectively. The first glioblastoma in the right frontal lobe was treated with surgery and radiotherapy. Ten years later, the patient developed a second, left frontal glioblastoma. Discordant patterns of TP53 and PTEN mutations suggested that the second tumor was not a recurrence but an independently developed glioblastoma. To determine the molecular mechanism underlying this enigmatic case with 10-year survival, we performed whole-exome sequencing. We found that both tumors were IDH-wildtype, excluding the possibility of secondary glioblastomas that developed from a less malignant astrocytic precursor lesion. We here report that the patient carried a heterozygous germline mutation [c.3305_3306insT; p.1102-fs-insT(Gly1105/TrpfsX3)] in the MSH6 mismatch repair gene. Further sequencing revealed that in addition to the germline MSH6 mutation, the first glioblastoma showed loss of the MSH6 wild-type allele, and the second glioblastoma carried a somatic MSH6 mutation [c.1403G>A; p.Arg468His]. Our results indicate that both glioblastomas had 2 hits in the MSH6 gene, and that loss of MSH6 function was the key event in the pathogenesis of these 2 independent primary glioblastomas.