Recurrent IDH2 R172X mutations in sinonasal undifferentiated carcinoma
Sequencing showed that most sinonasal undifferentiated carcinomas, a cancer long defined only by what it is not, carry a mutation in the IDH2 gene found in no other head and neck cancer, giving the disease a molecular identity, a diagnostic antibody test and a possible drug target.
Overview
Targeted next-generation sequencing of 300 cancer-related genes in 11 sinonasal undifferentiated carcinomas from Brigham and Women's Hospital and Dana-Farber Cancer Institute. IDH2 R172 mutations (R172S, R172T and R172M) were found in 55 percent of cases, and a multispecific mutant IDH1/2 antibody stained all mutant tumours with available tissue (3 of 3) and none of the wild-type (0 of 4). Review of 412 sequenced head and neck tumours at the same institutions found IDH-activating mutations in no other tumour type.
IDH2 wild-type cases carried SMARCA4 loss with loss of protein expression, NOTCH1 gain-of-function or TET2 loss-of-function alterations, foreshadowing the later separation of SWI/SNF-deficient sinonasal carcinoma. Published alongside a Memorial Sloan Kettering series with the same finding, the paper established IDH2 R172 as the defining alteration of the disease.
- IDH2 R172 mutations in 55 percent of 11 sinonasal undifferentiated carcinomas (R172S, R172T, R172M).
- Mutant IDH1/2 immunohistochemistry was positive in 3 of 3 mutant and negative in 4 of 4 wild-type tumours.
- No IDH-activating mutation in 412 other head and neck tumours; IDH2 wild-type cases showed SMARCA4, NOTCH1 or TET2 alterations.
Sinonasal undifferentiated carcinoma can be confirmed by IDH2 testing or mutant-IDH immunohistochemistry rather than diagnosed by exclusion, and IDH2 inhibitors such as enasidenib became rational candidates for trials.
- Eleven cases from two institutions; later series put the IDH2 mutation rate at roughly 50 to 80 percent.
- Diagnostic value rests on the mutation being absent from mimics, which larger cohorts have since confirmed for carcinomas but not for a subset of high-grade esthesioneuroblastomas.
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