Frequent IDH2 R172 mutations in undifferentiated and poorly-differentiated sinonasal carcinomas

Abstract

Sinonasal undifferentiated carcinoma (SNUC) is a high-grade malignancy with limited treatment options and poor outcome. A morphologic spectrum of 47 sinonasal tumors including 17 (36.2%) SNUCs were analyzed at genomic level. Thirty carcinomas (Cohort 1) were subjected to a hybridization exon-capture next-generation sequencing assay (MSK-IMPACT™) to interrogate somatic variants in 279 or 410 cancer-related genes. Seventeen sinonasal tumors (Cohort 2) were examined only for presence of IDH1/2 exon 4 mutations by Sanger sequencing. IDH2 R172 single nucleotide variants were overall detected in 14 (82.4%) SNUCs, in 2 (20%) poorly-differentiated carcinomas with glandular/acinar differentiation, and in one of 2 high-grade neuroendocrine carcinomas, large cell type (HGNEC). No IDH2 mutation was detected in any of 5 olfactory neuroblastomas or in any of 5 SMARCB1–deficient carcinomas. Among 12 IDH2-mutated cases in Cohort 1, 5 (41.7%) harbored co-existing TP53 mutations, 4 (33.3%) CDKN2A/2B loss-of-function alterations, 4 (33.3%) MYC amplification, and 3 (25%) had concurrent SETD2 mutations. AKT1 E17K and KIT D816V hotspot variants were each detected in one IDH2-mutated SNUC. The vast majority of SNUCs and variable proportions of other poorly differentiated sinonasal carcinomas may be amenable to IDH2-targeted therapy.

Sinonasal adenocarcinoma involving the anterior cranial fossa: An exceptional entity in the pediatric population

“…In low‐grade SNAC, recurrent translocations involving EV6 have been described 12 as well as recurrent mutations in CTNNB1 and BRAF 13,14 . High‐grade SNAC have been shown to carry IDH2 mutations in approximately 25% of cases, in addition to recurrent mutations in CREBBP, APC, and NOTCH1 15,16 . In the present case describing a high‐grade SNAC, whole exome sequencing did not reveal somatic mutations in these genes.…”

An update on head and neck cancer: new entities and their histopathology, molecular background, treatment, and outcome

“…Data on the molecular features of olfactory neuroblastoma and sinonasal neuroendocrine carcinoma (SNEC) are limited. In small cell SNEC, the pattern of copy-number alterations is complex and genetics seem to show overlap with small cell neuroendocrine carcinoma of the lung with mutations of TP53 and RB1, upregulation of BCL2 signaling, and activation of MYC and PI3K pathways (86,92). A similar overlap in copy number alterations between neuroendocrine carcinoma of the salivary gland a lung has also been reported (93).…”

“…Approximately, half of SNUC harbor activating IDH2 R172 mutations which are also known from other malignancies, especially glioma, but is restricted to SNUC in the head and neck (Fig. B; ). Inhibitors of mutant IDH2 have been shown to induce differentiation in acute myeloid leukemia, which opens up for a new venue for targeted treatment in SNUC .…”

Genomic profiles of nasopharyngeal carcinoma: The importance of histological subtyping and Epstein‐Barr virus in situ assays

“…1 Tumors arising from the nasopharynx are different from those arising from the paranasal sinuses. 7,8 Third, the genomic profile of NPSCC in the 62 cases reported in the study by Ali et al 1 appears to be largely similar to that of head and neck SCC. In fact, from the tumor sites shown by the authors in Table 1, 1 it is highly possible that tumors from other head and neck regions, instead of the nasopharynx, were included in their genome profiling.…”

“…Thus, the unconventional "combined site" defined by Ali et al as "nasopharynx and paranasal sinuses" 1 may suggest a possible inclusion of sinonasal carcinoma for sequencing, which is known to harbor a high rate of IDH2 mutations. 7,8 Third, the genomic profile of NPSCC in the 62 cases reported in the study by Ali et al 1 appears to be largely similar to that of head and neck SCC. 9 The tumor sites listed in Table 1 under the NPSCC subtype indeed included various head and neck regions (ear, head and neck, larynx, mouth, lymph nodes, nasal cavity, etc).…”