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

Snjezana Dogan; Deborah J. Chute; Bin Xu; Ryan N. Ptashkin; Raghu Chandramohan; Jacklyn Casanova-Murphy; Khedoudja Nafa; Justin A. Bishop; Simion I. Chiosea; Edward B. Stelow; Ian Ganly; David G. Pfister; Nora Katabi; Ronald A. Ghossein; Michael F. Berger

doi:10.1002/path.4915

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

Snjezana Dogan, Deborah J. Chute, Bin Xu, Ryan N. Ptashkin, Raghu Chandramohan, Jacklyn Casanova-Murphy, Khedoudja Nafa, Justin A. Bishop, Simion I. Chiosea, Edward B. Stelow, Ian Ganly, David G. Pfister, Nora Katabi, Ronald A. Ghossein, Michael F. Berger

Research output: Contribution to journal › Article › peer-review

84 Scopus citations

Abstract

Sinonasal undifferentiated carcinoma (SNUC) is a high-grade malignancy with limited treatment options and poor outcome. A morphological spectrum of 47 sinonasal tumours including 17 (36.2%) SNUCs was analysed at genomic level. Thirty carcinomas (cohort 1) were subjected to a hybridization exon-capture next-generation sequencing assay (MSK-IMPACT^TM) to interrogate somatic variants in 279 or 410 cancer-related genes. Seventeen sinonasal tumours (cohort 2) were examined only for the presence of IDH1/2 exon 4 mutations by Sanger sequencing. IDH2 R172 single nucleotide variants were overall detected in 14 (82.4%) SNUCs, in two (20%) poorly-differentiated carcinomas with glandular/acinar differentiation, and in one of two high-grade neuroendocrine carcinomas, large cell type (HGNECs). No IDH2 mutation was detected in any of five olfactory neuroblastomas or in any of five SMARCB1-deficient carcinomas. Among 12 IDH2-mutated cases in cohort 1, five (41.7%) harboured co-existing TP53 mutations, four (33.3%) CDKN2A/2B loss-of-function alterations, four (33.3%) MYC amplification, and three (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.

Original language	English (US)
Pages (from-to)	400-408
Number of pages	9
Journal	Journal of Pathology
Volume	242
Issue number	4
DOIs	https://doi.org/10.1002/path.4915
State	Published - Aug 2017

Keywords

IDH2 R172
SNUC
sinonasal undifferentiated carcinoma

ASJC Scopus subject areas

Pathology and Forensic Medicine

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10.1002/path.4915

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Dogan, S., Chute, D. J., Xu, B., Ptashkin, R. N., Chandramohan, R., Casanova-Murphy, J., Nafa, K., Bishop, J. A., Chiosea, S. I., Stelow, E. B., Ganly, I., Pfister, D. G., Katabi, N., Ghossein, R. A., & Berger, M. F. (2017). Frequent IDH2 R172 mutations in undifferentiated and poorly-differentiated sinonasal carcinomas. Journal of Pathology, 242(4), 400-408. https://doi.org/10.1002/path.4915

Dogan, S, Chute, DJ, Xu, B, Ptashkin, RN, Chandramohan, R, Casanova-Murphy, J, Nafa, K, Bishop, JA, Chiosea, SI, Stelow, EB, Ganly, I, Pfister, DG, Katabi, N, Ghossein, RA & Berger, MF 2017, 'Frequent IDH2 R172 mutations in undifferentiated and poorly-differentiated sinonasal carcinomas', Journal of Pathology, vol. 242, no. 4, pp. 400-408. https://doi.org/10.1002/path.4915

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title = "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 morphological spectrum of 47 sinonasal tumours including 17 (36.2%) SNUCs was analysed at genomic level. Thirty carcinomas (cohort 1) were subjected to a hybridization exon-capture next-generation sequencing assay (MSK-IMPACTTM) to interrogate somatic variants in 279 or 410 cancer-related genes. Seventeen sinonasal tumours (cohort 2) were examined only for the presence of IDH1/2 exon 4 mutations by Sanger sequencing. IDH2 R172 single nucleotide variants were overall detected in 14 (82.4%) SNUCs, in two (20%) poorly-differentiated carcinomas with glandular/acinar differentiation, and in one of two high-grade neuroendocrine carcinomas, large cell type (HGNECs). No IDH2 mutation was detected in any of five olfactory neuroblastomas or in any of five SMARCB1-deficient carcinomas. Among 12 IDH2-mutated cases in cohort 1, five (41.7%) harboured co-existing TP53 mutations, four (33.3%) CDKN2A/2B loss-of-function alterations, four (33.3%) MYC amplification, and three (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.",

keywords = "IDH2 R172, SNUC, sinonasal undifferentiated carcinoma",

author = "Snjezana Dogan and Chute, {Deborah J.} and Bin Xu and Ptashkin, {Ryan N.} and Raghu Chandramohan and Jacklyn Casanova-Murphy and Khedoudja Nafa and Bishop, {Justin A.} and Chiosea, {Simion I.} and Stelow, {Edward B.} and Ian Ganly and Pfister, {David G.} and Nora Katabi and Ghossein, {Ronald A.} and Berger, {Michael F.}",

note = "Funding Information: We would like to thank Dr Diane L Carlson from the Cleveland Clinic, Weston, FL and Dr William H Westra from The Johns Hopkins Hospital, Baltimore, MD for their help in collecting the study cases. We also thank Allyne Manzo, our expert photographer at MSKCC, for her assistance in arranging the microphotographs. Research reported in this article was supported in part by the Farmer Family Foundation and the Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute under award number P30CA008748. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: Copyright {\textcopyright} 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.",

year = "2017",

month = aug,

doi = "10.1002/path.4915",

language = "English (US)",

volume = "242",

pages = "400--408",

journal = "Journal of Pathology",

issn = "0022-3417",

publisher = "John Wiley and Sons Ltd",

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T1 - Frequent IDH2 R172 mutations in undifferentiated and poorly-differentiated sinonasal carcinomas

AU - Dogan, Snjezana

AU - Chute, Deborah J.

AU - Xu, Bin

AU - Ptashkin, Ryan N.

AU - Chandramohan, Raghu

AU - Casanova-Murphy, Jacklyn

AU - Nafa, Khedoudja

AU - Bishop, Justin A.

AU - Chiosea, Simion I.

AU - Stelow, Edward B.

AU - Ganly, Ian

AU - Pfister, David G.

AU - Katabi, Nora

AU - Ghossein, Ronald A.

AU - Berger, Michael F.

N1 - Funding Information: We would like to thank Dr Diane L Carlson from the Cleveland Clinic, Weston, FL and Dr William H Westra from The Johns Hopkins Hospital, Baltimore, MD for their help in collecting the study cases. We also thank Allyne Manzo, our expert photographer at MSKCC, for her assistance in arranging the microphotographs. Research reported in this article was supported in part by the Farmer Family Foundation and the Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute under award number P30CA008748. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

PY - 2017/8

Y1 - 2017/8

N2 - Sinonasal undifferentiated carcinoma (SNUC) is a high-grade malignancy with limited treatment options and poor outcome. A morphological spectrum of 47 sinonasal tumours including 17 (36.2%) SNUCs was analysed at genomic level. Thirty carcinomas (cohort 1) were subjected to a hybridization exon-capture next-generation sequencing assay (MSK-IMPACTTM) to interrogate somatic variants in 279 or 410 cancer-related genes. Seventeen sinonasal tumours (cohort 2) were examined only for the presence of IDH1/2 exon 4 mutations by Sanger sequencing. IDH2 R172 single nucleotide variants were overall detected in 14 (82.4%) SNUCs, in two (20%) poorly-differentiated carcinomas with glandular/acinar differentiation, and in one of two high-grade neuroendocrine carcinomas, large cell type (HGNECs). No IDH2 mutation was detected in any of five olfactory neuroblastomas or in any of five SMARCB1-deficient carcinomas. Among 12 IDH2-mutated cases in cohort 1, five (41.7%) harboured co-existing TP53 mutations, four (33.3%) CDKN2A/2B loss-of-function alterations, four (33.3%) MYC amplification, and three (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.

AB - Sinonasal undifferentiated carcinoma (SNUC) is a high-grade malignancy with limited treatment options and poor outcome. A morphological spectrum of 47 sinonasal tumours including 17 (36.2%) SNUCs was analysed at genomic level. Thirty carcinomas (cohort 1) were subjected to a hybridization exon-capture next-generation sequencing assay (MSK-IMPACTTM) to interrogate somatic variants in 279 or 410 cancer-related genes. Seventeen sinonasal tumours (cohort 2) were examined only for the presence of IDH1/2 exon 4 mutations by Sanger sequencing. IDH2 R172 single nucleotide variants were overall detected in 14 (82.4%) SNUCs, in two (20%) poorly-differentiated carcinomas with glandular/acinar differentiation, and in one of two high-grade neuroendocrine carcinomas, large cell type (HGNECs). No IDH2 mutation was detected in any of five olfactory neuroblastomas or in any of five SMARCB1-deficient carcinomas. Among 12 IDH2-mutated cases in cohort 1, five (41.7%) harboured co-existing TP53 mutations, four (33.3%) CDKN2A/2B loss-of-function alterations, four (33.3%) MYC amplification, and three (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.

KW - IDH2 R172

KW - SNUC

KW - sinonasal undifferentiated carcinoma

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ER -

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

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