Frequent HRAS mutations in malignant ectomesenchymoma

Shih Chiang Huang, Rita Alaggio, Yun Shao Sung, Chun Liang Chen, Lei Zhang, Yu-Chien Kao, Narasimhan P. Agaram, Leonard H. Wexler, Cristina R. Antonescu

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Malignant ectomesenchymoma (MEM) is an exceedingly rare pediatric sarcoma with a predilection for infants and young children and is composed of dual malignant mesenchymal and neuroectodermal components. Microscopically, MEM displays areas of rhabdomyosarcoma (RMS) with intermixed neuronal/neuroblastic foci. The molecular alterations associated with MEM and its relationship with embryonal RMS (ERMS) and malignant peripheral nerve sheath tumor (MPNST) have not yet been elucidated. In this study we used whole-transcriptome sequencing in 2 MEM index cases with available frozen tissue, followed by screening of the identified genetic abnormalities in 5 additional cases. No candidate fusion genes were detected by FusionSeq analysis; however, the mutation detection algorithms revealed HRAS and PTPRD hotspot mutations in both index cases, with 1 case harboring an additional FBXW7 mutation. As these mutation profiles have been previously described in ERMS we have tested their incidence in a control group of 7 age-matched ERMS. In addition, the gene signature of MEM was compared with that of RMS, MPNST, and neuronal lineage. All 7 MEM patients were male, with a mean age of 7.5 months (range, 0.6 to 17 mo). All except 1 occurred in the pelvic/urogenital region. Most cases showed ERMS elements, with occasional spindle or undifferentiated/round cell areas. The intermixed neuroectodermal components were mostly scattered ganglion cells, ganglioneuroma, or ganglioneuroblastoma. By Sanger sequencing, 6 of 7 (86%) MEMs had HRAS mutations, with no additional case harboring PTPRD or FBXW7 mutations. The only case lacking HRAS mutation showed neuroblastic micronodules without ganglion cells. The trimethylation at lysine 27 of histone H3 (H3K27me3) expression, typically lost in MPNST, was retained in all cases. In the control ERMS group, 5 of 7 (71%) showed RAS mutations, equally distributed among NRAS, KRAS, and HRAS genes. The expression profiling of MEM showed upregulation of skeletal muscle and neuronal genes, with no significant overlap with MPNST. Our results of common HRAS mutations and composite gene signature with RMS and neuronal/neuroblastic elements suggest a closer genetic link of MEM to RMS rather than to MPNST.

Original languageEnglish
Pages (from-to)876-885
Number of pages10
JournalAmerican Journal of Surgical Pathology
Volume40
Issue number7
DOIs
Publication statusPublished - Jan 1 2016

Fingerprint

Neurilemmoma
Mutation
Rhabdomyosarcoma
Ganglia
Genes
Ganglioneuroblastoma
Embryonal Rhabdomyosarcoma
Ganglioneuroma
Gene Fusion
Genetic Testing
Pelvis
Transcriptome
Sarcoma
Histones
Lysine
Skeletal Muscle
Up-Regulation
Pediatrics
Control Groups
Incidence

Keywords

  • ectomesenchymoma
  • FBXW7
  • HRAS
  • PTPRD
  • rhabdomyosarcoma

ASJC Scopus subject areas

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine

Cite this

Huang, S. C., Alaggio, R., Sung, Y. S., Chen, C. L., Zhang, L., Kao, Y-C., ... Antonescu, C. R. (2016). Frequent HRAS mutations in malignant ectomesenchymoma. American Journal of Surgical Pathology, 40(7), 876-885. https://doi.org/10.1097/PAS.0000000000000612

Frequent HRAS mutations in malignant ectomesenchymoma. / Huang, Shih Chiang; Alaggio, Rita; Sung, Yun Shao; Chen, Chun Liang; Zhang, Lei; Kao, Yu-Chien; Agaram, Narasimhan P.; Wexler, Leonard H.; Antonescu, Cristina R.

In: American Journal of Surgical Pathology, Vol. 40, No. 7, 01.01.2016, p. 876-885.

Research output: Contribution to journalArticle

Huang, SC, Alaggio, R, Sung, YS, Chen, CL, Zhang, L, Kao, Y-C, Agaram, NP, Wexler, LH & Antonescu, CR 2016, 'Frequent HRAS mutations in malignant ectomesenchymoma', American Journal of Surgical Pathology, vol. 40, no. 7, pp. 876-885. https://doi.org/10.1097/PAS.0000000000000612
Huang, Shih Chiang ; Alaggio, Rita ; Sung, Yun Shao ; Chen, Chun Liang ; Zhang, Lei ; Kao, Yu-Chien ; Agaram, Narasimhan P. ; Wexler, Leonard H. ; Antonescu, Cristina R. / Frequent HRAS mutations in malignant ectomesenchymoma. In: American Journal of Surgical Pathology. 2016 ; Vol. 40, No. 7. pp. 876-885.
@article{5bf2840018404cf7bdf8d97f736c400c,
title = "Frequent HRAS mutations in malignant ectomesenchymoma",
abstract = "Malignant ectomesenchymoma (MEM) is an exceedingly rare pediatric sarcoma with a predilection for infants and young children and is composed of dual malignant mesenchymal and neuroectodermal components. Microscopically, MEM displays areas of rhabdomyosarcoma (RMS) with intermixed neuronal/neuroblastic foci. The molecular alterations associated with MEM and its relationship with embryonal RMS (ERMS) and malignant peripheral nerve sheath tumor (MPNST) have not yet been elucidated. In this study we used whole-transcriptome sequencing in 2 MEM index cases with available frozen tissue, followed by screening of the identified genetic abnormalities in 5 additional cases. No candidate fusion genes were detected by FusionSeq analysis; however, the mutation detection algorithms revealed HRAS and PTPRD hotspot mutations in both index cases, with 1 case harboring an additional FBXW7 mutation. As these mutation profiles have been previously described in ERMS we have tested their incidence in a control group of 7 age-matched ERMS. In addition, the gene signature of MEM was compared with that of RMS, MPNST, and neuronal lineage. All 7 MEM patients were male, with a mean age of 7.5 months (range, 0.6 to 17 mo). All except 1 occurred in the pelvic/urogenital region. Most cases showed ERMS elements, with occasional spindle or undifferentiated/round cell areas. The intermixed neuroectodermal components were mostly scattered ganglion cells, ganglioneuroma, or ganglioneuroblastoma. By Sanger sequencing, 6 of 7 (86{\%}) MEMs had HRAS mutations, with no additional case harboring PTPRD or FBXW7 mutations. The only case lacking HRAS mutation showed neuroblastic micronodules without ganglion cells. The trimethylation at lysine 27 of histone H3 (H3K27me3) expression, typically lost in MPNST, was retained in all cases. In the control ERMS group, 5 of 7 (71{\%}) showed RAS mutations, equally distributed among NRAS, KRAS, and HRAS genes. The expression profiling of MEM showed upregulation of skeletal muscle and neuronal genes, with no significant overlap with MPNST. Our results of common HRAS mutations and composite gene signature with RMS and neuronal/neuroblastic elements suggest a closer genetic link of MEM to RMS rather than to MPNST.",
keywords = "ectomesenchymoma, FBXW7, HRAS, PTPRD, rhabdomyosarcoma",
author = "Huang, {Shih Chiang} and Rita Alaggio and Sung, {Yun Shao} and Chen, {Chun Liang} and Lei Zhang and Yu-Chien Kao and Agaram, {Narasimhan P.} and Wexler, {Leonard H.} and Antonescu, {Cristina R.}",
year = "2016",
month = "1",
day = "1",
doi = "10.1097/PAS.0000000000000612",
language = "English",
volume = "40",
pages = "876--885",
journal = "American Journal of Surgical Pathology",
issn = "0147-5185",
publisher = "Lippincott Williams and Wilkins",
number = "7",

}

TY - JOUR

T1 - Frequent HRAS mutations in malignant ectomesenchymoma

AU - Huang, Shih Chiang

AU - Alaggio, Rita

AU - Sung, Yun Shao

AU - Chen, Chun Liang

AU - Zhang, Lei

AU - Kao, Yu-Chien

AU - Agaram, Narasimhan P.

AU - Wexler, Leonard H.

AU - Antonescu, Cristina R.

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Malignant ectomesenchymoma (MEM) is an exceedingly rare pediatric sarcoma with a predilection for infants and young children and is composed of dual malignant mesenchymal and neuroectodermal components. Microscopically, MEM displays areas of rhabdomyosarcoma (RMS) with intermixed neuronal/neuroblastic foci. The molecular alterations associated with MEM and its relationship with embryonal RMS (ERMS) and malignant peripheral nerve sheath tumor (MPNST) have not yet been elucidated. In this study we used whole-transcriptome sequencing in 2 MEM index cases with available frozen tissue, followed by screening of the identified genetic abnormalities in 5 additional cases. No candidate fusion genes were detected by FusionSeq analysis; however, the mutation detection algorithms revealed HRAS and PTPRD hotspot mutations in both index cases, with 1 case harboring an additional FBXW7 mutation. As these mutation profiles have been previously described in ERMS we have tested their incidence in a control group of 7 age-matched ERMS. In addition, the gene signature of MEM was compared with that of RMS, MPNST, and neuronal lineage. All 7 MEM patients were male, with a mean age of 7.5 months (range, 0.6 to 17 mo). All except 1 occurred in the pelvic/urogenital region. Most cases showed ERMS elements, with occasional spindle or undifferentiated/round cell areas. The intermixed neuroectodermal components were mostly scattered ganglion cells, ganglioneuroma, or ganglioneuroblastoma. By Sanger sequencing, 6 of 7 (86%) MEMs had HRAS mutations, with no additional case harboring PTPRD or FBXW7 mutations. The only case lacking HRAS mutation showed neuroblastic micronodules without ganglion cells. The trimethylation at lysine 27 of histone H3 (H3K27me3) expression, typically lost in MPNST, was retained in all cases. In the control ERMS group, 5 of 7 (71%) showed RAS mutations, equally distributed among NRAS, KRAS, and HRAS genes. The expression profiling of MEM showed upregulation of skeletal muscle and neuronal genes, with no significant overlap with MPNST. Our results of common HRAS mutations and composite gene signature with RMS and neuronal/neuroblastic elements suggest a closer genetic link of MEM to RMS rather than to MPNST.

AB - Malignant ectomesenchymoma (MEM) is an exceedingly rare pediatric sarcoma with a predilection for infants and young children and is composed of dual malignant mesenchymal and neuroectodermal components. Microscopically, MEM displays areas of rhabdomyosarcoma (RMS) with intermixed neuronal/neuroblastic foci. The molecular alterations associated with MEM and its relationship with embryonal RMS (ERMS) and malignant peripheral nerve sheath tumor (MPNST) have not yet been elucidated. In this study we used whole-transcriptome sequencing in 2 MEM index cases with available frozen tissue, followed by screening of the identified genetic abnormalities in 5 additional cases. No candidate fusion genes were detected by FusionSeq analysis; however, the mutation detection algorithms revealed HRAS and PTPRD hotspot mutations in both index cases, with 1 case harboring an additional FBXW7 mutation. As these mutation profiles have been previously described in ERMS we have tested their incidence in a control group of 7 age-matched ERMS. In addition, the gene signature of MEM was compared with that of RMS, MPNST, and neuronal lineage. All 7 MEM patients were male, with a mean age of 7.5 months (range, 0.6 to 17 mo). All except 1 occurred in the pelvic/urogenital region. Most cases showed ERMS elements, with occasional spindle or undifferentiated/round cell areas. The intermixed neuroectodermal components were mostly scattered ganglion cells, ganglioneuroma, or ganglioneuroblastoma. By Sanger sequencing, 6 of 7 (86%) MEMs had HRAS mutations, with no additional case harboring PTPRD or FBXW7 mutations. The only case lacking HRAS mutation showed neuroblastic micronodules without ganglion cells. The trimethylation at lysine 27 of histone H3 (H3K27me3) expression, typically lost in MPNST, was retained in all cases. In the control ERMS group, 5 of 7 (71%) showed RAS mutations, equally distributed among NRAS, KRAS, and HRAS genes. The expression profiling of MEM showed upregulation of skeletal muscle and neuronal genes, with no significant overlap with MPNST. Our results of common HRAS mutations and composite gene signature with RMS and neuronal/neuroblastic elements suggest a closer genetic link of MEM to RMS rather than to MPNST.

KW - ectomesenchymoma

KW - FBXW7

KW - HRAS

KW - PTPRD

KW - rhabdomyosarcoma

UR - http://www.scopus.com/inward/record.url?scp=84957927613&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84957927613&partnerID=8YFLogxK

U2 - 10.1097/PAS.0000000000000612

DO - 10.1097/PAS.0000000000000612

M3 - Article

VL - 40

SP - 876

EP - 885

JO - American Journal of Surgical Pathology

JF - American Journal of Surgical Pathology

SN - 0147-5185

IS - 7

ER -