Inactivation of the tumor suppressor WTX in a subset of pediatric tumors

Sara Akhavanfard, Sara O. Vargas, Moonjoo Han, Mai Nitta, Clarice B. Chang, Long P. Le, Ladan Fazlollahi, Quan Nguyen, Yunqing Ma, Arjola Cosper, Dora Dias-Santagata, Jae Y. Han, Kristin Bergethon, Darrell R. Borger, Leif W. Ellisen, Scott L. Pomeroy, Daniel A. Haber, A. John Iafrate, Miguel N. Rivera

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

WTX is a tumor suppressor gene expressed during embryonic development and inactivated in 20-30% of cases of Wilms tumor, the most common pediatric kidney cancer. WTX has been implicated in several cellular processes including Wnt signaling, WT1 transcription, NRF2 degradation, and p53 function. Given that WTX is widely expressed during embryonic development and has been recently shown to regulate mesenchymal precursor cells in several organs, we tested for the potential involvement of WTX in a panel of pediatric tumors and adult sarcomas. A total of 353 tumors were screened for WTX deletions by fluorescence in situ hybridization (FISH). Discrete somatic WTX deletions were identified in two cases, one hepatoblastoma and one embryonal rhabdomyosarcoma, and confirmed by array comparative genomic hybridization. Direct sequencing of the full WTX open reading frame in 24 hepatoblastomas and 21 embryonal rhabdomyosarcomas did not identify additional mutations in these tumor types. The presence of WTX mRNA was confirmed in hepatoblastomas and embryonal rhabdomyosarcomas without WTX deletions by RNA-in situ hybridization. Notably, tumors with evidence of WTX inactivation, Wilms tumor, hepatoblastoma and rhabdomyosarcoma, are primitive tumors that resemble undifferentiated precursor cells and are linked to overgrowth syndromes. These results indicate that WTX inactivation occurs in a wider variety of tumor types than previously appreciated and point to shared pathogenic mechanisms between a subset of pediatric malignancies.

Original languageEnglish (US)
Pages (from-to)67-77
Number of pages11
JournalGenes Chromosomes and Cancer
Volume53
Issue number1
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

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Hepatoblastoma
Pediatrics
Embryonal Rhabdomyosarcoma
Neoplasms
Wilms Tumor
Embryonic Development
Comparative Genomic Hybridization
Rhabdomyosarcoma
Kidney Neoplasms
Tumor Suppressor Genes
Fluorescence In Situ Hybridization
Sarcoma
Open Reading Frames
In Situ Hybridization
RNA
Messenger RNA
Mutation

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

Cite this

Akhavanfard, S., Vargas, S. O., Han, M., Nitta, M., Chang, C. B., Le, L. P., ... Rivera, M. N. (2014). Inactivation of the tumor suppressor WTX in a subset of pediatric tumors. Genes Chromosomes and Cancer, 53(1), 67-77. https://doi.org/10.1002/gcc.22118

Inactivation of the tumor suppressor WTX in a subset of pediatric tumors. / Akhavanfard, Sara; Vargas, Sara O.; Han, Moonjoo; Nitta, Mai; Chang, Clarice B.; Le, Long P.; Fazlollahi, Ladan; Nguyen, Quan; Ma, Yunqing; Cosper, Arjola; Dias-Santagata, Dora; Han, Jae Y.; Bergethon, Kristin; Borger, Darrell R.; Ellisen, Leif W.; Pomeroy, Scott L.; Haber, Daniel A.; Iafrate, A. John; Rivera, Miguel N.

In: Genes Chromosomes and Cancer, Vol. 53, No. 1, 01.01.2014, p. 67-77.

Research output: Contribution to journalArticle

Akhavanfard, S, Vargas, SO, Han, M, Nitta, M, Chang, CB, Le, LP, Fazlollahi, L, Nguyen, Q, Ma, Y, Cosper, A, Dias-Santagata, D, Han, JY, Bergethon, K, Borger, DR, Ellisen, LW, Pomeroy, SL, Haber, DA, Iafrate, AJ & Rivera, MN 2014, 'Inactivation of the tumor suppressor WTX in a subset of pediatric tumors', Genes Chromosomes and Cancer, vol. 53, no. 1, pp. 67-77. https://doi.org/10.1002/gcc.22118
Akhavanfard, Sara ; Vargas, Sara O. ; Han, Moonjoo ; Nitta, Mai ; Chang, Clarice B. ; Le, Long P. ; Fazlollahi, Ladan ; Nguyen, Quan ; Ma, Yunqing ; Cosper, Arjola ; Dias-Santagata, Dora ; Han, Jae Y. ; Bergethon, Kristin ; Borger, Darrell R. ; Ellisen, Leif W. ; Pomeroy, Scott L. ; Haber, Daniel A. ; Iafrate, A. John ; Rivera, Miguel N. / Inactivation of the tumor suppressor WTX in a subset of pediatric tumors. In: Genes Chromosomes and Cancer. 2014 ; Vol. 53, No. 1. pp. 67-77.
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abstract = "WTX is a tumor suppressor gene expressed during embryonic development and inactivated in 20-30{\%} of cases of Wilms tumor, the most common pediatric kidney cancer. WTX has been implicated in several cellular processes including Wnt signaling, WT1 transcription, NRF2 degradation, and p53 function. Given that WTX is widely expressed during embryonic development and has been recently shown to regulate mesenchymal precursor cells in several organs, we tested for the potential involvement of WTX in a panel of pediatric tumors and adult sarcomas. A total of 353 tumors were screened for WTX deletions by fluorescence in situ hybridization (FISH). Discrete somatic WTX deletions were identified in two cases, one hepatoblastoma and one embryonal rhabdomyosarcoma, and confirmed by array comparative genomic hybridization. Direct sequencing of the full WTX open reading frame in 24 hepatoblastomas and 21 embryonal rhabdomyosarcomas did not identify additional mutations in these tumor types. The presence of WTX mRNA was confirmed in hepatoblastomas and embryonal rhabdomyosarcomas without WTX deletions by RNA-in situ hybridization. Notably, tumors with evidence of WTX inactivation, Wilms tumor, hepatoblastoma and rhabdomyosarcoma, are primitive tumors that resemble undifferentiated precursor cells and are linked to overgrowth syndromes. These results indicate that WTX inactivation occurs in a wider variety of tumor types than previously appreciated and point to shared pathogenic mechanisms between a subset of pediatric malignancies.",
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AU - Akhavanfard, Sara

AU - Vargas, Sara O.

AU - Han, Moonjoo

AU - Nitta, Mai

AU - Chang, Clarice B.

AU - Le, Long P.

AU - Fazlollahi, Ladan

AU - Nguyen, Quan

AU - Ma, Yunqing

AU - Cosper, Arjola

AU - Dias-Santagata, Dora

AU - Han, Jae Y.

AU - Bergethon, Kristin

AU - Borger, Darrell R.

AU - Ellisen, Leif W.

AU - Pomeroy, Scott L.

AU - Haber, Daniel A.

AU - Iafrate, A. John

AU - Rivera, Miguel N.

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N2 - WTX is a tumor suppressor gene expressed during embryonic development and inactivated in 20-30% of cases of Wilms tumor, the most common pediatric kidney cancer. WTX has been implicated in several cellular processes including Wnt signaling, WT1 transcription, NRF2 degradation, and p53 function. Given that WTX is widely expressed during embryonic development and has been recently shown to regulate mesenchymal precursor cells in several organs, we tested for the potential involvement of WTX in a panel of pediatric tumors and adult sarcomas. A total of 353 tumors were screened for WTX deletions by fluorescence in situ hybridization (FISH). Discrete somatic WTX deletions were identified in two cases, one hepatoblastoma and one embryonal rhabdomyosarcoma, and confirmed by array comparative genomic hybridization. Direct sequencing of the full WTX open reading frame in 24 hepatoblastomas and 21 embryonal rhabdomyosarcomas did not identify additional mutations in these tumor types. The presence of WTX mRNA was confirmed in hepatoblastomas and embryonal rhabdomyosarcomas without WTX deletions by RNA-in situ hybridization. Notably, tumors with evidence of WTX inactivation, Wilms tumor, hepatoblastoma and rhabdomyosarcoma, are primitive tumors that resemble undifferentiated precursor cells and are linked to overgrowth syndromes. These results indicate that WTX inactivation occurs in a wider variety of tumor types than previously appreciated and point to shared pathogenic mechanisms between a subset of pediatric malignancies.

AB - WTX is a tumor suppressor gene expressed during embryonic development and inactivated in 20-30% of cases of Wilms tumor, the most common pediatric kidney cancer. WTX has been implicated in several cellular processes including Wnt signaling, WT1 transcription, NRF2 degradation, and p53 function. Given that WTX is widely expressed during embryonic development and has been recently shown to regulate mesenchymal precursor cells in several organs, we tested for the potential involvement of WTX in a panel of pediatric tumors and adult sarcomas. A total of 353 tumors were screened for WTX deletions by fluorescence in situ hybridization (FISH). Discrete somatic WTX deletions were identified in two cases, one hepatoblastoma and one embryonal rhabdomyosarcoma, and confirmed by array comparative genomic hybridization. Direct sequencing of the full WTX open reading frame in 24 hepatoblastomas and 21 embryonal rhabdomyosarcomas did not identify additional mutations in these tumor types. The presence of WTX mRNA was confirmed in hepatoblastomas and embryonal rhabdomyosarcomas without WTX deletions by RNA-in situ hybridization. Notably, tumors with evidence of WTX inactivation, Wilms tumor, hepatoblastoma and rhabdomyosarcoma, are primitive tumors that resemble undifferentiated precursor cells and are linked to overgrowth syndromes. These results indicate that WTX inactivation occurs in a wider variety of tumor types than previously appreciated and point to shared pathogenic mechanisms between a subset of pediatric malignancies.

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