Germline mutations of the POU6F2 gene in wilms tumors with loss of heterozygosity on chromosome 7p14

Daniela Perotti, Giovanna De Vecchi, Maria A. Testi, Elena Lualdi, Piergiorgio Modena, Patrizia Mondini, Fernando Ravagnani, Paola Collini, Francesca Di Renzo, Filippo Spreafico, Monica Terenziani, Gabriella Sozzi, Franca Fossati-Bellani, Paolo Radice

Research output: Contribution to journalArticle

Abstract

Wilms tumor (WT) is a kidney malignancy of childhood characterized by highly heterogeneous genetic alterations. We previously reported the molecular and cytogenetic characterization of a WT (Case 30) carrying an interstitial deletion in chromosome 7p14 between markers D7S555 and D7S668. Loss of heterozygosity (LOH) analyses had revealed that this same region was lost in 8 out of 38 examined WTs, suggesting that the identified interval contains a putative tumor suppressor gene. To confirm this hypothesis, in this work, we analyzed an additional 35 WTs, four of which showed LOH in the region of interest. Furthermore, we were able to more accurately define the extension of the deletion in Case 30, mapping it within an interval not exceeding 390 kb, proximally to D7S555. To date, only a single expressed gene, POU6F2 (the POU domain, class 6, transcription factor 2; also known as RPF1), has been recognized in this interval. Sequencing of the gene in the 12 WTs showing LOH and in a corresponding numbers of WT cases without LOH, led to the identification of two germline nucleotide substitutions. The first occurred in the 5′-untranslated region, while the second caused an amino acid change in a glutamine repeat domain. These mutations, whose occurrence was not observed in more than 100 control subjects, were detected in two patients showing the loss of the constitutionally wild-type allele in tumor DNA. Together with the finding of the expression of the POU6F2 mouse homolog in both fetal and adult kidney, our observations suggest that the gene is a tumor suppressor and is involved in hereditary predisposition to WT.

Original languageEnglish
Pages (from-to)400-407
Number of pages8
JournalHuman Mutation
Volume24
Issue number5
DOIs
Publication statusPublished - 2004

Fingerprint

Wilms' Tumor Genes
Wilms Tumor
Germ-Line Mutation
Loss of Heterozygosity
Chromosomes
Genes
Kidney
Neoplasms
Chromosome Deletion
5' Untranslated Regions
Tumor Suppressor Genes
Glutamine
Cytogenetics
Transcription Factors
Nucleotides
Alleles
Amino Acids
Mutation
DNA

Keywords

  • Loss of heterozygosity
  • POU6F2
  • RPF1
  • Tumor
  • Wilms tumor
  • WT

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Germline mutations of the POU6F2 gene in wilms tumors with loss of heterozygosity on chromosome 7p14. / Perotti, Daniela; De Vecchi, Giovanna; Testi, Maria A.; Lualdi, Elena; Modena, Piergiorgio; Mondini, Patrizia; Ravagnani, Fernando; Collini, Paola; Di Renzo, Francesca; Spreafico, Filippo; Terenziani, Monica; Sozzi, Gabriella; Fossati-Bellani, Franca; Radice, Paolo.

In: Human Mutation, Vol. 24, No. 5, 2004, p. 400-407.

Research output: Contribution to journalArticle

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abstract = "Wilms tumor (WT) is a kidney malignancy of childhood characterized by highly heterogeneous genetic alterations. We previously reported the molecular and cytogenetic characterization of a WT (Case 30) carrying an interstitial deletion in chromosome 7p14 between markers D7S555 and D7S668. Loss of heterozygosity (LOH) analyses had revealed that this same region was lost in 8 out of 38 examined WTs, suggesting that the identified interval contains a putative tumor suppressor gene. To confirm this hypothesis, in this work, we analyzed an additional 35 WTs, four of which showed LOH in the region of interest. Furthermore, we were able to more accurately define the extension of the deletion in Case 30, mapping it within an interval not exceeding 390 kb, proximally to D7S555. To date, only a single expressed gene, POU6F2 (the POU domain, class 6, transcription factor 2; also known as RPF1), has been recognized in this interval. Sequencing of the gene in the 12 WTs showing LOH and in a corresponding numbers of WT cases without LOH, led to the identification of two germline nucleotide substitutions. The first occurred in the 5′-untranslated region, while the second caused an amino acid change in a glutamine repeat domain. These mutations, whose occurrence was not observed in more than 100 control subjects, were detected in two patients showing the loss of the constitutionally wild-type allele in tumor DNA. Together with the finding of the expression of the POU6F2 mouse homolog in both fetal and adult kidney, our observations suggest that the gene is a tumor suppressor and is involved in hereditary predisposition to WT.",
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T1 - Germline mutations of the POU6F2 gene in wilms tumors with loss of heterozygosity on chromosome 7p14

AU - Perotti, Daniela

AU - De Vecchi, Giovanna

AU - Testi, Maria A.

AU - Lualdi, Elena

AU - Modena, Piergiorgio

AU - Mondini, Patrizia

AU - Ravagnani, Fernando

AU - Collini, Paola

AU - Di Renzo, Francesca

AU - Spreafico, Filippo

AU - Terenziani, Monica

AU - Sozzi, Gabriella

AU - Fossati-Bellani, Franca

AU - Radice, Paolo

PY - 2004

Y1 - 2004

N2 - Wilms tumor (WT) is a kidney malignancy of childhood characterized by highly heterogeneous genetic alterations. We previously reported the molecular and cytogenetic characterization of a WT (Case 30) carrying an interstitial deletion in chromosome 7p14 between markers D7S555 and D7S668. Loss of heterozygosity (LOH) analyses had revealed that this same region was lost in 8 out of 38 examined WTs, suggesting that the identified interval contains a putative tumor suppressor gene. To confirm this hypothesis, in this work, we analyzed an additional 35 WTs, four of which showed LOH in the region of interest. Furthermore, we were able to more accurately define the extension of the deletion in Case 30, mapping it within an interval not exceeding 390 kb, proximally to D7S555. To date, only a single expressed gene, POU6F2 (the POU domain, class 6, transcription factor 2; also known as RPF1), has been recognized in this interval. Sequencing of the gene in the 12 WTs showing LOH and in a corresponding numbers of WT cases without LOH, led to the identification of two germline nucleotide substitutions. The first occurred in the 5′-untranslated region, while the second caused an amino acid change in a glutamine repeat domain. These mutations, whose occurrence was not observed in more than 100 control subjects, were detected in two patients showing the loss of the constitutionally wild-type allele in tumor DNA. Together with the finding of the expression of the POU6F2 mouse homolog in both fetal and adult kidney, our observations suggest that the gene is a tumor suppressor and is involved in hereditary predisposition to WT.

AB - Wilms tumor (WT) is a kidney malignancy of childhood characterized by highly heterogeneous genetic alterations. We previously reported the molecular and cytogenetic characterization of a WT (Case 30) carrying an interstitial deletion in chromosome 7p14 between markers D7S555 and D7S668. Loss of heterozygosity (LOH) analyses had revealed that this same region was lost in 8 out of 38 examined WTs, suggesting that the identified interval contains a putative tumor suppressor gene. To confirm this hypothesis, in this work, we analyzed an additional 35 WTs, four of which showed LOH in the region of interest. Furthermore, we were able to more accurately define the extension of the deletion in Case 30, mapping it within an interval not exceeding 390 kb, proximally to D7S555. To date, only a single expressed gene, POU6F2 (the POU domain, class 6, transcription factor 2; also known as RPF1), has been recognized in this interval. Sequencing of the gene in the 12 WTs showing LOH and in a corresponding numbers of WT cases without LOH, led to the identification of two germline nucleotide substitutions. The first occurred in the 5′-untranslated region, while the second caused an amino acid change in a glutamine repeat domain. These mutations, whose occurrence was not observed in more than 100 control subjects, were detected in two patients showing the loss of the constitutionally wild-type allele in tumor DNA. Together with the finding of the expression of the POU6F2 mouse homolog in both fetal and adult kidney, our observations suggest that the gene is a tumor suppressor and is involved in hereditary predisposition to WT.

KW - Loss of heterozygosity

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KW - RPF1

KW - Tumor

KW - Wilms tumor

KW - WT

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