Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25-q27

Rossano Cesari, Eric S. Martin, George A. Calin, Francesca Pentimalli, Roberta Bichi, Holly McAdams, Francesco Trapasso, Alessandra Drusco, Masayoshi Shimizu, Valeria Masciullo, Giuseppina D'Andrilli, Giovanni Scambia, Maria Cristina Picchio, Hansjuerg Alder, Andrew K. Godwin, Carlo M. Croce

Research output: Contribution to journalArticle

Abstract

In an effort to identify tumor suppressor gene(s) associated with the frequent loss of heterozygosity observed on chromosome 6q25-q27, we constructed a contig derived from the sequences of bacterial artificial chromosome/P1 bacteriophage artificial chromosome clones defined by the genetic interval D6S1581-D6S1579- D6S305-D6S1599-D6S1008. Sequence analysis of this contig found it to contain eight known genes, including the complete genomic structure of the Parkin gene. Loss of heterozygosity (LOH) analysis of 40 malignant breast and ovarian tumors identified a common minimal region of loss, including the markers D6S305 (50%) and D6S1599 (32%). Both loci exhibited the highest frequencies of LOH in this study and are each located within the Parkin genomic structure. Whereas mutation analysis revealed no missense substitutions, expression of the Parkin gene appeared to be downregulated or absent in the tumor biopsies and tumor cell lines examined. In addition, the identification of two truncating deletions in 3 of 20 ovarian tumor samples, as well as homozygous deletion of exon 2 in the lung adenocarcinoma cell lines Calu-3 and H-1573, supports the hypothesis that hemizygous or homozygous deletions are responsible for the abnormal expression of Parkin in these samples. These data suggest that the LOH observed at chromosome 6q25-q26 may contribute to the initiation and/or progression of cancer by inactivating or reducing the expression of the Parkin gene. Because Parkin maps to FRA6E, one of the most active common fragile sites in the human genome, it represents another example of a large tumor suppressor gene, like FHIT and WWOX, located at a common fragile site.

Original languageEnglish
Pages (from-to)5956-5961
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number10
DOIs
Publication statusPublished - May 13 2003

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Loss of Heterozygosity
Parkinsonian Disorders
Tumor Suppressor Genes
Chromosomes
Genes
P1 Bacteriophage Artificial Chromosomes
Bacterial Artificial Chromosomes
Gene Expression
Neoplasms
Human Genome
Tumor Cell Line
Sequence Analysis
Exons
Down-Regulation
Clone Cells
Breast Neoplasms
Biopsy
Cell Line
Mutation

ASJC Scopus subject areas

  • Genetics
  • General

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Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25-q27. / Cesari, Rossano; Martin, Eric S.; Calin, George A.; Pentimalli, Francesca; Bichi, Roberta; McAdams, Holly; Trapasso, Francesco; Drusco, Alessandra; Shimizu, Masayoshi; Masciullo, Valeria; D'Andrilli, Giuseppina; Scambia, Giovanni; Picchio, Maria Cristina; Alder, Hansjuerg; Godwin, Andrew K.; Croce, Carlo M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 10, 13.05.2003, p. 5956-5961.

Research output: Contribution to journalArticle

Cesari, R, Martin, ES, Calin, GA, Pentimalli, F, Bichi, R, McAdams, H, Trapasso, F, Drusco, A, Shimizu, M, Masciullo, V, D'Andrilli, G, Scambia, G, Picchio, MC, Alder, H, Godwin, AK & Croce, CM 2003, 'Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25-q27', Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 10, pp. 5956-5961. https://doi.org/10.1073/pnas.0931262100
Cesari, Rossano ; Martin, Eric S. ; Calin, George A. ; Pentimalli, Francesca ; Bichi, Roberta ; McAdams, Holly ; Trapasso, Francesco ; Drusco, Alessandra ; Shimizu, Masayoshi ; Masciullo, Valeria ; D'Andrilli, Giuseppina ; Scambia, Giovanni ; Picchio, Maria Cristina ; Alder, Hansjuerg ; Godwin, Andrew K. ; Croce, Carlo M. / Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25-q27. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 10. pp. 5956-5961.
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abstract = "In an effort to identify tumor suppressor gene(s) associated with the frequent loss of heterozygosity observed on chromosome 6q25-q27, we constructed a contig derived from the sequences of bacterial artificial chromosome/P1 bacteriophage artificial chromosome clones defined by the genetic interval D6S1581-D6S1579- D6S305-D6S1599-D6S1008. Sequence analysis of this contig found it to contain eight known genes, including the complete genomic structure of the Parkin gene. Loss of heterozygosity (LOH) analysis of 40 malignant breast and ovarian tumors identified a common minimal region of loss, including the markers D6S305 (50{\%}) and D6S1599 (32{\%}). Both loci exhibited the highest frequencies of LOH in this study and are each located within the Parkin genomic structure. Whereas mutation analysis revealed no missense substitutions, expression of the Parkin gene appeared to be downregulated or absent in the tumor biopsies and tumor cell lines examined. In addition, the identification of two truncating deletions in 3 of 20 ovarian tumor samples, as well as homozygous deletion of exon 2 in the lung adenocarcinoma cell lines Calu-3 and H-1573, supports the hypothesis that hemizygous or homozygous deletions are responsible for the abnormal expression of Parkin in these samples. These data suggest that the LOH observed at chromosome 6q25-q26 may contribute to the initiation and/or progression of cancer by inactivating or reducing the expression of the Parkin gene. Because Parkin maps to FRA6E, one of the most active common fragile sites in the human genome, it represents another example of a large tumor suppressor gene, like FHIT and WWOX, located at a common fragile site.",
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AU - Cesari, Rossano

AU - Martin, Eric S.

AU - Calin, George A.

AU - Pentimalli, Francesca

AU - Bichi, Roberta

AU - McAdams, Holly

AU - Trapasso, Francesco

AU - Drusco, Alessandra

AU - Shimizu, Masayoshi

AU - Masciullo, Valeria

AU - D'Andrilli, Giuseppina

AU - Scambia, Giovanni

AU - Picchio, Maria Cristina

AU - Alder, Hansjuerg

AU - Godwin, Andrew K.

AU - Croce, Carlo M.

PY - 2003/5/13

Y1 - 2003/5/13

N2 - In an effort to identify tumor suppressor gene(s) associated with the frequent loss of heterozygosity observed on chromosome 6q25-q27, we constructed a contig derived from the sequences of bacterial artificial chromosome/P1 bacteriophage artificial chromosome clones defined by the genetic interval D6S1581-D6S1579- D6S305-D6S1599-D6S1008. Sequence analysis of this contig found it to contain eight known genes, including the complete genomic structure of the Parkin gene. Loss of heterozygosity (LOH) analysis of 40 malignant breast and ovarian tumors identified a common minimal region of loss, including the markers D6S305 (50%) and D6S1599 (32%). Both loci exhibited the highest frequencies of LOH in this study and are each located within the Parkin genomic structure. Whereas mutation analysis revealed no missense substitutions, expression of the Parkin gene appeared to be downregulated or absent in the tumor biopsies and tumor cell lines examined. In addition, the identification of two truncating deletions in 3 of 20 ovarian tumor samples, as well as homozygous deletion of exon 2 in the lung adenocarcinoma cell lines Calu-3 and H-1573, supports the hypothesis that hemizygous or homozygous deletions are responsible for the abnormal expression of Parkin in these samples. These data suggest that the LOH observed at chromosome 6q25-q26 may contribute to the initiation and/or progression of cancer by inactivating or reducing the expression of the Parkin gene. Because Parkin maps to FRA6E, one of the most active common fragile sites in the human genome, it represents another example of a large tumor suppressor gene, like FHIT and WWOX, located at a common fragile site.

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