An integrated genomic approach identifies ARID1A as a candidate tumor-suppressor gene in breast cancer

A. Mamo, L. Cavallone, S. Tuzmen, C. Chabot, C. Ferrario, S. Hassan, Henrik Edgren, Olli Kallioniemi, O. Aleynikova, E. Przybytkowski, K. Malcolm, S. Mousses, P.N. Tonin, M. Basik (Corresponding Author)

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Abstract

Tumor-suppressor genes (TSGs) have been classically defined as genes whose loss of function in tumor cells contributes to the formation and/or maintenance of the tumor phenotype. TSGs containing nonsense mutations may not be expressed because of nonsense-mediated RNA decay (NMD). We combined inhibition of the NMD process, which clears transcripts that contain nonsense mutations, with the application of high-density single-nucleotide polymorphism arrays analysis to discriminate allelic content in order to identify candidate TSGs in five breast cancer cell lines. We identified ARID1A as a target of NMD in the T47D breast cancer cell line, likely as a consequence of a mutation in exon-9, which introduces a premature stop codon at position Q944. ARID1A encodes a human homolog of yeast SWI1, which is an integral member of the hSWI/SNF complex, an ATP-dependent, chromatin-remodeling, multiple-subunit enzyme. Although we did not find any somatic mutations in 11 breast tumors, which show DNA copy-number loss at the 1p36 locus adjacent to ARID1A, we show that low ARID1A RNA or nuclear protein expression is associated with more aggressive breast cancer phenotypes, such as high tumor grade, in two independent cohorts of over 200 human breast cancer cases each. We also found that low ARID1A nuclear expression becomes more prevalent during the later stages of breast tumor progression. Finally, we found that ARID1A re-expression in the T47D cell line results in significant inhibition of colony formation in soft agar. These results suggest that ARID1A may be a candidate TSG in breast cancer.
Original languageEnglish
Pages (from-to)2090-2100
JournalOncogene
Volume31
Issue number16
DOIs
Publication statusPublished - 2012
MoE publication typeA1 Journal article-refereed

Fingerprint

Tumor Suppressor Genes
Breast Neoplasms
Nonsense Codon
RNA Stability
Cell Line
Phenotype
Neoplasms
Mutation
Chromatin Assembly and Disassembly
Nuclear Proteins
Agar
Single Nucleotide Polymorphism
Exons
Adenosine Triphosphate
Yeasts
Maintenance
RNA
DNA
Enzymes
Genes

Cite this

Mamo, A., Cavallone, L., Tuzmen, S., Chabot, C., Ferrario, C., Hassan, S., ... Basik, M. (2012). An integrated genomic approach identifies ARID1A as a candidate tumor-suppressor gene in breast cancer. Oncogene, 31(16), 2090-2100. https://doi.org/10.1038/onc.2011.386
Mamo, A. ; Cavallone, L. ; Tuzmen, S. ; Chabot, C. ; Ferrario, C. ; Hassan, S. ; Edgren, Henrik ; Kallioniemi, Olli ; Aleynikova, O. ; Przybytkowski, E. ; Malcolm, K. ; Mousses, S. ; Tonin, P.N. ; Basik, M. / An integrated genomic approach identifies ARID1A as a candidate tumor-suppressor gene in breast cancer. In: Oncogene. 2012 ; Vol. 31, No. 16. pp. 2090-2100.
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abstract = "Tumor-suppressor genes (TSGs) have been classically defined as genes whose loss of function in tumor cells contributes to the formation and/or maintenance of the tumor phenotype. TSGs containing nonsense mutations may not be expressed because of nonsense-mediated RNA decay (NMD). We combined inhibition of the NMD process, which clears transcripts that contain nonsense mutations, with the application of high-density single-nucleotide polymorphism arrays analysis to discriminate allelic content in order to identify candidate TSGs in five breast cancer cell lines. We identified ARID1A as a target of NMD in the T47D breast cancer cell line, likely as a consequence of a mutation in exon-9, which introduces a premature stop codon at position Q944. ARID1A encodes a human homolog of yeast SWI1, which is an integral member of the hSWI/SNF complex, an ATP-dependent, chromatin-remodeling, multiple-subunit enzyme. Although we did not find any somatic mutations in 11 breast tumors, which show DNA copy-number loss at the 1p36 locus adjacent to ARID1A, we show that low ARID1A RNA or nuclear protein expression is associated with more aggressive breast cancer phenotypes, such as high tumor grade, in two independent cohorts of over 200 human breast cancer cases each. We also found that low ARID1A nuclear expression becomes more prevalent during the later stages of breast tumor progression. Finally, we found that ARID1A re-expression in the T47D cell line results in significant inhibition of colony formation in soft agar. These results suggest that ARID1A may be a candidate TSG in breast cancer.",
author = "A. Mamo and L. Cavallone and S. Tuzmen and C. Chabot and C. Ferrario and S. Hassan and Henrik Edgren and Olli Kallioniemi and O. Aleynikova and E. Przybytkowski and K. Malcolm and S. Mousses and P.N. Tonin and M. Basik",
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Mamo, A, Cavallone, L, Tuzmen, S, Chabot, C, Ferrario, C, Hassan, S, Edgren, H, Kallioniemi, O, Aleynikova, O, Przybytkowski, E, Malcolm, K, Mousses, S, Tonin, PN & Basik, M 2012, 'An integrated genomic approach identifies ARID1A as a candidate tumor-suppressor gene in breast cancer', Oncogene, vol. 31, no. 16, pp. 2090-2100. https://doi.org/10.1038/onc.2011.386

An integrated genomic approach identifies ARID1A as a candidate tumor-suppressor gene in breast cancer. / Mamo, A.; Cavallone, L.; Tuzmen, S.; Chabot, C.; Ferrario, C.; Hassan, S.; Edgren, Henrik; Kallioniemi, Olli; Aleynikova, O.; Przybytkowski, E.; Malcolm, K.; Mousses, S.; Tonin, P.N.; Basik, M. (Corresponding Author).

In: Oncogene, Vol. 31, No. 16, 2012, p. 2090-2100.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - An integrated genomic approach identifies ARID1A as a candidate tumor-suppressor gene in breast cancer

AU - Mamo, A.

AU - Cavallone, L.

AU - Tuzmen, S.

AU - Chabot, C.

AU - Ferrario, C.

AU - Hassan, S.

AU - Edgren, Henrik

AU - Kallioniemi, Olli

AU - Aleynikova, O.

AU - Przybytkowski, E.

AU - Malcolm, K.

AU - Mousses, S.

AU - Tonin, P.N.

AU - Basik, M.

PY - 2012

Y1 - 2012

N2 - Tumor-suppressor genes (TSGs) have been classically defined as genes whose loss of function in tumor cells contributes to the formation and/or maintenance of the tumor phenotype. TSGs containing nonsense mutations may not be expressed because of nonsense-mediated RNA decay (NMD). We combined inhibition of the NMD process, which clears transcripts that contain nonsense mutations, with the application of high-density single-nucleotide polymorphism arrays analysis to discriminate allelic content in order to identify candidate TSGs in five breast cancer cell lines. We identified ARID1A as a target of NMD in the T47D breast cancer cell line, likely as a consequence of a mutation in exon-9, which introduces a premature stop codon at position Q944. ARID1A encodes a human homolog of yeast SWI1, which is an integral member of the hSWI/SNF complex, an ATP-dependent, chromatin-remodeling, multiple-subunit enzyme. Although we did not find any somatic mutations in 11 breast tumors, which show DNA copy-number loss at the 1p36 locus adjacent to ARID1A, we show that low ARID1A RNA or nuclear protein expression is associated with more aggressive breast cancer phenotypes, such as high tumor grade, in two independent cohorts of over 200 human breast cancer cases each. We also found that low ARID1A nuclear expression becomes more prevalent during the later stages of breast tumor progression. Finally, we found that ARID1A re-expression in the T47D cell line results in significant inhibition of colony formation in soft agar. These results suggest that ARID1A may be a candidate TSG in breast cancer.

AB - Tumor-suppressor genes (TSGs) have been classically defined as genes whose loss of function in tumor cells contributes to the formation and/or maintenance of the tumor phenotype. TSGs containing nonsense mutations may not be expressed because of nonsense-mediated RNA decay (NMD). We combined inhibition of the NMD process, which clears transcripts that contain nonsense mutations, with the application of high-density single-nucleotide polymorphism arrays analysis to discriminate allelic content in order to identify candidate TSGs in five breast cancer cell lines. We identified ARID1A as a target of NMD in the T47D breast cancer cell line, likely as a consequence of a mutation in exon-9, which introduces a premature stop codon at position Q944. ARID1A encodes a human homolog of yeast SWI1, which is an integral member of the hSWI/SNF complex, an ATP-dependent, chromatin-remodeling, multiple-subunit enzyme. Although we did not find any somatic mutations in 11 breast tumors, which show DNA copy-number loss at the 1p36 locus adjacent to ARID1A, we show that low ARID1A RNA or nuclear protein expression is associated with more aggressive breast cancer phenotypes, such as high tumor grade, in two independent cohorts of over 200 human breast cancer cases each. We also found that low ARID1A nuclear expression becomes more prevalent during the later stages of breast tumor progression. Finally, we found that ARID1A re-expression in the T47D cell line results in significant inhibition of colony formation in soft agar. These results suggest that ARID1A may be a candidate TSG in breast cancer.

U2 - 10.1038/onc.2011.386

DO - 10.1038/onc.2011.386

M3 - Article

VL - 31

SP - 2090

EP - 2100

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 16

ER -