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Excessive genomic DNA copy number variation in the L1—Fraumeni cancer predisposition syndrome.

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Title: Excessive genomic DNA copy number variation in the L1—Fraumeni cancer predisposition syndrome.
Authors: Shlien, Adam1,2, Tabori, Uri1,3,4, Marshall, Christian R.1,5,6, Pienkowska, Malgorzata1, Feuk, Lars1,5,6, Novokmet, Ana1,4, Nanda, Sonia4, Druker, Harriet4, Scherer, Stephen W.1,5,6, Malkin, David1,2,3,4 david.malkin@sickkids.ca
Source: Proceedings of the National Academy of Sciences of the United States of America. 8/12/2008, Vol. 105 Issue 32, p11264-11269. 6p. 1 Diagram, 3 Graphs.
Subjects: Cancer cells, Nucleic acids, DNA, Breast cancer, Cancer genetics
Abstract: DNA copy number variations (CNVs) are a significant and ubiquitous source of inherited human genetic variation. However, the importance of CNVs to cancer susceptibility and tumor progression has not yet been explored. Li-Fraumeni syndrome (LFS) is an autosomal dominantly inherited disorder characterized by a strikingly increased risk of early-onset breast cancer, sarcomas, brain tumors and other neoplasms in individuals harboring germline TP53 mutations. Known genetic determinants of LFS do not fully explain the variable clinical phenotype in affected family members. As part of a wider study of CNVs and cancer, we conducted a genome-wide profile of germline CNVs in LFS families. Here, by examining DNA from a large healthy population and an LFS cohort using high-density oligonucleotide arrays, we show that the number of CNVs per genome is well conserved in the healthy population, but strikingly enriched in these cancer-prone individuals. We found a highly significant increase in CNVs among carriers of germline TP53 mutations with a familial cancer history. Furthermore, we identified a remarkable number of genomic regions in which known cancer-related genes coincide with CNVs, in both LFS families and healthy individuals. Germline CNVs may provide a foundation that enables the more dramatic chromosomal changes characteristic of TP53-related tumors to be established. Our results suggest that screening families predisposed to cancer for CNVs may identify individuals with an abnormally high number of these events. [ABSTRACT FROM AUTHOR]
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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PubType: Academic Journal
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  Data: Excessive genomic DNA copy number variation in the L1—Fraumeni cancer predisposition syndrome.
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  Data: <searchLink fieldCode="AR" term="%22Shlien%2C+Adam%22">Shlien, Adam</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Tabori%2C+Uri%22">Tabori, Uri</searchLink><relatesTo>1,3,4</relatesTo><br /><searchLink fieldCode="AR" term="%22Marshall%2C+Christian+R%2E%22">Marshall, Christian R.</searchLink><relatesTo>1,5,6</relatesTo><br /><searchLink fieldCode="AR" term="%22Pienkowska%2C+Malgorzata%22">Pienkowska, Malgorzata</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Feuk%2C+Lars%22">Feuk, Lars</searchLink><relatesTo>1,5,6</relatesTo><br /><searchLink fieldCode="AR" term="%22Novokmet%2C+Ana%22">Novokmet, Ana</searchLink><relatesTo>1,4</relatesTo><br /><searchLink fieldCode="AR" term="%22Nanda%2C+Sonia%22">Nanda, Sonia</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Druker%2C+Harriet%22">Druker, Harriet</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Scherer%2C+Stephen+W%2E%22">Scherer, Stephen W.</searchLink><relatesTo>1,5,6</relatesTo><br /><searchLink fieldCode="AR" term="%22Malkin%2C+David%22">Malkin, David</searchLink><relatesTo>1,2,3,4</relatesTo><i> david.malkin@sickkids.ca</i>
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  Data: <searchLink fieldCode="DE" term="%22Cancer+cells%22">Cancer cells</searchLink><br /><searchLink fieldCode="DE" term="%22Nucleic+acids%22">Nucleic acids</searchLink><br /><searchLink fieldCode="DE" term="%22DNA%22">DNA</searchLink><br /><searchLink fieldCode="DE" term="%22Breast+cancer%22">Breast cancer</searchLink><br /><searchLink fieldCode="DE" term="%22Cancer+genetics%22">Cancer genetics</searchLink>
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  Data: DNA copy number variations (CNVs) are a significant and ubiquitous source of inherited human genetic variation. However, the importance of CNVs to cancer susceptibility and tumor progression has not yet been explored. Li-Fraumeni syndrome (LFS) is an autosomal dominantly inherited disorder characterized by a strikingly increased risk of early-onset breast cancer, sarcomas, brain tumors and other neoplasms in individuals harboring germline TP53 mutations. Known genetic determinants of LFS do not fully explain the variable clinical phenotype in affected family members. As part of a wider study of CNVs and cancer, we conducted a genome-wide profile of germline CNVs in LFS families. Here, by examining DNA from a large healthy population and an LFS cohort using high-density oligonucleotide arrays, we show that the number of CNVs per genome is well conserved in the healthy population, but strikingly enriched in these cancer-prone individuals. We found a highly significant increase in CNVs among carriers of germline TP53 mutations with a familial cancer history. Furthermore, we identified a remarkable number of genomic regions in which known cancer-related genes coincide with CNVs, in both LFS families and healthy individuals. Germline CNVs may provide a foundation that enables the more dramatic chromosomal changes characteristic of TP53-related tumors to be established. Our results suggest that screening families predisposed to cancer for CNVs may identify individuals with an abnormally high number of these events. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
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  Group: Ab
  Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1073/pnas.0802970105
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        Text: English
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        Type: general
      – SubjectFull: Nucleic acids
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      – SubjectFull: DNA
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      – SubjectFull: Breast cancer
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      – SubjectFull: Cancer genetics
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      – TitleFull: Excessive genomic DNA copy number variation in the L1—Fraumeni cancer predisposition syndrome.
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              Text: 8/12/2008
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