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Cancer chromosome breakpoints cluster in gene-rich genomic regions

Mitelman, Felix LU ; Johansson, Bertil LU ; Mertens, Fredrik LU ; Schyman, Tommy and Mandahl, Nils LU (2018) In Genes Chromosomes and Cancer
Abstract

Cancer cells are characterized by chromosome abnormalities, of which some, in particular balanced rearrangements, are associated with distinct tumor entities and/or with specific gene rearrangements that represent important steps in the carcinogenic process. However, the vast majority of cytogenetically detectable structural aberrations in cancer cells have not been characterized at the nucleotide level; hence, their importance and functional consequences are unknown. By ascertaining the chromosomal breakpoints in 22 344 different clonal structural chromosome abnormalities identified in the karyotypes of 49 626 cases of neoplastic disorders we here show that the distribution of breakpoints is strongly associated (P < 0.0001) with... (More)

Cancer cells are characterized by chromosome abnormalities, of which some, in particular balanced rearrangements, are associated with distinct tumor entities and/or with specific gene rearrangements that represent important steps in the carcinogenic process. However, the vast majority of cytogenetically detectable structural aberrations in cancer cells have not been characterized at the nucleotide level; hence, their importance and functional consequences are unknown. By ascertaining the chromosomal breakpoints in 22 344 different clonal structural chromosome abnormalities identified in the karyotypes of 49 626 cases of neoplastic disorders we here show that the distribution of breakpoints is strongly associated (P < 0.0001) with gene content within the affected chromosomal bands. This association also remains highly significant in separate analyses of recurrent and nonrecurrent chromosome abnormalities as well as of specific subtypes of cancer (P < 0.0001 for all comparisons). In contrast, the impact of band length was negligible. The breakpoint distribution is thus not stochastic—gene-rich regions are preferentially affected. Several genomic features relating to transcription, replication, and chromatin organization have been found to enhance chromosome breakage frequencies; this indicates that gene-rich regions may be more break-prone. The salient finding in the present study is that a substantial fraction of all structural chromosome abnormalities, not only those specifically associated with certain tumor types, may affect genes that are pathogenetically important. If this interpretation is correct, then the prevailing view that the great majority of cancer chromosome aberrations is cytogenetic noise can be seriously questioned.

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author
organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
breakpoint distribution, cancer chromosome abnormalities, cancer chromosome breakpoints, cytogenetic noise, gene-rich regions
in
Genes Chromosomes and Cancer
publisher
John Wiley & Sons
external identifiers
  • scopus:85058984403
ISSN
1045-2257
DOI
10.1002/gcc.22713
language
English
LU publication?
yes
id
cf8cb985-812a-4705-b6a1-807dc4a2505c
date added to LUP
2019-01-09 12:15:17
date last changed
2019-05-19 05:05:17
@article{cf8cb985-812a-4705-b6a1-807dc4a2505c,
  abstract     = {<p>Cancer cells are characterized by chromosome abnormalities, of which some, in particular balanced rearrangements, are associated with distinct tumor entities and/or with specific gene rearrangements that represent important steps in the carcinogenic process. However, the vast majority of cytogenetically detectable structural aberrations in cancer cells have not been characterized at the nucleotide level; hence, their importance and functional consequences are unknown. By ascertaining the chromosomal breakpoints in 22 344 different clonal structural chromosome abnormalities identified in the karyotypes of 49 626 cases of neoplastic disorders we here show that the distribution of breakpoints is strongly associated (P &lt; 0.0001) with gene content within the affected chromosomal bands. This association also remains highly significant in separate analyses of recurrent and nonrecurrent chromosome abnormalities as well as of specific subtypes of cancer (P &lt; 0.0001 for all comparisons). In contrast, the impact of band length was negligible. The breakpoint distribution is thus not stochastic—gene-rich regions are preferentially affected. Several genomic features relating to transcription, replication, and chromatin organization have been found to enhance chromosome breakage frequencies; this indicates that gene-rich regions may be more break-prone. The salient finding in the present study is that a substantial fraction of all structural chromosome abnormalities, not only those specifically associated with certain tumor types, may affect genes that are pathogenetically important. If this interpretation is correct, then the prevailing view that the great majority of cancer chromosome aberrations is cytogenetic noise can be seriously questioned.</p>},
  author       = {Mitelman, Felix and Johansson, Bertil and Mertens, Fredrik and Schyman, Tommy and Mandahl, Nils},
  issn         = {1045-2257},
  keyword      = {breakpoint distribution,cancer chromosome abnormalities,cancer chromosome breakpoints,cytogenetic noise,gene-rich regions},
  language     = {eng},
  month        = {11},
  publisher    = {John Wiley & Sons},
  series       = {Genes Chromosomes and Cancer},
  title        = {Cancer chromosome breakpoints cluster in gene-rich genomic regions},
  url          = {http://dx.doi.org/10.1002/gcc.22713},
  year         = {2018},
}