Impact of chromosomal instability on colorectal cancer progression and outcome
It remains presently unclear whether disease progression in colorectal carcinoma (CRC), from early, to invasive and metastatic forms, is associated to a gradual increase in genetic instability and to a scheme of sequentially occurring Copy Number Alterations (CNAs). In this work we set to determine...
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| creator | Orsetti, Béatrice Selves, Janick Bascoul-Mollevi, Caroline Lasorsa, Laurence Gordien, Karine Bibeau, Frédéric Massemin, Blandine Paraf, François Soubeyran, Isabelle Hostein, Isabelle Dapremont, Valérie Guimbaud, Rosine Cazaux, Christophe Longy, Michel Theillet, Charles |
| description | It remains presently unclear whether disease progression in colorectal carcinoma (CRC), from early, to invasive and metastatic forms, is associated to a gradual increase in genetic instability and to a scheme of sequentially occurring Copy Number Alterations (CNAs).
In this work we set to determine the existence of such links between CRC progression and genetic instability and searched for associations with patient outcome. To this aim we analyzed a set of 162 Chromosomal Instable (CIN) CRCs comprising 131 primary carcinomas evenly distributed through stage 1 to 4, 31 metastases and 14 adenomas by array-CGH. CNA profiles were established according to disease stage and compared. We, also, asked whether the level of genomic instability was correlated to disease outcome in stage 2 and 3 CRCs. Two metrics of chromosomal instability were used; (i) Global Genomic Index (GGI), corresponding to the fraction of the genome involved in CNA, (ii) number of breakpoints (nbBP).
Stage 1, 2, 3 and 4 tumors did not differ significantly at the level of their CNA profiles precluding the conventional definition of a progression scheme based on increasing levels of genetic instability. Combining GGI and nbBP,we classified genomic profiles into 5 groups presenting distinct patterns of chromosomal instability and defined two risk classes of tumors, showing strong differences in outcome and hazard risk (RFS: p = 0.012, HR = 3; OS: p |
| doi_str_mv | 10.1186/1471-2407-14-121 |
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In this work we set to determine the existence of such links between CRC progression and genetic instability and searched for associations with patient outcome. To this aim we analyzed a set of 162 Chromosomal Instable (CIN) CRCs comprising 131 primary carcinomas evenly distributed through stage 1 to 4, 31 metastases and 14 adenomas by array-CGH. CNA profiles were established according to disease stage and compared. We, also, asked whether the level of genomic instability was correlated to disease outcome in stage 2 and 3 CRCs. Two metrics of chromosomal instability were used; (i) Global Genomic Index (GGI), corresponding to the fraction of the genome involved in CNA, (ii) number of breakpoints (nbBP).
Stage 1, 2, 3 and 4 tumors did not differ significantly at the level of their CNA profiles precluding the conventional definition of a progression scheme based on increasing levels of genetic instability. Combining GGI and nbBP,we classified genomic profiles into 5 groups presenting distinct patterns of chromosomal instability and defined two risk classes of tumors, showing strong differences in outcome and hazard risk (RFS: p = 0.012, HR = 3; OS: p < 0.001, HR = 9.7). While tumors of the high risk group were characterized by frequent fractional CNAs, low risk tumors presented predominantly whole chromosomal arm CNAs. Searching for CNAs correlating with negative outcome we found that losses at 16p13.3 and 19q13.3 observed in 10% (7/72) of stage 2-3 tumors showed strong association with early relapse (p < 0.001) and death (p < 0.007, p < 0.016). Both events showed frequent co-occurrence (p < 1x10-8) and could, therefore, mark for stage 2-3 CRC susceptible to negative outcome.
Our data show that CRC disease progression from stage 1 to stage 4 is not paralleled by increased levels of genetic instability. However, they suggest that stage 2-3 CRC with elevated genetic instability and particularly profiles with fractional CNA represent a subset of aggressive tumors.</description><identifier>ISSN: 1471-2407</identifier><identifier>EISSN: 1471-2407</identifier><identifier>DOI: 10.1186/1471-2407-14-121</identifier><identifier>PMID: 24559140</identifier><language>eng</language><publisher>England: BioMed Central</publisher><subject>Acquisitions & mergers ; Adult ; Aged ; Apoptosis ; Cancer ; Carcinoma in Situ - genetics ; Chromosomal Instability - genetics ; Chromosome Breakpoints ; Colorectal cancer ; Colorectal Neoplasms - genetics ; Colorectal Neoplasms - pathology ; Comparative Genomic Hybridization ; Deoxyribonucleic acid ; Disease Progression ; DNA ; Female ; Genomics ; Hospitals ; Humans ; Life Sciences ; Male ; Medical research ; Middle Aged ; Mutation ; Neoplasm Metastasis ; Neoplasm Recurrence, Local - genetics ; Neoplasm Recurrence, Local - pathology ; Prognosis ; Studies ; Treatment Outcome ; Tumors</subject><ispartof>BMC cancer, 2014-02, Vol.14 (1), p.121-121, Article 121</ispartof><rights>2014 Orsetti et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><rights>Copyright © 2014 Orsetti et al.; licensee BioMed Central Ltd. 2014 Orsetti et al.; licensee BioMed Central Ltd.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b620t-3ce040b5f4d71031d76b5368715b3d24e6b056b8f0b0b6771a76fb38dbddc6393</citedby><cites>FETCH-LOGICAL-b620t-3ce040b5f4d71031d76b5368715b3d24e6b056b8f0b0b6771a76fb38dbddc6393</cites><orcidid>0000-0003-4827-3684</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4233623/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4233623/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24559140$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://inserm.hal.science/inserm-00952435$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Orsetti, Béatrice</creatorcontrib><creatorcontrib>Selves, Janick</creatorcontrib><creatorcontrib>Bascoul-Mollevi, Caroline</creatorcontrib><creatorcontrib>Lasorsa, Laurence</creatorcontrib><creatorcontrib>Gordien, Karine</creatorcontrib><creatorcontrib>Bibeau, Frédéric</creatorcontrib><creatorcontrib>Massemin, Blandine</creatorcontrib><creatorcontrib>Paraf, François</creatorcontrib><creatorcontrib>Soubeyran, Isabelle</creatorcontrib><creatorcontrib>Hostein, Isabelle</creatorcontrib><creatorcontrib>Dapremont, Valérie</creatorcontrib><creatorcontrib>Guimbaud, Rosine</creatorcontrib><creatorcontrib>Cazaux, Christophe</creatorcontrib><creatorcontrib>Longy, Michel</creatorcontrib><creatorcontrib>Theillet, Charles</creatorcontrib><title>Impact of chromosomal instability on colorectal cancer progression and outcome</title><title>BMC cancer</title><addtitle>BMC Cancer</addtitle><description>It remains presently unclear whether disease progression in colorectal carcinoma (CRC), from early, to invasive and metastatic forms, is associated to a gradual increase in genetic instability and to a scheme of sequentially occurring Copy Number Alterations (CNAs).
In this work we set to determine the existence of such links between CRC progression and genetic instability and searched for associations with patient outcome. To this aim we analyzed a set of 162 Chromosomal Instable (CIN) CRCs comprising 131 primary carcinomas evenly distributed through stage 1 to 4, 31 metastases and 14 adenomas by array-CGH. CNA profiles were established according to disease stage and compared. We, also, asked whether the level of genomic instability was correlated to disease outcome in stage 2 and 3 CRCs. Two metrics of chromosomal instability were used; (i) Global Genomic Index (GGI), corresponding to the fraction of the genome involved in CNA, (ii) number of breakpoints (nbBP).
Stage 1, 2, 3 and 4 tumors did not differ significantly at the level of their CNA profiles precluding the conventional definition of a progression scheme based on increasing levels of genetic instability. Combining GGI and nbBP,we classified genomic profiles into 5 groups presenting distinct patterns of chromosomal instability and defined two risk classes of tumors, showing strong differences in outcome and hazard risk (RFS: p = 0.012, HR = 3; OS: p < 0.001, HR = 9.7). While tumors of the high risk group were characterized by frequent fractional CNAs, low risk tumors presented predominantly whole chromosomal arm CNAs. Searching for CNAs correlating with negative outcome we found that losses at 16p13.3 and 19q13.3 observed in 10% (7/72) of stage 2-3 tumors showed strong association with early relapse (p < 0.001) and death (p < 0.007, p < 0.016). Both events showed frequent co-occurrence (p < 1x10-8) and could, therefore, mark for stage 2-3 CRC susceptible to negative outcome.
Our data show that CRC disease progression from stage 1 to stage 4 is not paralleled by increased levels of genetic instability. However, they suggest that stage 2-3 CRC with elevated genetic instability and particularly profiles with fractional CNA represent a subset of aggressive tumors.</description><subject>Acquisitions & mergers</subject><subject>Adult</subject><subject>Aged</subject><subject>Apoptosis</subject><subject>Cancer</subject><subject>Carcinoma in Situ - genetics</subject><subject>Chromosomal Instability - genetics</subject><subject>Chromosome Breakpoints</subject><subject>Colorectal cancer</subject><subject>Colorectal Neoplasms - genetics</subject><subject>Colorectal Neoplasms - pathology</subject><subject>Comparative Genomic Hybridization</subject><subject>Deoxyribonucleic acid</subject><subject>Disease Progression</subject><subject>DNA</subject><subject>Female</subject><subject>Genomics</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Male</subject><subject>Medical research</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Neoplasm Metastasis</subject><subject>Neoplasm Recurrence, Local - 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genetics</topic><topic>Chromosomal Instability - genetics</topic><topic>Chromosome Breakpoints</topic><topic>Colorectal cancer</topic><topic>Colorectal Neoplasms - genetics</topic><topic>Colorectal Neoplasms - pathology</topic><topic>Comparative Genomic Hybridization</topic><topic>Deoxyribonucleic acid</topic><topic>Disease Progression</topic><topic>DNA</topic><topic>Female</topic><topic>Genomics</topic><topic>Hospitals</topic><topic>Humans</topic><topic>Life Sciences</topic><topic>Male</topic><topic>Medical research</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>Neoplasm Metastasis</topic><topic>Neoplasm Recurrence, Local - genetics</topic><topic>Neoplasm Recurrence, Local - pathology</topic><topic>Prognosis</topic><topic>Studies</topic><topic>Treatment Outcome</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Orsetti, Béatrice</creatorcontrib><creatorcontrib>Selves, Janick</creatorcontrib><creatorcontrib>Bascoul-Mollevi, Caroline</creatorcontrib><creatorcontrib>Lasorsa, Laurence</creatorcontrib><creatorcontrib>Gordien, Karine</creatorcontrib><creatorcontrib>Bibeau, Frédéric</creatorcontrib><creatorcontrib>Massemin, Blandine</creatorcontrib><creatorcontrib>Paraf, François</creatorcontrib><creatorcontrib>Soubeyran, Isabelle</creatorcontrib><creatorcontrib>Hostein, Isabelle</creatorcontrib><creatorcontrib>Dapremont, Valérie</creatorcontrib><creatorcontrib>Guimbaud, Rosine</creatorcontrib><creatorcontrib>Cazaux, Christophe</creatorcontrib><creatorcontrib>Longy, Michel</creatorcontrib><creatorcontrib>Theillet, Charles</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>ProQuest Health and Medical</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>BMC cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Orsetti, Béatrice</au><au>Selves, Janick</au><au>Bascoul-Mollevi, Caroline</au><au>Lasorsa, Laurence</au><au>Gordien, Karine</au><au>Bibeau, Frédéric</au><au>Massemin, Blandine</au><au>Paraf, François</au><au>Soubeyran, Isabelle</au><au>Hostein, Isabelle</au><au>Dapremont, Valérie</au><au>Guimbaud, Rosine</au><au>Cazaux, Christophe</au><au>Longy, Michel</au><au>Theillet, Charles</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Impact of chromosomal instability on colorectal cancer progression and outcome</atitle><jtitle>BMC cancer</jtitle><addtitle>BMC Cancer</addtitle><date>2014-02-22</date><risdate>2014</risdate><volume>14</volume><issue>1</issue><spage>121</spage><epage>121</epage><pages>121-121</pages><artnum>121</artnum><issn>1471-2407</issn><eissn>1471-2407</eissn><abstract>It remains presently unclear whether disease progression in colorectal carcinoma (CRC), from early, to invasive and metastatic forms, is associated to a gradual increase in genetic instability and to a scheme of sequentially occurring Copy Number Alterations (CNAs).
In this work we set to determine the existence of such links between CRC progression and genetic instability and searched for associations with patient outcome. To this aim we analyzed a set of 162 Chromosomal Instable (CIN) CRCs comprising 131 primary carcinomas evenly distributed through stage 1 to 4, 31 metastases and 14 adenomas by array-CGH. CNA profiles were established according to disease stage and compared. We, also, asked whether the level of genomic instability was correlated to disease outcome in stage 2 and 3 CRCs. Two metrics of chromosomal instability were used; (i) Global Genomic Index (GGI), corresponding to the fraction of the genome involved in CNA, (ii) number of breakpoints (nbBP).
Stage 1, 2, 3 and 4 tumors did not differ significantly at the level of their CNA profiles precluding the conventional definition of a progression scheme based on increasing levels of genetic instability. Combining GGI and nbBP,we classified genomic profiles into 5 groups presenting distinct patterns of chromosomal instability and defined two risk classes of tumors, showing strong differences in outcome and hazard risk (RFS: p = 0.012, HR = 3; OS: p < 0.001, HR = 9.7). While tumors of the high risk group were characterized by frequent fractional CNAs, low risk tumors presented predominantly whole chromosomal arm CNAs. Searching for CNAs correlating with negative outcome we found that losses at 16p13.3 and 19q13.3 observed in 10% (7/72) of stage 2-3 tumors showed strong association with early relapse (p < 0.001) and death (p < 0.007, p < 0.016). Both events showed frequent co-occurrence (p < 1x10-8) and could, therefore, mark for stage 2-3 CRC susceptible to negative outcome.
Our data show that CRC disease progression from stage 1 to stage 4 is not paralleled by increased levels of genetic instability. However, they suggest that stage 2-3 CRC with elevated genetic instability and particularly profiles with fractional CNA represent a subset of aggressive tumors.</abstract><cop>England</cop><pub>BioMed Central</pub><pmid>24559140</pmid><doi>10.1186/1471-2407-14-121</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0003-4827-3684</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Acquisitions & mergers Adult Aged Apoptosis Cancer Carcinoma in Situ - genetics Chromosomal Instability - genetics Chromosome Breakpoints Colorectal cancer Colorectal Neoplasms - genetics Colorectal Neoplasms - pathology Comparative Genomic Hybridization Deoxyribonucleic acid Disease Progression DNA Female Genomics Hospitals Humans Life Sciences Male Medical research Middle Aged Mutation Neoplasm Metastasis Neoplasm Recurrence, Local - genetics Neoplasm Recurrence, Local - pathology Prognosis Studies Treatment Outcome Tumors |
| title | Impact of chromosomal instability on colorectal cancer progression and outcome |
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