Impact of chromosomal instability on colorectal cancer progression and outcome

Autor: Blandine Massemin, Janick Selves, Karine Gordien, Christophe Cazaux, Valérie Dapremont, Frédéric Bibeau, Béatrice Orsetti, Charles Theillet, Rosine Guimbaud, Laurence Lasorsa, Isabelle Soubeyran, François Paraf, Caroline Bascoul-Mollevi, Michel Longy, Isabelle Hostein
Přispěvatelé: Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Service d'Anatomie et Cytologie Pathologiques, CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Homéostasie Cellulaire et Pathologies (HCP), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-CHU Limoges, Plateforme de génétique moléculaire des cancers d'Aquitaine, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Gastro - Entérologie et Nutrition, CHU Toulouse [Toulouse]-Hôpital de Rangueil, Validation et identification de nouvelles cibles en oncologie (VINCO), UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), This study was supported by INCA (Canceropole GSO, grant ACI 'Genetic instability as a negative outcome' 2004/2007 and 2008/2009)., Institut de recherche en cancérologie de Montpellier ( IRCM ), Université Montpellier 1 ( UM1 ) -CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), UNICANCER - Institut régional du Cancer [Montpellier] ( ICM ), CRLCC Val d'Aurelle - Paul Lamarque, Centre de Recherche en Cancérologie de Toulouse ( CRCT ), Université Paul Sabatier - Toulouse 3 ( UPS ) -CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Homéostasie Cellulaire et Pathologies ( HCP ), Université de Limoges ( UNILIM ) -CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ), Génétique tumorale - Pathologie, CHU Bordeaux [Bordeaux]-Centre Régional de Lutte Contre le Cancer Institut Bergonié (Bordeaux), Centre Hospitalier Universitaire de Toulouse - CHU Toulouse (FRANCE), Validation et identification de nouvelles cibles en oncologie ( VINCO ), Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié - CRLCC Bordeaux-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Institut Bergonié - CRLCC Bordeaux, Université de Limoges ( UNILIM ) -Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ) -CHU Limoges, Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié - CRLCC Bordeaux-Institut National de la Santé et de la Recherche Médicale (INSERM), BMC, Ed., Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service Endocrinologie, maladies métaboliques et nutrition [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse]
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Male
Genome instability
Oncology
Cancer Research
Colorectal cancer
Array CGH
[ SDV.CAN ] Life Sciences [q-bio]/Cancer
Metastasis
Chromosome Breakpoints
Surgical oncology
Chromosome instability
Medicine
Neoplasm Metastasis
Stage (cooking)
Outcome
Comparative Genomic Hybridization
16p13.3
Middle Aged
Prognosis
19q13.3
3. Good health
Treatment Outcome
[ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry
Molecular Biology/Genomics [q-bio.GN]
Breakpoint
Disease Progression
Female
Colorectal Neoplasms
Carcinoma in Situ
Research Article
Adult
Genomic instability
Adenoma
medicine.medical_specialty
[SDV.CAN]Life Sciences [q-bio]/Cancer
[SDV.CAN] Life Sciences [q-bio]/Cancer
CIN tumors
Chromosomal Instability
Internal medicine
Genetics
Humans
Aged
business.industry
Primary tumors
Carcinoma in situ
medicine.disease
Neoplasm Recurrence
Local
business
Comparative genomic hybridization
Zdroj: BMC Cancer
BMC Cancer, BioMed Central, 2014, 14 (1), pp.121. ⟨10.1186/1471-2407-14-121⟩
BMC Cancer, BioMed Central, 2014, 14 (1), pp.121. 〈10.1186/1471-2407-14-121〉
BMC Cancer, 2014, 14 (1), pp.121. ⟨10.1186/1471-2407-14-121⟩
ISSN: 1471-2407
DOI: 10.1186/1471-2407-14-121⟩
Popis: International audience; BACKGROUND: 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). METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.
Databáze: OpenAIRE
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