Impact of chromosomal instability on colorectal cancer progression and outcome

BMC Cancer

Charles Theillet⁴  Michel Longy³  Christophe Cazaux¹  Rosine Guimbaud⁶  Valérie Dapremont³  Isabelle Hostein³  Isabelle Soubeyran³  François Paraf²  Blandine Massemin⁴  Frédéric Bibeau⁴  Karine Gordien⁵  Laurence Lasorsa⁴  Caroline Bascoul-Mollevi⁴  Janick Selves⁵  Béatrice Orsetti⁴ 

[1]Cancer Research Center of Toulouse, INSERM U1037 CNRS ERL5994, University Paul Sabatier, University of Toulouse, Toulouse, France

[2]Centre Hospitalier Universitaire Dupuytren and EA 3842 Faculté de Médecine, Limoges, France

[3]Cancer genetics unit, Institut Bergonié, Bordeaux, France

[4]Institut régional du Cancer Montpellier, F-34298 Montpellier, France

[5]Cancer Research Center of Toulouse – UMR 1037 INSERM, University of Toulouse, Toulouse, France

[6]University Hospital of Rangueil, Toulouse, France

关键词: 19q13.3;    16p13.3;    Outcome;    Metastasis;    Primary tumors;    Adenoma;    CIN tumors;    Array CGH;    Breakpoint;    Genomic instability;    Colorectal cancer;   

Others  :  859036
DOI  :  10.1186/1471-2407-14-121

 received in 2013-09-11, accepted in 2014-02-07,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Orsetti et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Halazonetis TD, Gorgoulis VG, Bartek J: An oncogene-induced DNA damage model for cancer development. Science 2008, 319:1352-1355.
• [2]Bartek J, Lukas J, Bartkova J: DNA damage response as an anti-cancer barrier: damage threshold and the concept of “conditional haploinsufficiency. Cell Cycle 2007, 6:2344-2347.
• [3]Issa J-P: Colon cancer: it’s CIN or CIMP. Clin Cancer Res 2008, 14:5939-5940.
• [4]Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky Y, Karchin R, Wilson PA, Kaminker JS, Zhang Z, Croshaw R, Willis J, Dawson D, Shipitsin M, Willson JK, Sukumar S, Polyak K, Park BH, Pethiyagoda CL, Pant PV, Ballinger DG, Sparks AB, Hartigan J, Smith DR, Suh E, Papadopoulos N, Buckhaults P, Markowitz SD, Parmigiani G, Kinzler KW, Velculescu VE, Vogelstein B: The genomic landscapes of human breast and colorectal cancers. Science 2007, 318:1108-1113.
• [5]Markowitz SD, Bertagnolli MM: Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med 2009, 361:2449-2460.
• [6]Pillaire M-J, Selves J, Gordien K, Gouraud P-A, Gentil C, Danjoux M, Do C, Negre V, Bieth A, Guimbaud R, Trouche D, Pasero P, Méchali M, Hoffmann J-S, Cazaux C: A “DNA replication” signature of progression and negative outcome in colorectal cancer. Oncogene 2010, 29:876-887.
• [7]Diep CB, Kleivi K, Ribeiro FR, Teixeira MR, Lindgjærde OC, Lothe RA: The order of genetic events associated with colorectal cancer progression inferred from meta-analysis of copy number changes. Genes Chromosom Cancer 2006, 45:31-41.
• [8]Sheffer M, Bacolod MD, Zuk O, Giardina SF, Pincas H, Barany F, Paty PB, Gerald WL, Notterman DA, Domany E: Association of survival and disease progression with chromosomal instability: a genomic exploration of colorectal cancer. Proc Natl Acad Sci U S A 2009, 106:7131-7136.
• [9]Bass AJ, Lawrence MS, Brace LE, Ramos AH, Drier Y, Cibulskis K, Sougnez C, Voet D, Saksena G, Sivachenko A, Jing R, Parkin M, Pugh T, Verhaak RG, Stransky N, Boutin AT, Barretina J, Solit DB, Vakiani E, Shao W, Mishina Y, Warmuth M, Jimenez J, Chiang DY, Signoretti S, Kaelin WG, Spardy N, Hahn WC, Hoshida Y, Ogino S, Depinho RA, Chin L, Garraway LA, Fuchs CS, Baselga J, Tabernero J, Gabriel S, Lander ES, Getz G, Meyerson M: Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion. Nat Genet 2011, 43:964-968.
• [10]Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 1990, 61:759-767.
• [11]Carvalho B, Postma C, Mongera S, Hopmans E, Diskin S, van de Wiel MA, van Criekinge W, Thas O, Matthäi A, Cuesta MA, Terhaar sive Droste JS, Craanen M, Schröck E, Ylstra B, Meijer GA: Multiple putative oncogenes at the chromosome 20q amplicon contribute to colorectal adenoma to carcinoma progression. Gut 2009, 58:79-89.
• [12]Orsetti B, Nugoli M, Cervera N, Lasorsa L, Chuchana P, Rouge C, Ursule L, Nguyen C, Bibeau F, Rodriguez C, Theillet C: Genetic profiling of chromosome 1 in breast cancer: mapping of regions of gains and losses and identification of candidate genes on 1q. Br J Cancer 2006, 95:1439-1447.
• [13]Postma C, Koopman M, Buffart TE, Eijk PP, Carvalho B, Peters GJ, Ylstra B, van Krieken JH, Punt CJA, Meijer GA: DNA copy number profiles of primary tumors as predictors of response to chemotherapy in advanced colorectal cancer. Ann Oncol 2009, 20:1048-1056.
• [14]O’Connell JB, Maggard MA, Ko CY: Colon cancer survival rates with the new American joint committee on cancer sixth edition staging. J Natl Cancer Inst 2004, 96:1420-1425.
• [15]Kurashina K, Yamashita Y, Ueno T, Koinuma K, Ohashi J, Horie H, Miyakura Y, Hamada T, Haruta H, Hatanaka H, Soda M, Choi YL, Takada S, Yasuda Y, Nagai H, Mano H: Chromosome copy number analysis in screening for prognosis-related genomic regions in colorectal carcinoma. Cancer Sci 2008, 99:1835-1840.
• [16]Brosens RP, Haan JC, Carvalho B, Rustenburg F, Grabsch H, Quirke P, Engel AF, Cuesta MA, Maughan N, Flens M, Meijer GA, Ylstra B: Candidate driver genes in focal chromosomal aberrations of stage II colon cancer. J Pathol 2010, 221:411-424.
• [17]Poulogiannis G, Ichimura K, Hamoudi RA, Luo F, Leung SY, Yuen ST, Harrison DJ, Wyllie AH, Arends MJ: Prognostic relevance of DNA copy number changes in colorectal cancer. J Pathol 2010, 220:338-347.
• [18]Brosens RPM, Belt EJTH, Haan JC, Buffart TE, Carvalho B, Grabsch H, Quirke P, Cuesta MA, Engel AF, Ylstra B, Meijer GA: Deletion of chromosome 4q predicts outcome in stage II colon cancer patients. Anal Cell Pathol 2010, 33:95-104.
• [19]Meijer GA, Hermsen MA, Baak JP, van Diest PJ, Meuwissen SG, Beliën JA, Hoovers JM, Joenje H, Snijders PJ, Walboomers JM: Progression from colorectal adenoma to carcinoma is associated with non-random chromosomal gains as detected by comparative genomic hybridisation. J Clin Pathol 1998, 51:901-909.
• [20]Nakao M, Kawauchi S, Furuya T, Uchiyama T, Adachi J, Okada T, Ikemoto K, Oga A, Sasaki K: Identification of DNA copy number aberrations associated with metastases of colorectal cancer using array CGH profiles. Cancer Genet Cytogenet 2009, 188:70-76.
• [21]Trautmann K, Terdiman JP, French AJ, Roydasgupta R, Sein N, Kakar S, Fridlyand J, Snijders AM, Albertson DG, Thibodeau SN, Waldman FM: Chromosomal instability in microsatellite-unstable and stable colon cancer. Clin Cancer Res 2006, 12:6379-6385.
• [22]Mehta KR, Nakao K, Zuraek MB, Ruan DT, Bergsland EK, Venook AP, Moore DH, Tokuyasu TA, Jain AN, Warren RS, Terdiman JP, Waldman FM: Fractional genomic alteration detected by array-based comparative genomic hybridization independently predicts survival after hepatic resection for metastatic colorectal cancer. Clin Cancer Res 2005, 11:1791-1797.
• [23]Janoueix-Lerosey I, Schleiermacher G, Michels E, Mosseri V, Ribeiro A, Lequin D, Vermeulen J, Couturier J, Peuchmaur M, Valent A, Plantaz D, Rubie H, Valteau-Couanet D, Thomas C, Combaret V, Rousseau R, Eggert A, Michon J, Speleman F, Delattre O: Overall genomic pattern is a predictor of outcome in neuroblastoma. J Clin Oncol 2009, 27:1026-1033.
• [24]Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, Kawasoe T, Ishiguro H, Fujita M, Tokino T, Sasaki Y, Imaoka S, Murata M, Shimano T, Yamaoka Y, Nakamura Y: AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet 2000, 24:245-250.
• [25]Segditsas S, Tomlinson I: Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene 2006, 25:7531-7537.
• [26]Nehls O, Okech T, Hsieh C-J, Enzinger T, Sarbia M, Borchard F, Gruenagel H-H, Gaco V, Hass HG, Arkenau HT, Hartmann JT, Porschen R, Gregor M, Klump B: Studies on p53, BAX and Bcl-2 protein expression and microsatellite instability in stage III (UICC) colon cancer treated by adjuvant chemotherapy: major prognostic impact of proapoptotic BAX. Br J Cancer 2007, 96:1409-1418.
• [27]Miyabe I, Kunkel TA, Carr AM: The major roles of DNA polymerases epsilon and delta at the eukaryotic replication fork are evolutionarily conserved. PLoS Genet 2011, 7:e1002407.