An array CGH based genomic instability index (G2I) is predictive of clinical outcome in breast cancer and reveals a subset of tumors without lymph node involvement but with poor prognosis

BMC Medical Genomics

Michel Longy⁹  Gaëtan MacGrogan²  Aurélien de Reynies⁴  Nicolas Sévenet⁵  Charles Theillet⁶  Isabelle de Mascarel²  Marc Debled⁷  Christine Tunon de Lara¹  Charlotte Primois⁵  Béatrice Orsetti⁶  Guillaume Banneau⁸  Nabila Elarouci⁴  Véronique Brouste³  Sana Sfar⁸  Natalie Jones⁸  Mickael Guedj⁴  Françoise Bonnet⁵ 

[1] Surgery Department, Institut Bergonié, Bordeaux, France;Pathology Department, Institut Bergonié, Bordeaux, France;Clinical and Epidemiological Research Unit, Institut Bergonié, Bordeaux, France;«Cartes d’Identité des Tumeurs »(CIT) program, Ligue Nationale Contre le Cancer, Paris, France;Cancer Genetics Unit, Institut Bergonié, Bordeaux, France;Inserm U 896, IRCM – Centre Val d’Aurelle – Paul Lamarque, Montpellier, France;Medical Oncology Department, Institut Bergonié, Bordeaux, France;Inserm U 916 Institut Bergonié, Université de Bordeaux, Bordeaux, France;Inserm U916, Institut Bergonié, 229 Cours de l’Argonne, Bordeaux cedex, 33076, France

关键词: Genetic instability;    Prognosis;    Array CGH;    Breast cancer;   

Others  :  1134557
DOI  :  10.1186/1755-8794-5-54

 received in 2012-01-04, accepted in 2012-11-12,  发布年份 2012

【 摘 要 】

Background

Despite entering complete remission after primary treatment, a substantial proportion of patients with early stage breast cancer will develop metastases. Prediction of such an outcome remains challenging despite the clinical use of several prognostic parameters. Several reports indicate that genomic instability, as reflected in specific chromosomal aneuploidies and variations in DNA content, influences clinical outcome but no precise definition of this parameter has yet been clearly established.

Methods

To explore the prognostic value of genomic alterations present in primary tumors, we performed a comparative genomic hybridization study on BAC arrays with a panel of breast carcinomas from 45 patients with metastatic relapse and 95 others, matched for age and axillary node involvement, without any recurrence after at least 11 years of follow-up. Array-CGH data was used to establish a two-parameter index representative of the global level of aneusomy by chromosomal arm, and of the number of breakpoints throughout the genome.

Results

Application of appropriate thresholds allowed us to distinguish three classes of tumors highly associated with metastatic relapse. This index used with the same thresholds on a published set of tumors confirms its prognostic significance with a hazard ratio of 3.24 [95CI: 1.76-5.96] p = 6.7x10^-5 for the bad prognostic group with respect to the intermediate group. The high prognostic value of this genomic index is related to its ability to individualize a specific group of breast cancers, mainly luminal type and axillary node negative, showing very high genetic instability and poor outcome. Indirect transcriptomic validation was obtained on independent data sets.

Conclusion

Accurate evaluation of genetic instability in breast cancers by a genomic instability index (G2I) helps individualizing specific tumors with previously unexpected very poor prognosis.

【 授权许可】

   
2012 Bonnet et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Natarajan L, Pu M, Parker BA, Thomson CA, Caan BJ, Flatt SW, Madlensky L, Hajek RA, Al-Delaimy WK, Saquib N, et al.: Time-varying effects of prognostic factors associated with disease-free survival in breast cancer. Am J Epidemiol 2009, 169:1463-1470.
• [2]Willis L, Alarcon T, Elia G, Jones JL, Wright NA, Tomlinson IP, Graham TA, Page KM: Breast cancer dormancy can be maintained by small numbers of micrometastases. Cancer Res 2010, 70:4310-4317.
• [3]Velasco-Velazquez MA, Popov VM, Lisanti MP, Pestell RG: The role of breast cancer stem cells in metastasis and therapeutic implications. Am J Pathol 2011, 179:2-11.
• [4]Early Breast Cancer Trailists’ Collaborative Group (EBCTCG): Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005, 365:1687-1717.
• [5]Carter CL, Allen C, Henson DE: Relation of tumor size, lymph node status, and survival in 24,740 breast cancer cases. Cancer 1989, 63:181-187.
• [6]Goldhirsch A, Glick JH, Gelber RD, Coates AS, Thurlimann B, Senn HJ: Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol 2005, 16:1569-1583.
• [7]Rakha EA, El-Sayed ME, Lee AH, Elston CW, Grainge MJ, Hodi Z, Blamey RW, Ellis IO: Prognostic significance of Nottingham Histologic grade in invasive breast carcinoma. J Clin Oncol 2008, 26:3153-3158.
• [8]Van Belle V, Van Calster B, Brouckaert O, Vanden Bempt I, Pintens S, Harvey V, Murray P, Naume B, Wiedswang G, Paridaens R, et al.: Qualitative assessment of the progesterone receptor and HER2 improves the Nottingham prognostic index up to 5 years after breast cancer diagnosis. J Clin Oncol 2010, 28:4129-4134.
• [9]Hu Z, Fan C, Oh DS, Marron JS, He X, Qaqish BF, Livasy C, Carey LA, Reynolds E, Dressler L, et al.: The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genomics 2006, 7:96.
• [10]Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, et al.: Molecular portraits of human breast tumours. Nature 2000, 406:747-752.
• [11]Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, Van de Rijn M, Jeffrey SS, et al.: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 2001, 98:10869-10874.
• [12]Desmedt C, Giobbie-Hurder A, Neven P, Paridaens R, Christiaens MR, Smeets A, Lallemand F, Haibe-Kains B, Viale G, Gelber RD, et al.: The Gene expression grade index: a potential predictor of relapse for endocrine-treated breast cancer patients in the BIG 1–98 trial. BMC Med Genomics 2009, 2:40.
• [13]Loi S, Haibe-Kains B, Desmedt C, Wirapati P, Lallemand F, Tutt AM, Gillet C, Ellis P, Ryder K, Reid JF, et al.: Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen. BMC Genomics 2008, 9:239.
• [14]Hynes RO: Metastatic potential: generic predisposition of the primary tumor or rare, metastatic variants-or both? Cell 2003, 113:821-823.
• [15]Nguyen DX, Massague J: Genetic determinants of cancer metastasis. Nat Rev Genet 2007, 8:341-352.
• [16]Wirapati P, Sotiriou C, Kunkel S, Farmer P, Pradervand S, Haibe-Kains B, Desmedt C, Ignatiadis M, Sengstag T, Schutz F, et al.: Meta-analysis of gene expression profiles in breast cancer: toward a unified understanding of breast cancer subtyping and prognosis signatures. Breast Cancer Res 2008, 10:R65.
• [17]Carter SL, Eklund AC, Kohane IS, Harris LN, Szallasi Z: A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat Genet 2006, 38:1043-1048.
• [18]Mettu RK, Wan YW, Habermann JK, Ried T, Guo NL: A 12-gene genomic instability signature predicts clinical outcomes in multiple cancer types. Int J Biol Markers 2010, 25:219-228.
• [19]La Rosa P, Viara E, Hupe P, Pierron G, Liva S, Neuvial P, Brito I, Lair S, Servant N, Robine N, et al.: VAMP: visualization and analysis of array-CGH, transcriptome and other molecular profiles. Bioinformatics 2006, 22:2066-2073.
• [20]Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, et al.: Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 2004, 10:5367-5374.
• [21]Gravier E, Pierron G, Vincent-Salomon A, Gruel N, Raynal V, Savignoni A, De Rycke Y, Pierga JY, Lucchesi C, Reyal F, et al.: A prognostic DNA signature for T1T2 node-negative breast cancer patients. Genes Chromosomes Cancer 2010, 49:1125-1134.
• [22]Van’t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, et al.: Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002, 415:530-536.
• [23]Sotiriou C, Wirapati P, Loi S, Harris A, Fox S, Smeds J, Nordgren H, Farmer P, Praz V, Haibe-Kains B, et al.: Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. J Natl Cancer Inst 2006, 98:262-272.
• [24]Fan C, Oh DS, Wessels L, Weigelt B, Nuyten DS, Nobel AB, van’t Veer LJ, Perou CM: Concordance among gene-expression-based predictors for breast cancer. N Engl J Med 2006, 355:560-569.
• [25]Wang Y, Klijn JG, Zhang Y, Sieuwerts AM, Look MP, Yang F, Talantov D, Timmermans M, Meijer-van Gelder ME, Yu J, et al.: Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 2005, 365:671-679.
• [26]Loi S, Haibe-Kains B, Desmedt C, Lallemand F, Tutt AM, Gillet C, Ellis P, Harris A, Bergh J, Foekens JA, et al.: Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade. J Clin Oncol 2007, 25:1239-1246.
• [27]Hicks J, Krasnitz A, Lakshmi B, Navin NE, Riggs M, Leibu E, Esposito D, Alexander J, Troge J, Grubor V, et al.: Novel patterns of genome rearrangement and their association with survival in breast cancer. Genome Res 2006, 16:1465-1479.
• [28]Chin K, DeVries S, Fridlyand J, Spellman PT, Roydasgupta R, Kuo WL, Lapuk A, Neve RM, Qian Z, Ryder T, et al.: Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell 2006, 10:529-541.
• [29]Fridlyand J, Snijders AM, Ylstra B, Li H, Olshen A, Segraves R, Dairkee S, Tokuyasu T, Ljung BM, Jain AN, et al.: Breast tumor copy number aberration phenotypes and genomic instability. BMC Cancer 2006, 6:96.
• [30]Natrajan R, Lambros MB, Rodriguez-Pinilla SM, Moreno-Bueno G, Tan DS, Marchio C, Vatcheva R, Rayter S, Mahler-Araujo B, Fulford LG, et al.: Tiling path genomic profiling of grade 3 invasive ductal breast cancers. Clin Cancer Res 2009, 15:2711-2722.
• [31]Bergamaschi A, Kim YH, Wang P, Sorlie T, Hernandez-Boussard T, Lonning PE, Tibshirani R, Borresen-Dale AL, Pollack JR: Distinct patterns of DNA copy number alteration are associated with different clinicopathological features and gene-expression subtypes of breast cancer. Genes Chromosomes Cancer 2006, 45:1033-1040.
• [32]Jonsson G, Staaf J, Vallon-Christersson J, Ringner M, Holm K, Hegardt C, Gunnarsson H, Fagerholm R, Strand C, Agnarsson BA, et al.: Genomic subtypes of breast cancer identified by array-comparative genomic hybridization display distinct molecular and clinical characteristics. Breast Cancer Res 2010, 12:R42.
• [33]Chin SF, Teschendorff AE, Marioni JC, Wang Y, Barbosa-Morais NL, Thorne NP, Costa JL, Pinder SE, van de Wiel MA, Green AR, et al.: High-resolution aCGH and expression profiling identifies a novel genomic subtype of ER negative breast cancer. Genome Biol 2007, 8:R215.
• [34]Cervantes M, Glassman AB: Breast cancer cytogenetics: a review and proposal for clinical application. Ann Clin Lab Sci 1996, 26:208-214.
• [35]Bernardino J, Gerbault-Seureau M, Zafrani B, Dericke Y, Boudou E, Magdelenat H, Dutrillaux B: Homogeneously staining regions in 223 breast carcinomas: cytogenetic and clinicopathological correlations. Br J Cancer 1998, 78:1214-1218.
• [36]Courjal F, Cuny M, Simony-Lafontaine J, Louason G, Speiser P, Zeillinger R, Rodriguez C, Theillet C: Mapping of DNA amplifications at 15 chromosomal localizations in 1875 breast tumors: definition of phenotypic groups. Cancer Res 1997, 57:4360-4367.
• [37]Al-Kuraya K, Schraml P, Torhorst J, Tapia C, Zaharieva B, Novotny H, Spichtin H, Maurer R, Mirlacher M, Kochli O, et al.: Prognostic relevance of gene amplifications and coamplifications in breast cancer. Cancer Res 2004, 64:8534-8540.
• [38]Andre F, Job B, Dessen P, Tordai A, Michiels S, Liedtke C, Richon C, Yan K, Wang B, Vassal G, et al.: Molecular characterization of breast cancer with high-resolution oligonucleotide comparative genomic hybridization array. Clin Cancer Res 2009, 15:441-451.
• [39]Roylance R, Gorman P, Papior T, Wan YL, Ives M, Watson JE, Collins C, Wortham N, Langford C, Fiegler H, et al.: A comprehensive study of chromosome 16q in invasive ductal and lobular breast carcinoma using array CGH. Oncogene 2006, 25:6544-6553.
• [40]Dellas A, Torhorst J, Schultheiss E, Mihatsch MJ, Moch H: DNA sequence losses on chromosomes 11p and 18q are associated with clinical outcome in lymph node-negative ductal breast cancer. Clin Cancer Res 2002, 8:1210-1216.
• [41]Zhang Y, Martens JW, Yu JX, Jiang J, Sieuwerts AM, Smid M, Klijn JG, Wang Y, Foekens JA: Copy number alterations that predict metastatic capability of human breast cancer. Cancer Res 2009, 69:3795-3801.
• [42]Staaf J, Ringner M, Vallon-Christersson J, Jonsson G, Bendahl PO, Holm K, Arason A, Gunnarsson H, Hegardt C, Agnarsson BA, et al.: Identification of subtypes in human epidermal growth factor receptor 2–positive breast cancer reveals a gene signature prognostic of outcome. J Clin Oncol 2010, 28:1813-1820.
• [43]Russnes HG, Vollan HK, Lingjaerde OC, Krasnitz A, Lundin P, Naume B, Sorlie T, Borgen E, Rye IH, Langerod A, Russnes HG, Vollan HK, Lingjaerde OC, Krasnitz A, Lundin P, Naume B, Sorlie T, Borgen E, Rye IH, Langerod A, et al.: Genomic architecture characterizes tumor progression paths and fate in breast cancer patients. Sci Transl Med 2010, 2:38ra47.
• [44]Reyal F, van Vliet MH, Armstrong NJ, Horlings HM, de Visser KE, Kok M, Teschendorff AE, Mook S, Van’t Veer L, Caldas C, et al.: A comprehensive analysis of prognostic signatures reveals the high predictive capacity of the proliferation, immune response and RNA splicing modules in breast cancer. Breast Cancer Res 2008, 10:R93.