Journal of the National Cancer Institute Advance Access published online on December 25, 2007
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djm266
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© The Author 2007. Published by Oxford University Press.
ARTICLES |
High-Resolution Mapping of DNA Breakpoints to Define True Recurrences Among Ipsilateral Breast Cancers
Affiliations of authors: Département d’oncologie radiothérapie (MAB, AF), Service de Bio-informatique (NS, PN, GR, PH, EB), Département de Transfert (CD, JPM, JPT), Département de Biologie des tumeurs (IL, BSZ), Service de Biostatistiques (YDR, AS), and Centre National de la Recherche Scientifique, Unité Mixtes de Recherche 144 (CD, PH), Institut Curie, Paris, France; Institute of Molecular and Cell Biology Biopolis A*STAR, Singapore (JPT)
Correspondence to: Marc A. Bollet, MD, Département d’oncologie radiothérapie, Institut Curie, 26, rue d’Ulm, 75248 Paris cedex 05, France (e-mail: marc.bollet{at}curie.net).
Background: To distinguish new primary breast cancers from true recurrences, pangenomic analyses of DNA copy number alterations (CNAs) using single-nucleotide polymorphism arrays have proven useful.
Methods: The pangenomic profiles of 22 pairs of primary breast carcinoma (ductal or lobular) and ipsilateral breast cancers from the same patients were analyzed. Hierarchical clustering was performed using CNAs and DNA breakpoint information. A partial identity score developed using DNA breakpoint information was used to quantify partial identities between two tumors. The nature of ipsilateral breast cancers (true recurrence vs new primary tumor) as defined using the clustering methods and the partial identity score was compared with that based on clinical characteristics. Metastasis-free survival was compared among patients with primary tumors and true recurrences as defined using the partial identity score and by clinical characteristics. All statistical tests were two-sided.
Results: All methods agreed on the nature of ipsilateral breast cancers for 14 pairs of samples. For five pairs, the clinical definition disagreed with both clustering methods. For three pairs, the two clustering methods were discordant and the one using DNA breakpoints agreed with the clinical definition. The partial identity score confirmed the nature of ipsilateral breast cancers as defined by clustering of DNA breakpoints in 21 of 22 pairs. The difference in metastasis-free survival of patients with new primary tumors and those with true recurrences was not statistically significant when tumors were defined based on clinical and histologic characteristics (5-year metastasis-free survival: 76%, 95% confidence interval [CI] = 52% to 100% for new primary tumors and 38%, 95% CI = 17% to 83% for true recurrences; P = .18; new primary tumor vs true recurrence, hazard ratio = 2.8, 95% CI = 0.6 to 13.7), but the difference was statistically significant when tumors were defined using the partial identity score (5-year metastasis-free survival: 100% for new primary tumors and 29%, 95% CI = 11% to 78% for true recurrences; P = .01).
Conclusions: DNA breakpoint information more often agreed with the clinical determination than CNAs in this population. The partial identity score, which was calculated based on DNA breakpoints, allows statistical discrimination between new primary tumors and true recurrences that could outperform the clinical determination in terms of prognosis.
| CONTEXT AND CAVEATS Prior knowledge Detecting changes in DNA copy number using single nucleotide polymorphism arrays has been a useful tool in distinguishing new primary breast tumors from recurrences. Study design Comparison of hierarchical clustering of DNA copy number and DNA breakpoints, an identity score based on the DNA breakpoint information, and clinical characteristics to accurately designate ipsilateral breast tumors as new primary tumors or true recurrences in breast tumor pairs from 22 patients. Contributions For 14 of the pairs, all methods agreed on the designation of the ipsilateral breast cancer as a new primary tumor or a true recurrence; however, for five pairs and three pairs, both clustering methods and clustering by DNA breakpoints, respectively, agreed with the clinical definition. For 21 pairs, the partial identity score confirmed the designation of the tumor as defined by both clustering methods. Patients with recurrences had poorer metastasis-free survival than patients with new primary tumors, according to the partial identity score, but this difference was not statistically significant using the clinical definition. Implications The partial identity score may outperform clinical determination for the prognosis of ipsilateral breast cancers. Limitations Freshly frozen tissue samples that contain a large number of cells from both the initial primary tumor and the ipsilateral tumor are needed to perform the DNA breakpoint analyses.
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M. A. Bollet and N. Servant contributed equally to this work. The authors thank the members of the departments of Tumor Biology (Martial Caly, Blandine Massemin, Michèle Galut), Biostatistics (Eléonore Gravier, Chantal Gautier), Translational Research (David Gentien, Cécile Reyes, Audrey Rapinat, Benoît Albaud, Vincent Lepetit), and Bioinformatics (Philippe La Rosa, Séverine Lair) who participated in this study. The authors are also indebted to Anne Vincent-Salomon, Patricia de Crémoux, Dominique Stoppa-Lyonnet, and particularly Olivier Delattre for their very valuable comments on this work. Finally, they thank all the members of the Institut Curie Breast Cancer Group.
The sponsors had no role in the study design, data collection, interpretation of the results, preparation of the manuscript, or the decision to submit the manuscript for publication.
Manuscript received June 4, 2007; revised October 16, 2007; accepted November 13, 2007.
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