MICROARRAY ANALYSIS OF DNA COPY NUMBER ABERRATION IN BREAST TUMOR: CORRELATION WITH THE EFFICACY OF NEOADJUVANT CHEMOTHERAPY
Abstract
This study presents the new evidences for DNA Copy Number Aberration (CNA) within breast tumors and its association with the efficacy of preoperative (neoadjuvant) chemotherapy.
Methods. 68 breast cancer patients were treated with 2–4 courses of neoadjuvant chemotherapy. Unbalanced chromosome abnormalities – numeric and structural CNA in biopsy specimens were tested using high-density microarray platform CytoScanTM HD Array (Affymetrix, USA). Immediate tumor response to NAC was measured in accordance with recommendations of WHO.
Results. 1q43 amplification correlated with good response to NAC. Partial tumor regression was observed in 83 % (33/39) of patients with 1q43 amplification, whereas no response to NAC was found in 78 % (18/23) of patients with normal 1q43 region (р=0.00085 Fisher test, Bonferroni correction). Among patients with chromosomal deletions at 11q22.1-23.3, 83 % (25/30) manifested the response to NAC, whereas 68 % (23/34) deletion-free persons did not respond to therapy. Combination of amplification and deletion markers increased the sensitivity and specificity for predicting response to NАС. Amplification in 1q43 along with deletion in 18р11.21 loci resulted in partial tumor regression in 92 % (35/38) of patients. In the case of the normal status of these loci, 81 % (21/26) of patients had no response to NAC (р=0.000002).
Conclusion. The presence of unbalanced, chromosome abnormalities in 1q, 11q и 18p loci within breast tumors before treatment correlates with good response to NAC and can be used as a marker for predicting response to neoadjuvant chemotherapy with high confidence interval.
About the Authors
N. V. LitviakovRussian Federation
5, Kooperativnyi Street, 634050-Tomsk
М. М. Tsyganov
Russian Federation
5, Kooperativnyi Street, 634050-Tomsk
N. V. Cherdyntseva
Russian Federation
5, Kooperativnyi Street, 634050-Tomsk
Е. М. Slonimskaya
Russian Federation
5, Kooperativnyi Street, 634050-Tomsk
P. V. Ivankovskaya
Russian Federation
5, Kooperativnyi Street, 634050-Tomsk
М. К. Ibragimova
Russian Federation
5, Kooperativnyi Street, 634050-Tomsk
Е. Yu. Garbukov
Russian Federation
5, Kooperativnyi Street, 634050-Tomsk
S. А. Korostelev
Russian Federation
5, Kooperativnyi Street, 634050-Tomsk
О. Yu. Potapova
United States
5, Kooperativnyi Street, 634050-Tomsk
Е. L. Choinzonov
Russian Federation
5, Kooperativnyi Street, 634050-Tomsk
References
1. Gerashhenko T.S., Denisov E.V., Litvjakov N.V., Zav’jalova M.V., Vtorushin S.V., Cyganov M.M., Perel’muter V.M., Cherdynceva N.V. Intratumoral Heterogeneity: Nature and Biological Significance (review) // Biohimija. 2013. Vol. 78 (11). P. 1531–1549. [in Russian]
2. Gervas P.A., Litvjakov N.V., Staheeva M.N., Miller S.V., Dobrodeev A.Ju., Garbukov E.Ju., Babyshkina N.N., Kuharev Ja.V., Vasil’eva M.V., Slonimskaja E.M., Beljavskaja V.A., Tuzikov S.A., Cherdynceva N.V. Influence of apoptosis and repair gene polymorphism on neoadjuvant chemotherapy response of malignant tumors // Sibirskij onkologicheskij zhurnal. 2009. № 4 (34). P. 41–47. [in Russian]
3. Cherdynceva N.V., Litvjakov N.V., Denisov E.V. Major advances in basic oncology in 2012 // Prakticheskaja onkologija. 2013. Vol. 14 (1). P. 1–12. [in Russian]
4. Bergamaschi A., Kim Y.H., Wang P., Sørlie T., Hernandez-Boussard T., Lonning P.E., Tibshirani R., Børresen-Dale A.L., Pollack J.R. Distinct patterns of DNA copy number alteration are associated with different clinicopathological features and gene-expression subtypes of breast cancer.// Genes Chromosomes and Cancer. 2006. Vol. 45 (11). P.1033–1040.
5. Bhatia S., Frangioni J.V., Hoffman R.M. The challenges posed by cancer heterogeneity // Nat. Biotechnol. 2012. Vol. 30. P. 604–610. doi: 10.1038/nbt.2294.
6. Byrski T., Gronwald J., Huzarski T., Grzybowska E., Budryk M., Stawicka M., Mierzwa T., Szwiec M., Wiśniowski R., Siolek M. Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy // J. Clin. Oncol. 2010. Vol. 28 (3). P. 375–379. doi: 10.1200/JCO.2008.20.7019.
7. Cai H., Kumar N., Baudis M. Arraymap: A reference resource for genomic copy number imbalances in human malignancies // PLoS ONE. 2012. Vol. 7 (5). E. 36944. doi: 10.1371/journal.pone.0036944.
8. Chin S.F., Teschendorff A.E., Marioni J.C., Wang Y., Barbosa-Morais N.L., Thorne N.P., Costa J.L., Pinder S.E., van De Wiel M.A., Green A.R. Highresolution aCGH and expression profiling identifies a novel genomic subtype of ER negative breast cancer // Genome Biol. 2007. Vol. 8 (10). R. 215.
9. Climent J., Dimitrow P., Fridlyand J., Palacios J., Siebert R., Albertson D.G., Gray J.W., Pinkel D., Lluch A., Martinez-Climent J.A. Deletion of chromosome 11q predicts response to anthracycline-based chemotherapy in early breast cancer // Cancer Res. 2007. Vol. 67 (2). P. 818–826.
10. Goldhirsch A., Winer E., Coates A., Gelber R., Piccart-Gebhart M., Thürlimann B., Senn H.-J., Albain K.S., André F., Bergh J. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013 // Ann. Oncol. 2013. Vol. 24 (9). P. 2206–2223. doi: 10.1093/ annonc/mdt303.
11. Han S., Park K., Shin E., Kim H.-J., Kim J.Y., Kim J.Y., Gwak G. Genomic change of chromosome 8 predicts the response to taxane-based neoadjuvant chemotherapy in node-positive breast cancer // Oncol. Reports. 2010. Vol. 24 (1). P. 121–128.
12. Hanahan D., Weinberg R.A. Hallmarks of cancer: the next generation // Cell. 2011. Vol. 144 (5). P. 646–674. doi: 10.1016/j.cell.2011.02.013.
13. Horlings H.M., Lai C., Nuyten D.S., Halfwerk H., Kristel P., van Beers E., Joosse S.A., Klijn C., Nederlof P.M., Reinders M.J. Integration of DNA copy number alterations and prognostic gene expression signatures in breast cancer patients // Clin. Cancer Res. 2010. Vol. 16 (2). P. 651–663. doi: 10.1158/1078-0432.CCR-09-0709.
14. Huang N., Shah P.K., Li C. Lessons from a decade of integrating cancer copy number alterations with gene expression profiles // Brief. Bioinform. 2012. Vol. 13 (3). P. 305–316. doi: 10.1093/bib/bbr056.
15. Jönsson G., Staaf J., Vallon-Christersson J., Ringnér M., Holm K., Hegardt C., Gunnarsson H., Fagerholm R., Strand C., Agnarsson B.A. Research article Genomic subtypes of breast cancer identified by array-comparative genomic hybridization display distinct molecular and clinical characteristics // Breast Cancer Res. 2010. Vol. 12 (3). R. 42. doi: 10.1186/bcr2596.
16. Kaufmann M., von Minckwitz G., Mamounas E.P., Cameron D., Carey L.A., Cristofanilli M., Denkert C., Eiermann W., Gnant M., Harris J.R. Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer // Ann. Surg. Oncol. 2012. Vol. 19. P. 1508–1516. doi: 10.1245/ s10434-011-2108-2.
17. McClelland S.E., Burrell R.A., Swanton C. Chromosomal instability: a composite phenotype that influences sensitivity to chemotherapy // Cell Cycle. 2009. Vol. 8 (20). P. 3262–3266.
18. Schwartz G.F., Hortobagyi G.N. Proceedings of the Consensus Conference on Neoadjuvant Chemotherapy in Carcinoma of the Breast, April 26–28, 2003, Philadelphia, Pennsylvania // Breast J. 2004. Vol. 10 (4). P. 273–294.
19. Weigman V.J., Chao H.-H., Shabalin A.A., He X., Parker J.S., Nordgard S.H., Grushko T., Huo D., Nwachukwu C., Nobel A. Basal-like Breast cancer DNA copy number losses identify genes involved in genomic instability, response to therapy, and patient survival // Breast Cancer Res. Treat. 2012. Vol. 133 (3). P. 865–880. doi: 10.1007/s10549-011-1846-y.
20. Wikman H., Sielaff-Frimpong B., Kropidlowski J., Witzel I., MildeLangosch K., Sauter G., Westphal M., Lamszus K., Pantel K. Clinical Relevance of Loss of 11p15 in Primary and Metastatic Breast Cancer: Association with Loss of PRKCDBP Expression in Brain Metastases // PLoS ONE. 2012. Vol. 7 (10). E. 47537. doi: 10.1371/journal.pone.0047537.
21. Xu Y., DuanMu H., Chang Z., Zhang S., Li Z., Li Z., Liu Y., Li K., Qiu F., Li X. The application of gene co-expression network reconstruction based on CNVs and gene expression microarray data in breast cancer // Mol. Biol. Reports. 2012. Vol. 39 (2). P. 1627–1637. doi: 10.1007/s11033- 011-0902-3.
22. Zhang Y., Martens J.W., Jack X.Y., Jiang J., Sieuwerts A.M., Smid M., Klijn J.G., Wang Y., Foekens J.A. Copy number alterations that predict metastatic capability of human breast cancer // Cancer Res. 2009. Vol. 69 (9). P. 3795–3801. doi: 10.1158/0008-5472.CAN-08-4596.
Review
For citations:
Litviakov N.V., Tsyganov М.М., Cherdyntseva N.V., Slonimskaya Е.М., Ivankovskaya P.V., Ibragimova М.К., Garbukov Е.Yu., Korostelev S.А., Potapova О.Yu., Choinzonov Е.L. MICROARRAY ANALYSIS OF DNA COPY NUMBER ABERRATION IN BREAST TUMOR: CORRELATION WITH THE EFFICACY OF NEOADJUVANT CHEMOTHERAPY. Siberian journal of oncology. 2014;(3):19-27. (In Russ.)