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Open Access 01-12-2016 | Research article

Different Array CGH profiles within hereditary breast cancer tumors associated to BRCA1 expression and overall survival

Authors: Carolina Alvarez, Andrés Aravena, Teresa Tapia, Ester Rozenblum, Luisa Solís, Alejandro Corvalán, Mauricio Camus, Manuel Alvarez, David Munroe, Alejandro Maass, Pilar Carvallo

Published in: BMC Cancer | Issue 1/2016

Abstract

Background

Array CGH analysis of breast tumors has contributed to the identification of different genomic profiles in these tumors. Loss of DNA repair by BRCA1 functional deficiency in breast cancer has been proposed as a relevant contribution to breast cancer progression for tumors with no germline mutation. Identifying the genomic alterations taking place in BRCA1 not expressing tumors will lead us to a better understanding of the cellular functions affected in this heterogeneous disease. Moreover, specific genomic alterations may contribute to the identification of potential therapeutic targets and offer a more personalized treatment to breast cancer patients.

Methods

Forty seven tumors from hereditary breast cancer cases, previously analyzed for BRCA1 expression, and screened for germline BRCA1 and 2 mutations, were analyzed by Array based Comparative Genomic Hybridization (aCGH) using Agilent 4x44K arrays. Overall survival was established for tumors in different clusters using Log-rank (Mantel-Cox) Test. Gene lists obtained from aCGH analysis were analyzed for Gene Ontology enrichment using GOrilla and DAVID tools.

Results

Genomic profiling of the tumors showed specific alterations associated to BRCA1 or 2 mutation status, and BRCA1 expression in the tumors, affecting relevant cellular processes. Similar cellular functions were found affected in BRCA1 not expressing and BRCA1 or 2 mutated tumors. Hierarchical clustering classified hereditary breast tumors in four major, groups according to the type and amount of genomic alterations, showing one group with a significantly poor overall survival (p = 0.0221). Within this cluster, deletion of PLEKHO1, GDF11, DARC, DAG1 and CD63 may be associated to the worse outcome of the patients.

Conclusions

These results support the fact that BRCA1 lack of expression in tumors should be used as a marker for BRCAness and to select these patients for synthetic lethality approaches such as treatment with PARP inhibitors. In addition, the identification of specific alterations in breast tumors associated with poor survival, immune response or with a BRCAness phenotype will allow the use of a more personalized treatment in these patients.

Teschendorff AE, Caldas C. The breast cancer somatic ‘muta-ome’: tackling the complexity. Breast Cancer Res. 2009;11(2):301. doi:10.1186/bcr2236.CrossRefPubMedPubMedCentral

Esteller M. CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene. 2002;21(35):5427–40. doi:10.1038/sj.onc.1205600.CrossRefPubMed

Lerebours F, Lidereau R. Molecular alterations in sporadic breast cancer. Crit Rev Oncol Hematol. 2002;44(2):121–41.CrossRefPubMed

Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz Jr LA, Kinzler KW. Cancer genome landscapes. Science. 2013;339(6127):1546–58. doi:10.1126/science.1235122.CrossRefPubMedPubMedCentral

Davies JJ, Wilson IM, Lam WL. Array CGH technologies and their applications to cancer genomes. Chromosome Res. 2005;13(3):237–48. doi:10.1007/s10577-005-2168-x.CrossRefPubMed

Pinkel D, Albertson DG. Array comparative genomic hybridization and its applications in cancer. Nat Genet. 2005;37(Suppl):S11–7. doi:10.1038/ng1569.CrossRefPubMed

Gronwald J, Jauch A, Cybulski C, Schoell B, Bohm-Steuer B, Lener M, et al. Comparison of genomic abnormalities between BRCAX and sporadic breast cancers studied by comparative genomic hybridization. Int J Cancer. 2005;114(2):230–6. doi:10.1002/ijc.20723.CrossRefPubMed

Jonsson G, Naylor TL, Vallon-Christersson J, Staaf J, Huang J, Ward MR, et al. Distinct genomic profiles in hereditary breast tumors identified by array-based comparative genomic hybridization. Cancer Res. 2005;65(17):7612–21.PubMed

Naylor TL, Greshock J, Wang Y, Colligon T, Yu QC, Clemmer V, et al. High resolution genomic analysis of sporadic breast cancer using array-based comparative genomic hybridization. Breast Cancer Res. 2005;7(6):R1186–98. doi:10.1186/bcr1356.CrossRefPubMedPubMedCentral

10.

Nessling M, Richter K, Schwaenen C, Roerig P, Wrobel G, Wessendorf S, et al. Candidate genes in breast cancer revealed by microarray-based comparative genomic hybridization of archived tissue. Cancer Res. 2005;65(2):439–47.PubMed

11.

Fridlyand J, Snijders AM, Ylstra B, Li H, Olshen A, Segraves R, et al. Breast tumor copy number aberration phenotypes and genomic instability. BMC Cancer. 2006;6:96. doi:10.1186/1471-2407-6-96.CrossRefPubMedPubMedCentral

12.

van Beers EH, van Welsem T, Wessels LF, Li Y, Oldenburg RA, Devilee P, et al. Comparative genomic hybridization profiles in human BRCA1 and BRCA2 breast tumors highlight differential sets of genomic aberrations. Cancer Res. 2005;65(3):822–7.PubMed

13.

Stefansson OA, Jonasson JG, Johannsson OT, Olafsdottir K, Steinarsdottir M, Valgeirsdottir S, et al. Genomic profiling of breast tumours in relation to BRCA abnormalities and phenotypes. Breast Cancer Res. 2009;11(4):R47. doi:10.1186/bcr2334.CrossRefPubMedPubMedCentral

14.

Alvarez S, Diaz-Uriarte R, Osorio A, Barroso A, Melchor L, Paz MF, et al. A predictor based on the somatic genomic changes of the BRCA1/BRCA2 breast cancer tumors identifies the non-BRCA1/BRCA2 tumors with BRCA1 promoter hypermethylation. Clin Cancer Res. 2005;11(3):1146–53.PubMed

15.

Melchor L, Honrado E, Garcia MJ, Alvarez S, Palacios J, Osorio A, et al. Distinct genomic aberration patterns are found in familial breast cancer associated with different immunohistochemical subtypes. Oncogene. 2008;27(22):3165–75. doi:10.1038/sj.onc.1210975.CrossRefPubMed

16.

Birgisdottir V, Stefansson OA, Bodvarsdottir SK, Hilmarsdottir H, Jonasson JG, Eyfjord JE. Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer. Breast Cancer Res. 2006;8(4):R38. doi:10.1186/bcr1522.CrossRefPubMedPubMedCentral

17.

Tapia T, Smalley SV, Kohen P, Munoz A, Solis LM, Corvalan A, et al. Promoter hypermethylation of BRCA1 correlates with absence of expression in hereditary breast cancer tumors. Epigenetics. 2008;3(3):157–63.CrossRefPubMed

18.

Tan X, Peng J, Fu Y, An S, Rezaei K, Tabbara S, et al. miR-638 mediated regulation of BRCA1 affects DNA repair and sensitivity to UV and cisplatin in triple-negative breast cancer. Breast Cancer Res. 2014;16(5):435. doi:10.1186/s13058-014-0435-5.CrossRefPubMedPubMedCentral

19.

Garcia AI, Buisson M, Bertrand P, Rimokh R, Rouleau E, Lopez BS, et al. Down-regulation of BRCA1 expression by miR-146a and miR-146b-5p in triple negative sporadic breast cancers. EMBO Mol Med. 2011;3(5):279–90. doi:10.1002/emmm.201100136.CrossRefPubMedPubMedCentral

20.

Moskwa P, Buffa FM, Pan Y, Panchakshari R, Gottipati P, Muschel RJ, et al. miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors. Mol Cell. 2011;41(2):210–20. doi:10.1016/j.molcel.2010.12.005.CrossRefPubMedPubMedCentral

21.

Lips EH, Mulder L, Oonk A, van der Kolk LE, Hogervorst FBL, Imholz ALT, et al. Triple-negative breast cancer: BRCAness and concordance of clinical features with BRCA1-mutation carriers. Br J Cancer. 2013;108(10):2172–7. doi:10.1038/bjc.2013.144.CrossRefPubMedPubMedCentral

22.

Joosse SA, Brandwijk KI, Mulder L, Wesseling J, Hannemann J, Nederlof PM. Genomic signature of BRCA1 deficiency in sporadic basal-like breast tumors. Genes Chromosomes Cancer. 2011;50(2):71–81. doi:10.1002/gcc.20833.CrossRefPubMed

23.

Gallardo M, Silva A, Rubio L, Alvarez C, Torrealba C, Salinas M, et al. Incidence of BRCA1 and BRCA2 mutations in 54 Chilean families with breast/ovarian cancer, genotype-phenotype correlations. Breast Cancer Res Treat. 2006;95(1):81–7. doi:10.1007/s10549-005-9047-1.CrossRefPubMed

24.

Eden E, Navon R, Steinfeld I, Lipson D, Yakhini Z. GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics. 2009;10:48. doi:10.1186/1471-2105-10-48.CrossRefPubMedPubMedCentral

25.

Da Huang W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4(1):44–57.CrossRef

26.

Tokuda E, Fujita N, Oh-hara T, Sato S, Kurata A, Katayama R, et al. Casein kinase 2-interacting protein-1, a novel Akt pleckstrin homology domain-interacting protein, down-regulates PI3K/Akt signaling and suppresses tumor growth in vivo. Cancer Res. 2007;67(20):9666–76. doi:10.1158/0008-5472.can-07-1050.CrossRefPubMed

27.

Peltonen HM, Haapasalo A, Hiltunen M, Kataja V, Kosma VM, Mannermaa A. Gamma-secretase components as predictors of breast cancer outcome. PLoS One. 2013;8(11):e79249. doi:10.1371/journal.pone.0079249.CrossRefPubMedPubMedCentral

28.

Zheng F, Hasim A, Anwer J, Niyaz M, Sheyhidin I. LMP gene promoter hypermethylation is a mechanism for its down regulation in Kazak’s esophageal squamous cell carcinomas. Mol Biol Rep. 2013;40(3):2069–75. doi:10.1007/s11033-012-2138-2.CrossRefPubMed

29.

Callahan MJ, Nagymanyoki Z, Bonome T, Johnson ME, Litkouhi B, Sullivan EH, et al. Increased HLA-DMB expression in the tumor epithelium is associated with increased CTL infiltration and improved prognosis in advanced-stage serous ovarian cancer. Clin Cancer Res. 2008;14(23):7667–73. doi:10.1158/1078-0432.ccr-08-0479.CrossRefPubMedPubMedCentral

30.

Wong TS, Rajagopalan S, Townsley FM, Freund SM, Petrovich M, Loakes D, et al. Physical and functional interactions between human mitochondrial single-stranded DNA-binding protein and tumour suppressor p53. Nucleic Acids Res. 2009;37(2):568–81. doi:10.1093/nar/gkn974.CrossRefPubMedPubMedCentral

31.

Wikman H, Westphal L, Schmid F, Pollari S, Kropidlowski J, Sielaff-Frimpong B, et al. Loss of CADM1 expression is associated with poor prognosis and brain metastasis in breast cancer patients. Oncotarget. 2014;5(10):3076–87.CrossRefPubMedPubMedCentral

32.

Roubin R, Acquaviva C, Chevrier V, Sedjai F, Zyss D, Birnbaum D, et al. Myomegalin is necessary for the formation of centrosomal and Golgi-derived microtubules. Biol Open. 2013;2(2):238–50. doi:10.1242/bio.20123392.CrossRefPubMedPubMedCentral

33.

Shimada H, Kuboshima M, Shiratori T, Nabeya Y, Takeuchi A, Takagi H, et al. Serum anti-myomegalin antibodies in patients with esophageal squamous cell carcinoma. Int J Oncol. 2007;30(1):97–103.PubMed

34.

Hsing CH, Cheng HC, Hsu YH, Chan CH, Yeh CH, Li CF, et al. Upregulated IL-19 in breast cancer promotes tumor progression and affects clinical outcome. Clin Cancer Res. 2012;18(3):713–25. doi:10.1158/1078-0432.ccr-11-1532.CrossRefPubMed

35.

Hsu YH, Wei CC, Shieh DB, Chan CH, Chang MS. Anti-IL-20 monoclonal antibody alleviates inflammation in oral cancer and suppresses tumor growth. Mol Cancer Res. 2012;10(11):1430–9. doi:10.1158/1541-7786.mcr-12-0276.CrossRefPubMed

36.

Chen YY, Li CF, Yeh CH, Chang MS, Hsing CH. Interleukin-19 in breast cancer. Clin Dev Immunol. 2013;2013:294320. doi:10.1155/2013/294320.PubMedPubMedCentral

37.

Hancer VS, Diz-Kucukkaya R, Aktan M. Overexpression of Fc mu receptor (FCMR, TOSO) gene in chronic lymphocytic leukemia patients. Med Oncol. 2012;29(2):1068–72. doi:10.1007/s12032-011-9821-3.CrossRefPubMed

38.

Mosca E, Alfieri R, Merelli I, Viti F, Calabria A, Milanesi L. A multilevel data integration resource for breast cancer study. BMC Syst Biol. 2010;4:76. doi:10.1186/1752-0509-4-76.CrossRefPubMedPubMedCentral

39.

Ponten F, Jirstrom K, Uhlen M. The human protein atlas--a tool for pathology. J Pathol. 2008;216(4):387–93. doi:10.1002/path.2440.CrossRefPubMed

40.

MacDonald G, Stramwasser M, Mueller CR. Characterization of a negative transcriptional element in the BRCA1 promoter. Breast Cancer Res. 2007;9(4):R49. doi:10.1186/bcr1753.CrossRefPubMedPubMedCentral

41.

Tang H, Liu P, Yang L, Xie X, Ye F, Wu M, et al. miR-185 suppresses tumor proliferation by directly targeting E2F6 and DNMT1 and indirectly upregulating BRCA1 in triple-negative breast cancer. Mol Cancer Ther. 2014;13(12):3185–97. doi:10.1158/1535-7163.mct-14-0243.CrossRefPubMed

42.

Chen Y, Chen CF, Chiang HC, Pena M, Polci R, Wei RL, et al. Mutation of NIMA-related kinase 1 (NEK1) leads to chromosome instability. Mol Cancer. 2011;10(1):5. doi:10.1186/1476-4598-10-5.CrossRefPubMedPubMedCentral

43.

Xu Z, Kukekov NV, Greene LA. POSH acts as a scaffold for a multiprotein complex that mediates JNK activation in apoptosis. EMBO J. 2003;22(2):252–61. doi:10.1093/emboj/cdg021.CrossRefPubMedPubMedCentral

44.

Kim J, Kim MA, Jee CD, Jung EJ, Kim WH. Reduced expression and homozygous deletion of annexin A10 in gastric carcinoma. Int J Cancer. 2009;125(8):1842–50. doi:10.1002/ijc.24541.CrossRefPubMed

45.

Chang PH, Hwang-Verslues WW, Chang YC, Chen CC, Hsiao M, Jeng YM, et al. Activation of Robo1 signaling of breast cancer cells by Slit2 from stromal fibroblast restrains tumorigenesis via blocking PI3K/Akt/beta-catenin pathway. Cancer Res. 2012;72(18):4652–61. doi:10.1158/0008-5472.can-12-0877.CrossRefPubMedPubMedCentral

46.

Alvarez C, Tapia T, Cornejo V, Fernandez W, Munoz A, Camus M, et al. Silencing of tumor suppressor genes RASSF1A, SLIT2, and WIF1 by promoter hypermethylation in hereditary breast cancer. Mol Carcinog. 2013;52(6):475–87. doi:10.1002/mc.21881.CrossRefPubMed

47.

Kratochvilova K, Horak P, Esner M, Soucek K, Pils D, Anees M, et al. Tumor suppressor candidate 3 (TUSC3) prevents the epithelial-to-mesenchymal transition and inhibits tumor growth by modulating the endoplasmic reticulum stress response in ovarian cancer cells. Int J Cancer. 2015;137(6):1330–40. doi:10.1002/ijc.29502.CrossRefPubMed

48.

Wang C, Wang J, Liu H, Fu Z. Tumor suppressor DLC-1 induces apoptosis and inhibits the growth and invasion of colon cancer cells through the Wnt/beta-catenin signaling pathway. Oncol Rep. 2014;31(5):2270–8. doi:10.3892/or.2014.3057.PubMed

49.

Yan SM, Tang JJ, Huang CY, Xi SY, Huang MY, Liang JZ, et al. Reduced expression of ZDHHC2 is associated with lymph node metastasis and poor prognosis in gastric adenocarcinoma. PLoS One. 2013;8(2):e56366. doi:10.1371/journal.pone.0056366.CrossRefPubMedPubMedCentral

50.

Rodrigues-Ferreira S, Di Tommaso A, Dimitrov A, Cazaubon S, Gruel N, Colasson H, et al. 8p22 MTUS1 gene product ATIP3 is a novel anti-mitotic protein underexpressed in invasive breast carcinoma of poor prognosis. PLoS One. 2009;4(10):e7239. doi:10.1371/journal.pone.0007239.CrossRefPubMedPubMedCentral

51.

Ye F, Tang H, Liu Q, Xie X, Wu M, Liu X, et al. miR-200b as a prognostic factor in breast cancer targets multiple members of RAB family. J Transl Med. 2014;12:17. doi:10.1186/1479-5876-12-17.CrossRefPubMedPubMedCentral

52.

Wang J, Ou ZL, Hou YF, Luo JM, Shen ZZ, Ding J, et al. Enhanced expression of Duffy antigen receptor for chemokines by breast cancer cells attenuates growth and metastasis potential. Oncogene. 2006;25(54):7201–11. doi:10.1038/sj.onc.1209703.CrossRefPubMed

53.

Zeng XH, Ou ZL, Yu KD, Feng LY, Yin WJ, Li J, et al. Coexpression of atypical chemokine binders (ACBs) in breast cancer predicts better outcomes. Breast Cancer Res Treat. 2011;125(3):715–27. doi:10.1007/s10549-010-0875-2.CrossRefPubMed

54.

Sgambato A, Migaldi M, Montanari M, Camerini A, Brancaccio A, Rossi G, et al. Dystroglycan expression is frequently reduced in human breast and colon cancers and is associated with tumor progression. Am J Pathol. 2003;162(3):849–60. doi:10.1016/s0002-9440(10)63881-3.CrossRefPubMedPubMedCentral

55.

Melchor L, Honrado E, Huang J, Alvarez S, Naylor TL, Garcia MJ, et al. Estrogen receptor status could modulate the genomic pattern in familial and sporadic breast cancer. Clin Cancer Res. 2007;13(24):7305–13. doi:10.1158/1078-0432.ccr-07-0711.CrossRefPubMed

56.

Brennan PA, Jing J, Ethunandan M, Górecki D. Dystroglycan complex in cancer. Eur J Surg Oncol (EJSO). 2004;30(6):589-92. http://dx.doi.org/10.1016/j.ejso.2004.03.014.

57.

Network CGA. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70. doi:10.1038/nature11412.CrossRef

58.

Navolanic PM, Steelman LS, McCubrey JA. EGFR family signaling and its association with breast cancer development and resistance to chemotherapy (Review). Int J Oncol. 2003;22(2):237–52.PubMed

59.

Kim EK, Kim JH, Kim HA, Seol H, Seong MK, Lee JY, et al. Phosphorylated S6 kinase-1: a breast cancer marker predicting resistance to neoadjuvant chemotherapy. Anticancer Res. 2013;33(9):4073–9.PubMed

60.

Lupia A, Peppicelli S, Witort E, Bianchini F, Carloni V, Pimpinelli N, et al. CD63 tetraspanin is a negative driver of epithelial-to-mesenchymal transition in human melanoma cells. J Invest Dermatol. 2014;134(12):2947–56. doi:10.1038/jid.2014.258.CrossRefPubMed

61.

Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321(5897):1801–6. doi:10.1126/science.1164368.CrossRefPubMedPubMedCentral

62.

Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330-7. doi:10.1038/nature11252.

63.

Tao JJ, Castel P, Radosevic-Robin N, Elkabets M, Auricchio N, Aceto N, et al. Antagonism of EGFR and HER3 enhances the response to inhibitors of the PI3K-Akt pathway in triple-negative breast cancer. Sci Signal. 2014;7(318):ra29. doi:10.1126/scisignal.2005125.CrossRefPubMedPubMedCentral

Title: Different Array CGH profiles within hereditary breast cancer tumors associated to BRCA1 expression and overall survival
Authors: Carolina Alvarez
Andrés Aravena
Teresa Tapia
Ester Rozenblum
Luisa Solís
Alejandro Corvalán
Mauricio Camus
Manuel Alvarez
David Munroe
Alejandro Maass
Pilar Carvallo
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-016-2261-x

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