PMID- 25098819 OWN - NLM STAT- MEDLINE DCOM- 20150411 LR - 20220410 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 9 IP - 8 DP - 2014 TI - Adjusting breast cancer patient prognosis with non-HER2-gene patterns on chromosome 17. PG - e103707 LID - 10.1371/journal.pone.0103707 [doi] LID - e103707 AB - BACKGROUND: HER2 and TOP2A gene status are assessed for diagnostic and research purposes in breast cancer with fluorescence in situ hybridization (FISH). However, FISH probes do not target only the annotated gene, while chromosome 17 (chr17) is among the most unstable chromosomes in breast cancer. Here we asked whether the status of specifically targeted genes on chr17 might help in refining prognosis of early high-risk breast cancer patients. METHODS: Copy numbers (CN) for 14 genes on chr17, 4 of which were within and 10 outside the core HER2 amplicon (HER2- and non-HER2-genes, respectively) were assessed with qPCR in 485 paraffin-embedded tumor tissue samples from breast cancer patients treated with adjuvant chemotherapy in the frame of two randomized phase III trials. PRINCIPAL FINDINGS: HER2-genes CN strongly correlated to each other (Spearman's rho >0.6) and were concordant with FISH HER2 status (Kappa 0.6697 for ERBB2 CN). TOP2A CN were not concordant with TOP2A FISH status (Kappa 0.1154). CN hierarchical clustering revealed distinct patterns of gains, losses and complex alterations in HER2- and non-HER2-genes associated with IHC4 breast cancer subtypes. Upon multivariate analysis, non-HER2-gene gains independently predicted for shorter disease-free survival (DFS) and overall survival (OS) in patients with triple-negative cancer, as compared to luminal and HER2-positive tumors (interaction p = 0.007 for DFS and p = 0.011 for OS). Similarly, non-HER2-gene gains were associated with worse prognosis in patients who had undergone breast-conserving surgery as compared to modified radical mastectomy (p = 0.004 for both DFS and OS). Non-HER2-gene losses were unfavorable prognosticators in patients with 1-3 metastatic nodes, as compared to those with 4 or more nodes (p = 0.017 for DFS and p = 0.001 for OS). CONCLUSIONS: TOP2A FISH and qPCR may not identify the same pathology on chr17q. Non-HER2 chr17 CN patterns may further predict outcome in breast cancer patients with known favorable and unfavorable prognosis. FAU - Kotoula, Vassiliki AU - Kotoula V AD - Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece; Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. FAU - Bobos, Mattheos AU - Bobos M AD - Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. FAU - Alexopoulou, Zoi AU - Alexopoulou Z AD - Department of Biostatistics, Health Data Specialists Ltd, Athens, Greece. FAU - Papadimitriou, Christos AU - Papadimitriou C AD - Department of Clinical Therapeutics, "Alexandra" Hospital, University of Athens School of Medicine, Athens, Greece. FAU - Papadopoulou, Kyriaki AU - Papadopoulou K AD - Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. FAU - Charalambous, Elpida AU - Charalambous E AD - Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. FAU - Tsolaki, Eleftheria AU - Tsolaki E AD - Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. FAU - Xepapadakis, Grigorios AU - Xepapadakis G AD - Breast Clinic, "REA" Hospital, Piraeus, Greece. FAU - Nicolaou, Irene AU - Nicolaou I AD - Department of Histopathology, "Agii Anagriri" Cancer Hospital, Athens, Greece. FAU - Papaspirou, Irene AU - Papaspirou I AD - Department of Pathology, "Alexandra" Hospital, Athens, Greece. FAU - Aravantinos, Gerasimos AU - Aravantinos G AD - Second Department of Medical Oncology, "Agii Anargiri" Cancer Hospital, Athens, Greece. FAU - Christodoulou, Christos AU - Christodoulou C AD - Second Department of Medical Oncology, "Metropolitan" Hospital, Piraeus, Greece. FAU - Efstratiou, Ioannis AU - Efstratiou I AD - Department of Pathology, "Papageorgiou" Hospital, Thessaloniki, Greece. FAU - Gogas, Helen AU - Gogas H AD - First Department of Medicine, "Laiko" General Hospital, University of Athens, Medical School, Athens, Greece. FAU - Fountzilas, George AU - Fountzilas G AD - Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece; Department of Medical Oncology, "Papageorgiou" Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. LA - eng PT - Clinical Trial, Phase III PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20140806 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Antigens, Neoplasm) RN - 0 (DNA-Binding Proteins) RN - 0 (Poly-ADP-Ribose Binding Proteins) RN - EC 2.7.10.1 (ERBB2 protein, human) RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - EC 5.99.1.3 (DNA Topoisomerases, Type II) RN - EC 5.99.1.3 (TOP2A protein, human) SB - IM MH - Adult MH - Antigens, Neoplasm/*genetics MH - Breast Neoplasms/*genetics/*metabolism/pathology/therapy MH - *Chromosomal Instability MH - Chromosomes, Human, Pair 17/*genetics MH - DNA Topoisomerases, Type II/*genetics MH - DNA-Binding Proteins/*genetics MH - Disease-Free Survival MH - Female MH - Humans MH - In Situ Hybridization, Fluorescence MH - Middle Aged MH - Poly-ADP-Ribose Binding Proteins MH - Receptor, ErbB-2/*genetics MH - Survival Rate PMC - PMC4123879 COIS- Competing Interests: One of the authors (Z.A.) is employed in the commercial company "Health Data Specialists Ltd". This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. "Health Data Specialists Ltd" clearly states that it does not have any competing interests, financial, professional, or personal, that could interfere with the validity of the research, analyses, interpretation, or the complete and objective presentation of results. The company does not have any affiliations. EDAT- 2014/08/08 06:00 MHDA- 2015/04/12 06:00 PMCR- 2014/08/06 CRDT- 2014/08/08 06:00 PHST- 2014/03/31 00:00 [received] PHST- 2014/06/30 00:00 [accepted] PHST- 2014/08/08 06:00 [entrez] PHST- 2014/08/08 06:00 [pubmed] PHST- 2015/04/12 06:00 [medline] PHST- 2014/08/06 00:00 [pmc-release] AID - PONE-D-14-14327 [pii] AID - 10.1371/journal.pone.0103707 [doi] PST - epublish SO - PLoS One. 2014 Aug 6;9(8):e103707. doi: 10.1371/journal.pone.0103707. eCollection 2014.