Adjusting Breast Cancer Patient Prognosis with Non-HER2-Gene Patterns on Chromosome 17

Abstract

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.MethodsCopy 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.

MYC copy gain, chromosomal instability and PI3K activation as potential markers of unfavourable outcome in trastuzumab-treated patients with metastatic breast cancer

“…Although the cut-off for FISH amplification was substantially lower than the one recently proposed [ 42 ], the rate of MET amplified cases in the present series was very low and their number too small for meaningful statistical analyses. The discrepancy between FISH and qPCR MET status was probably due to the low copy number load even in tumors with MET CN gains, as previously discussed [ 38 , 40 ]. Nevertheless, MET CN gain showed a trend as an independent unfavourable marker in patients who presented with de novo mBC, which might be considered as a surrogate for an adverse effect of MET CN aberrations in the present clinical context.…”

“…MYC and MET were assessed at multiple molecular levels, by multiple methods, all of which have intrinsic characteristics. At the gene level, FISH probes detect, although not exclusively, the gene of interest on the corresponding chromosome, while CN assessment with qPCR is gene specific but may suffer from PCR target efficiency and calibrator DNA characteristics; hence, the two methods do not always yield the same information on gene copy status [ 38 ]. By using the criteria for MYC amplification provided by Perez et al [ 27 ], we recapitulated the findings of that study concerning the 15 % incidence of MYC amplification without any prognostic effect for this marker in HER2-positive patient, further supporting that co-amplified MYC and HER2 confer poor prognosis in patients treated with anthracyclines but not with anti-HER2 targeted drugs [ 39 ].…”

Proteasome 26S Subunit, non-ATPase 3 (PSMD3) Regulates Breast Cancer by Stabilizing HER2 from Degradation

“…HER2 is located at chr17q12 and in agreement with a previous study on the chr17q copy number (CN) patterns for HER2 and HER2-related genes. PSMD3s locate at ch17q21 and is considered as one of the close genes surrounding HER2 that exhibited high copy number (CN) in parallel with HER2 [35]. Due to the positive correlation between HER2 and PSMD3 in BC, loss of PSMD3 function analyses in several HER2+ cells was performed.…”

“…It has been reported that PSMD3 genotypes are associated with WBC and neutrophil counts and have interactions with dietary fatty acids and carbohydrates on glucose-related traits [33,34]. A recent study demonstrated that HER2 expression is strongly correlated with its surrounding genes, including PSMD3, which is co-expressed with HER2 in BC [35]. Co-silencing of PSMD3 and HER2 gave an additive effect for inhibiting the viability and cell proliferation of the tumor cells rather than a single treatment in the KPL4 cell line [36].…”

Prognostic significance of TOP2A in non-small cell lung cancer revealed by bioinformatic analysis

“…This enzyme has been known to be involved in processes such as chromosome condensation, chromatid separation, and the relief of torsional stress that occurs during DNA transcription and replication. A most well known disease associated with TOP2A is female breast cancer, it is usually deleted or amplified simultaneously with ERBB2, thus the two genes are commonly co-tested in breast cancer patients for further proper use of anticancer agent herceptin [44–46]. And, TOP2A was reported to be targeted by tumor suppressor like miR-144-3p in glioblastoma, thus resulting in cancer cell apoptosis [47].…”