Targeting chromosomal instability and tumour heterogeneity in HER2‐positive breast cancer

Burrell, Rebecca A.; Juul, Nicolai Stefan; Johnston, Stephen; Reis‐Filho, Jorge S.; Szállási, Zoltán; Swanton, Charles

doi:10.1002/jcb.22781

Cited by 46 publications

(36 citation statements)

References 77 publications

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“…Considering that the CN clusters reflect different levels and types of chr17 instability, this study supports the notion that HER2-positive tumors exhibit different patterns of CIN [46]. Herein we found that compact HER2 amplicon gains are more common in HER2-enriched, while complex gains are the main pattern in luminal-HER2 tumors.…”

Section: Discussionsupporting

confidence: 88%

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

Kotoula

Bobos

Alexopoulou³

et al. 2014

PLoS ONE

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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.

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Section: Discussionsupporting

confidence: 88%

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

Kotoula

Bobos

Alexopoulou³

et al. 2014

PLoS ONE

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“…Also, intratumoral genetic heterogeneity is commonly caused by chromosomal instability, cell-cell variation in chromosome structure or number across a tumor population, which is associated with poor prognosis in solid tumors, including breast cancer. 32,33 Therefore, intratumoral HER2 heterogeneity may be associated with poor prognosis of the patients.…”

Section: Discussionmentioning

confidence: 99%

Intratumoral heterogeneity of HER2 gene amplification in breast cancer: its clinicopathological significance

et al. 2012

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Intratumoral heterogeneity of human epidermal growth factor receptor 2 (HER2) gene amplification has been reported to occur with variable frequencies in breast cancers. However, there have been few studies of its clinicopathological significance. We used tissue microarrays to evaluate two aspects of intratumoral heterogeneity of HER2 gene amplification: regional heterogeneity and genetic heterogeneity. We examined 96 invasive breast cancers in which HER2 amplification had been diagnosed in whole sections, and determined the clincopathological characteristics of those tumors. HER2 regional heterogeneity, defined as the existence of amplification/negative or amplification/equivocal patterns in different tissue microarray cores of a tumor, was present in 17 (18%) of the 96 cases. HER2 genetic heterogeneity, defined as the presence of tumor cells with a HER2/chromosome enumeration probe 17 ratio higher than 2.2 in 5-50% of the tumor cells, was found in 11 cases (11%), all of which showed HER2 regional heterogeneity. The cases with intratumoral heterogeneity of HER2 gene amplification were characterized by low grade or equivocal HER2 amplification and equivocal (2 þ ) HER2 expression in whole sections. The patients with intratumoral heterogeneity of HER2 gene amplification had significantly shorter disease-free survival times than those with homogeneous HER2 gene amplification, and this effect was also evident in subgroup analysis by hormone receptor status. In multivariate analysis, intratumoral HER2 heterogeneity retained its status as an independent prognostic factor for disease-free survival. In conclusion, intratumoral heterogeneity of HER2 gene amplification is present in a subset of HER2-amplified breast cancers, especially in cases with low-grade HER2 amplification and equivocal HER2 expression, indicating a need for HER2 testing on more representative, larger tumor samples for accurate assessment of HER2 status in such cases. The patients with this heterogeneity have decreased disease-free survival, suggesting that genetic instability, and hence aberrant HER2 amplification in subclones of such tumors, may be associated with breast cancer progression. Modern Pathology (2012) 25, 938-948;

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“…Paradoxically, there is also evidence that excessive CIN is a disadvantage for tumor progression and is associated with better prognosis [411]. Whatever the case may be, and despite all controversy, direct targeting of CIN as a potential anti-cancer therapy is now the subject of active research [412,413]. …”

Section: Consequences Of Abnormal Congressionmentioning

confidence: 99%

Mechanisms of Chromosome Congression during Mitosis

Maiato

Gomes

Sousa

et al. 2017

Biology

155

168

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Chromosome congression during prometaphase culminates with the establishment of a metaphase plate, a hallmark of mitosis in metazoans. Classical views resulting from more than 100 years of research on this topic have attempted to explain chromosome congression based on the balance between opposing pulling and/or pushing forces that reach an equilibrium near the spindle equator. However, in mammalian cells, chromosome bi-orientation and force balance at kinetochores are not required for chromosome congression, whereas the mechanisms of chromosome congression are not necessarily involved in the maintenance of chromosome alignment after congression. Thus, chromosome congression and maintenance of alignment are determined by different principles. Moreover, it is now clear that not all chromosomes use the same mechanism for congressing to the spindle equator. Those chromosomes that are favorably positioned between both poles when the nuclear envelope breaks down use the so-called “direct congression” pathway in which chromosomes align after bi-orientation and the establishment of end-on kinetochore-microtubule attachments. This favors the balanced action of kinetochore pulling forces and polar ejection forces along chromosome arms that drive chromosome oscillatory movements during and after congression. The other pathway, which we call “peripheral congression”, is independent of end-on kinetochore microtubule-attachments and relies on the dominant and coordinated action of the kinetochore motors Dynein and Centromere Protein E (CENP-E) that mediate the lateral transport of peripheral chromosomes along microtubules, first towards the poles and subsequently towards the equator. How the opposite polarities of kinetochore motors are regulated in space and time to drive congression of peripheral chromosomes only now starts to be understood. This appears to be regulated by position-dependent phosphorylation of both Dynein and CENP-E and by spindle microtubule diversity by means of tubulin post-translational modifications. This so-called “tubulin code” might work as a navigation system that selectively guides kinetochore motors with opposite polarities along specific spindle microtubule populations, ultimately leading to the congression of peripheral chromosomes. We propose an integrated model of chromosome congression in mammalian cells that depends essentially on the following parameters: (1) chromosome position relative to the spindle poles after nuclear envelope breakdown; (2) establishment of stable end-on kinetochore-microtubule attachments and bi-orientation; (3) coordination between kinetochore- and arm-associated motors; and (4) spatial signatures associated with post-translational modifications of specific spindle microtubule populations. The physiological consequences of abnormal chromosome congression, as well as the therapeutic potential of inhibiting chromosome congression are also discussed.

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Targeting chromosomal instability and tumour heterogeneity in HER2‐positive breast cancer

Cited by 46 publications

References 77 publications

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

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

Intratumoral heterogeneity of HER2 gene amplification in breast cancer: its clinicopathological significance

Mechanisms of Chromosome Congression during Mitosis

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