Identification of Novel Gene Amplifications in Breast Cancer and Coexistence of Gene Amplification with an Activating Mutation of <i>PIK3CA</i>

Kadota, Mitsutaka; Sato, Misako; Duncan, Beverly; Ooshima, Akira; Yang, Howard H.; Diaz-Meyer, Natacha; Gere, Sheryl; Kageyama, Shun‐Ichiro; Fukuoka, Junya; Nagata, Takuya; Tsukada, Kazuhiro; Dunn, Barbara K.; Wakefield, Lalage M.; Lee, Maxwell P.

doi:10.1158/0008-5472.can-09-0064

Cited by 104 publications

(87 citation statements)

References 31 publications

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“…Furthermore, although not addressed in this study, genetic alterations may also play a role in predisposing patients with PAH to coronary comorbidities, such as SNPs in BRD4 but also gene copy number variation in this gene, which has been associated with cancer. 40,41 In this study, we also investigated whether the use of BRD4 inhibitors by intratracheal nebulization in the Sugen/ hypoxia-induced PAH rat model, which has beneficial effect on lung function, 12 could also affect the coronary circulation. This animal model, such as the monocrotaline-PAH model, exhibits increased vascular remodeling ( Figure 5B) and increased BRD4-positive cell within the coronary arteries ( Figure IIC in the online-only Data Supplement).…”

Section: Discussionmentioning

confidence: 99%

Implication of Inflammation and Epigenetic Readers in Coronary Artery Remodeling in Patients With Pulmonary Arterial Hypertension

Meloche

Lampron

Nadeau

et al. 2017

ATVB

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P ulmonary arterial hypertension (PAH) is a vascularremodeling disease (VRD) first described as an obstructive pathology affecting the distal pulmonary arteries. It is characterized by enhanced inflammation, vasoconstriction, and proliferation/apoptosis imbalance within the arterial wall, leading to increased pulmonary vascular resistance and right ventricular (RV) failure and death. 1 The smooth muscle cells (SMCs) within the pulmonary arterial wall exhibit exaggerated proliferation and resistance to apoptosis. Many groups have studied the underlying mechanisms of this "cancer-like" phenotype to find better ways to treat this deadly disease. The similarities in histological features between PAH and other VRDs suggest common pathogenic mechanisms. We and others have described the implication of the receptor of advanced glycation endproducts, 2-4 the oncoprotein kinase Pim-1 3, 5 and the transcription factor nuclear factor of activated T cells 6,7 in promoting proliferation in remodeling processes occurring in both VRD and PAH. In PAH patients' lung vasculature, these molecular actors are, at least in part, regulated by proinflammatory cytokines, alterations in the miR-223/DNA damage/ Poly[ADP-ribose] polymerase 1/miR-204 axis 8-11 and subsequent overexpression of the epigenetic reader bromodomain protein 4 (BRD4). 12 BRD4 functions as a scaffold for transcription factors at promoters and superenhancers, modulating the chromatin landscape and facilitating transcriptional activation of target genes. 13 Interestingly, BRD4 is also implicated in systemic VRD by triggering proinflammatory endothelial © 2017 American Heart Association, Inc. Objective-Pulmonary arterial hypertension (PAH) is a vascular disease not restricted to the lungs. Many signaling pathways described in PAH are also of importance in other vascular remodeling diseases, such as coronary artery disease (CAD). Intriguingly, CAD is 4× more prevalent in PAH compared with the global population, suggesting a link between these 2 diseases. Both PAH and CAD are associated with sustained inflammation and smooth muscle cell proliferation/ apoptosis imbalance and we demonstrated in PAH that this phenotype is, in part, because of the miR-223/DNA damage/ Poly[ADP-ribose] polymerase 1/miR-204 axis activation and subsequent bromodomain protein 4 (BRD4) overexpression. Interestingly, BRD4 is also a trigger for calcification and remodeling processes, both of which are important in CAD. Thus, we hypothesize that BRD4 activation in PAH influences the development of CAD. Approach and Results-PAH was associated with significant remodeling of the coronary arteries in both human and experimental models of the disease. As observed in PAH distal pulmonary arteries, coronary arteries of patients with PAH also exhibited increased DNA damage, inflammation, and BRD4 overexpression. In vitro, using human coronary artery smooth muscle cells from PAH, CAD and non-PAH-non-CAD patients, we showed that both PAH and CAD smooth muscle cells exhibited increased proliferation and suppres...

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Section: Discussionmentioning

confidence: 99%

Implication of Inflammation and Epigenetic Readers in Coronary Artery Remodeling in Patients With Pulmonary Arterial Hypertension

Meloche

Lampron

Nadeau

et al. 2017

ATVB

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“…Breast cancer is one of the most common cancers of women worldwide; the cumulative life-time incidence is ~11% (Kadota et al, 2009). The development of breast cancer is related to diverse genetic and environmental factors, thus it is a heterogeneous disease.…”

Section: Introductionmentioning

confidence: 99%

Mutational Analysis of Key EGFR Pathway Genes in Chinese Breast Cancer Patients

Lin

Yang²,

Liu³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Background: The epidermal growth factor receptor (EGFR) is a potential therapeutic target for breast cancer treatment; however, its use does not lead to a marked clinical response. Studies of non-small cell lung cancer and colorectal cancer showed that mutations of genes in the PIK3CA/AKT and RAS/RAF/MEK pathways, two major signalling cascades downstream of EGFR, might predict resistance to EGFR-targeted agents. Therefore, we examined the frequencies of mutations in these key EGFR pathway genes in Chinese breast cancer patients. Methods: We used a high-throughput mass-spectrometric based cancer gene mutation profiling platform to detect 22 mutations of the PIK3CA, AKT1, BRAF, EGFR, HRAS, and KRAS genes in 120 Chinese women with breast cancer. Results: Thirteen mutations were detected in 12 (10%) of the samples, all of which were invasive ductal carcinomas (two stage I, six stage II, three stage III, and one stage IV). These included one mutation (0.83%) in the EGFR gene (rs121913445-rs121913432), three (2.50%) in the KRAS gene (rs121913530, rs112445441), and nine (7.50%) in the PIK3CA gene (rs121913273, rs104886003, and rs121913279). No mutations were found in the AKT1, BRAF, and HRAS genes. Six (27.27%) of the 22 genotyping assays called mutations in at least one sample and three (50%) of the six assays queried were found to be mutated more than once. Conclusions: Mutations in the EGFR pathway occurred in a small fraction of Chinese breast cancers. However, therapeutics targeting these potential predictive markers should be investigated in depth, especially in Oriental populations.

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“…A combination of anti‐EGFR drugs and inhibitors of the PI3K‐mTOR pathway was suggested for this case 34.A potential activation of the HGF‐MET axis was reported in a thymoma case, a rare cancer with no approved drugs. Interestingly, both these genes which form a receptor–ligand pair were amplified implying potential sensitivity to drugs targeting this pathway.…”

Section: Resultsmentioning

confidence: 82%

“…A combination of anti‐EGFR drugs and inhibitors of the PI3K‐mTOR pathway was suggested for this case 34.…”

Section: Resultsmentioning

confidence: 91%

StrandAdvantage test for early‐line and advanced‐stage treatment decisions in solid tumors

et al. 2017

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Comprehensive genetic profiling of tumors using next‐generation sequencing (NGS) is gaining acceptance for guiding treatment decisions in cancer care. We designed a cancer profiling test combining both deep sequencing and immunohistochemistry (IHC) of relevant cancer targets to aid therapy choices in both standard‐of‐care (SOC) and advanced‐stage treatments for solid tumors. The SOC report is provided in a short turnaround time for four tumors, namely lung, breast, colon, and melanoma, followed by an investigational report. For other tumor types, an investigational report is provided. The NGS assay reports single‐nucleotide variants (SNVs), copy number variations (CNVs), and translocations in 152 cancer‐related genes. The tissue‐specific IHC tests include routine and less common markers associated with drugs used in SOC settings. We describe the standardization, validation, and clinical utility of the StrandAdvantage test (SA test) using more than 250 solid tumor formalin‐fixed paraffin‐embedded (FFPE) samples and control cell line samples. The NGS test showed high reproducibility and accuracy of >99%. The test provided relevant clinical information for SOC treatment as well as more information related to investigational options and clinical trials for >95% of advanced‐stage patients. In conclusion, the SA test comprising a robust and accurate NGS assay combined with clinically relevant IHC tests can detect somatic changes of clinical significance for strategic cancer management in all the stages.

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Identification of Novel Gene Amplifications in Breast Cancer and Coexistence of Gene Amplification with an Activating Mutation of PIK3CA

Cited by 104 publications

References 31 publications

Implication of Inflammation and Epigenetic Readers in Coronary Artery Remodeling in Patients With Pulmonary Arterial Hypertension

Implication of Inflammation and Epigenetic Readers in Coronary Artery Remodeling in Patients With Pulmonary Arterial Hypertension

Mutational Analysis of Key EGFR Pathway Genes in Chinese Breast Cancer Patients

StrandAdvantage test for early‐line and advanced‐stage treatment decisions in solid tumors

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