|مجال التميز||تميز دراسي وبحثي|
|عنوان البحث:||The prognostic significance of wild-type isocitrate dehydrogenase 2 (IDH2) in breast cancer|
|رابط إلى البحث:||Click here|
|موجز عن البحث:||
Background: Lymphovascular invasion (LVI) is a prerequisite step in breast cancer (BC) metastasis. We have previously identified wild-type isocitrate dehydrogenase 2 (IDH2) as a key putative driver of LVI. Thus, we explored the prognostic significance of IDH2 at transcriptome and protein expression levels in pre-invasive and invasive disease.
Methods: Utlising tissue microarrays from a large well annotated BC cohort including ductal carcinoma in situ and invasive breast cancer (IBC), IDH2 was assessed at the transcriptomic and proteomic level. The associations between clinicopathological factors including LVI status, prognosis and the expression of IDH2 were evaluated.
Results: In pure DCIS and IBC, high IDH2 protein expression was associated with features of aggressiveness including high nuclear grade, larger size, comedo necrosis and hormonal receptor negativity and LVI, higher grade, larger tumour size, high NPI, HER2 positivity, and hormonal receptor negativity, respectively. High expression of IDH2 either in mRNA or in protein levels was associated with poor patient’s outcome in both DCIS and IBC. Multivariate analysis revealed that IDH2 protein expression was an independent risk factor for shorter BC specific-survival.
Conclusion: Further functional studies to decipher the role of IDH2 and its mechanism of action as a driver of BC progression and LVI are warranted.
|عنوان البحث:||Myxovirus resistance 1 (MX1) is an independent predictor of poor outcome in invasive breast cancer|
|رابط إلى البحث:||Click here|
|موجز عن البحث:||
Background: Breast cancer (BC) is a disease with variable morphology, clinical behaviour and response to therapy. Identifying factors associated with the progression of early-stage BC can help understand the risk of metastasis and guide treatment decisions. Myxovirus resistance 1 (MX1), which is involved in the cellular antiviral mechanism, plays a role in some solid tumours; however, its role in invasive BC remains unknown. In this study, we aimed to explore the clinicopathological and prognostic significance of MX1 in BC.
Methods: MX1 was assessed at the protein level using tissue microarrays from a large well-annotated BC cohort (n = 845). The expression of MX1 mRNA was assessed at the transcriptomic level using the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; n = 1980) and validated using three publicly available cohorts on Breast Cancer Gene-Expression Miner (bc-GenExMiner version 4.4). The associations between MX1 expression and clinicopathological factors, and outcome were evaluated.
Results: High MX1 protein expression was associated with features of aggressiveness, including large tumour size, high tumour grade, high Nottingham prognostic index scores, hormone receptor negativity and high Ki67 expression. High MX1 expression showed an association with poor patient outcome and it was an independent predictor of short BC-specific survival (p = 0.028; HR = 1.5; 95% CI = 1.0-2.2). Consistent with the protein results, high MX1 mRNA levels showed an association with features of aggressive behaviour and with shorter survival.
Conclusion: This study identified MX1 as an independent predictor of poor outcome in patients with BC. Further functional studies are needed to investigate the biological role of MX1 in BC and its potential value as a therapeutic target.
|عنوان المؤتمر:||12th Joint Meeting of the British Division of the International Academy of Pathology and the Pathological Society of Great Britain and Ireland|
|مكان الإنعقاد:||Leeds, United Kingdom|
|طبيعة المشاركة:||Oral presentation|
|عنوان المشاركة:||The prognostic significance of wild-type isocitrate dehydrogenase 2 (IDH2): A key gene associated with lymphovascular invasion in breast cancer|
BACKGROUND: Lymphovascular invasion (LVI) is associated with metastasis and is a prognostic factor in early-stage invasive breast cancer (BC). Through stringent bioinformatics analysis we identified Isocitrate Dehydrogenase 2 (IDH2) as one of the candidates gene associated with LVI positivity using multiple BC cohorts. This study aimed to evaluate the clinicopathological significance of IDH2 at transcriptomic and proteomic levels using large BC cohorts with long term follow-up.
METHODS: IDH2 was probed at transcriptomic [using BC Gene miner, TCGA, and the METABRIC cohort] and proteomic level using immunohistochemistry in a large well-characterised BC cohort (n=859) prepared as tissue microarrays. Association with clinicopathological characteristics, and patient outcome were evaluated.
RESULTS: In METABRIC and TCGA cohorts, overexpression of IDH2 mRNA expression was significantly associated with LVI-positivity (both p<0.01), high histological grade and HER2-positivity (all p<0.05). IDH2 mRNA expression showed significant positive correlation with IDH2 protein expression (p=0.002). At protein level, high expression of IDH2 was associated with LVI-positivity, high histological grade, high Nottingham Prognostic Index, HER2 positivity, large tumour size, and hormonal receptor negativity (all p<0.01). Increased IDH2 protein expression was significantly correlated with features of aggressive phenotype including Ki67, EGFR, and E-cadherin loss (all p<0.05). High expression of IDH2 mRNA and protein was associated with shorter 10 years of BC specific survival (p=0.038). In publicly available datasets using BC gene miner, up-regulation of IIDH2 mRNA was positively associated with poor outcome (p=0.0002).
CONCLUSION: This study confirmed the association of IDH2 expression with LVI status, tumour proliferation and metastasis related biomarkers; results warranting further functional validation and suggesting IDH2 as a potential therapeutic target in BC.
|عنوان المؤتمر:||UK Interdisciplinary Breast Cancer Symposium 2020|
|مكان الإنعقاد:||Birmingham, United Kingdom|
|طبيعة المشاركة:||Poster presentation|
|عنوان المشاركة:||Prognostic significance of high mobility group protein 3 (HMGB3): A biomarker associated with lymphovascular invasion in breast cancer|
BACKGROUND: Lymphovascular invasion (LVI) is an initial step of the metastasis and a prognostic factor in early-stage invasive breast cancer (BC). Through stringent bioinformatics analysis we identified High Mobility Group Protein 3 (HMGB3) as one of the drivers gene associated with LVI positivity using multiple BC cohorts. High expression of HMGB3 is associated with poor outcome in various cancers; however, its role in BC still unclear. This study aimed to investigate the clinicopathological significance of HMGB3 at transcriptomic and proteomic levels using large BC cohorts with long term follow-up.
METHODS: HMGB3 was evaluated at transcriptomic level [using METABRIC cohort, TCGA and BC Gene Miner] and proteomic level using immunohistochemistry in a large well-characterised BC cohort (n=1647) prepared as tissue microarrays. Association with clinicopathological characteristics, and patient outcome were assessed.
RESULTS: In the METABRIC and TCGA datasets; high HMGB3 mRNA level was significantly correlated with LVI-positivity, higher histological grade, hormonal receptor negativity (all p<0.0001) and HER2 positivity (p<0.0001 in METABRIC; p=0.013 in TCGA). Moreover, in the METABRIC, high expression of HMGB3 mRNA was associated with lymph node (p=0.004). At protein level, high expression of HMGB3 was associated with LVI-positivity (p=0.008), high histological grade, poor Nottingham Prognostic Index, HER2 positivity, and ER negativity (all p<0.0001). In METABRIC and the BC Gene Miner v4.0, BCSS of patients with high HMGB3 mRNA expression was significantly shorter than those with lower expression (p<0.0001). Similar results were observed in the TCGA (p=0.003). High HMGB3 protein expression was associated with shorter BCSS, and TTDM (p<0.0001). In multivariate Cox regression analysis, high HMGB3 protein expression was an independent predictor of shorter BCSS (p=0.003) regardless the tumour grade, size, stage and LVI.
CONCLUSION: This study confirmed the association of HMGB3 expression with LVI status, results warranting further functional validation and suggesting HMGB3 as a potential therapeutic target in BC.