BioMedBC Project: Molecular Background
BC is highly heterogeneous at the molecular level. Early molecular profiling recapitulated a dual-track model
according to which, BC develops from two clinically and patho-genetically distinct forms- the papillary and the non-papillary (1,2).
The papillary NMIBCs develop via urothelial hyperplasia and are associated with disruption on the PI3K-AKT-mTOR pathway,
mutations in the FGFR3 and HRAS (3) genes. The non-papillary MIBCs are developed by flat dysplasia and carcinoma in situ (CIS) and
are characterized by genetic alterations in tumor suppressor genes that regulate cell cycle and apoptosis (TP53, CDKN2A, CCND1,
CDKN1B and RB1) (3). Although, this model included many characteristic features of BC, it does not fully address the heterogeneity
of the disease. Recent next- generation sequencing data on high grade MIBC indicate a sub-clonal cancer evolution (4-8). Two
new MIBC subtypes (basal and luminal) were described, each with different prognosis. The basal subtype is highly invasive and
metastatic, expressing squamous features and EMT markers, epithelial cytokeratins and high levels of HIF-1 and EGFR. The luminal
subtype comprises of papillary non-invasive tumors and a subset of invasive urothelial cancers. There, mostly, the PI-3 kinase/AKT
pathway is altered (9). Luminal tumors express epithelial biomarkers, high FGFR3 and activating mutations of FGFR3-, ERBB2-,
ERBB3- and PIK3CA- (8,9). BC patients with invasive basal tumors exhibit lower survival rates compared to those suffering
from invasive luminal tumors (8).
Mass spectrometry-derived (CE-MS) urinary profiling data are indicative of disease molecular changes (Figure 1) and have been
already used as diagnostic biomarkers.
In BioMedBC project, we aim at assessing the prognostic value of the urinary biomarkers, as tools for prediction of disease progression.
- Czerniak, B., C. Dinney, and D. McConkey, Origins of Bladder Cancer. Annu Rev Pathol, 2016.
- Knowles, M.A. and C.D. Hurst, Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer, 2015. 15(1): p. 25-41.
- Netto, G.J., Molecular biomarkers in urothelial carcinoma of the bladder: are we there yet? Nat Rev Urol, 2012. 9(1): p. 41-51.
- Gui, Y., et al., Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat Genet, 2011. 43(9): p. 875-8.
- Cancer Genome Atlas Research, N., Comprehensive molecular characterization of urothelial bladder carcinoma. Nature, 2014. 507(7492): p. 315-22.
- Iyer, G., et al., Prevalence and co-occurrence of actionable genomic alterations in high-grade bladder cancer. J Clin Oncol, 2013. 31(25): p. 3133-40.
- Sjodahl, G., et al., A molecular taxonomy for urothelial carcinoma. Clin Cancer Res, 2012. 18(12): p. 3377-86.
- Choi, W., et al., Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell, 2014. 25(2): p. 152-65.
- McConkey, D.J., W. Choi, and C.P. Dinney, Genetic subtypes of invasive bladder cancer. Curr Opin Urol, 2015. 25(5): p. 449-58.
BioMedBC is a Marie Sklodowska Curie Actions (MSCA) Individual Fellowship programme (H2020-MSCA-IF-2016)
funded by the European Union under the Horizon2020 Framework Programme (Grant Agreement:752755) and
coordinated by Mosaiques diagnostics