Risk Classification of Bladder Cancer by Gene Expression and Molecular Subtype

Abstract

This study evaluated a panel including the molecular taxonomy subtype and the expression of 27 genes as a diagnostic tool to stratify bladder cancer patients at risk of aggressive behavior, using a well-characterized series of non-muscle invasive bladder cancer (NMIBC) as well as muscle-invasive bladder cancer (MIBC). The study was conducted using the novel NanoString nCounter gene expression analysis. This technology allowed us to identify the molecular subtype and to analyze the gene expression of 27 bladder-cancer-related genes selected through a recent literature search. The differential gene expression was correlated with clinicopathological variables, such as the molecular subtypes (luminal, basal, null/double negative), histological subtype (conventional urothelial carcinoma, or carcinoma with variant histology), clinical subtype (NMIBC and MIBC), tumor stage category (Ta, T1, and T2–4), tumor grade, PD-L1 expression (high vs. low expression), and clinical risk categories (low, intermediate, high and very high). The multivariate analysis of the 19 genes significant for cancer-specific survival in our cohort study series identified TP53 (p = 0.0001), CCND1 (p = 0.0001), MKI67 (p < 0.0001), and molecular subtype (p = 0.005) as independent predictors. A scoring system based on the molecular subtype and the gene expression signature of TP53, CCND1, or MKI67 was used for risk assessment. A score ranging from 0 (best prognosis) to 7 (worst prognosis) was obtained and used to stratify our patients into two (low [score 0–2] vs. high [score 3–7], model A) or three (low [score 0–2] vs. intermediate [score 3–4] vs. high [score 5–7], model B) risk categories with different survival characteristics. Mean cancer-specific survival was longer (122 + 2.7 months) in low-risk than intermediate-risk (79.4 + 9.4 months) or high-risk (6.2 + 0.9 months) categories (p < 0.0001; model A); and was longer (122 + 2.7 months) in low-risk than high-risk (58 + 8.3 months) (p < 0.0001; model B). In conclusion, the molecular risk assessment model, as reported here, might be used better to select the appropriate management for patients with bladder cancer.

Advances in diagnosis and treatment of bladder cancer

“…By contrast, MIBCs require the inactivation of one or more tumor suppressor genes, such as TP53 , RB1 , and PTEN , and tumor development is preceded by the appearance of flat urothelial dysplasia and carcinoma in situ; interestingly, these lesions share molecular features with high grade and invasive bladder carcinomas (fig 3). 316182039…”

“…The CDKN2A locus (9p21) encodes p16 and p14ARF, which are negative regulators of the RB pathway and p53 pathway, respectively. Chromosome 9 loss also implicates TSC1 , a tumor suppressor that regulates mammalian target of rapamycin (mTOR) signaling 35101218212227282940414243. Additional deletions of chromosome arms 10q, 11p, 11q, 17p, 18q, 19p, and 19q have been described in up to 20% of cases.…”

“…Unfortunately, the five year overall survival of patients with distant metastasis remains low 13. Relevant clinicopathologic factors include the number and size of tumors, presurgical recurrence rates, T stage, presence of carcinoma in situ, and histologic grade and nodal status 35101214161718192021222324…”

Pesticides and Bladder Cancer: Mechanisms Leading to Anti-Cancer Drug Chemoresistance and New Chemosensitization Strategies

“…Ta, a papillary tumor, grows into the hollow area of the bladder with finger-like projections but does not spread to the connective tissue or muscle tissue of the bladder wall [38]. Cancers in the Ta and CIS stages account for 70% and 20% of all NMIBC, respectively [39]. Tumors in stage T1 spread into the connective tissue layer (lamina propria) under the lining layer of the bladder, but do not spread into the muscle layer.…”

Do Histology and Primary Tumor Location Influence Metastatic Patterns in Bladder Cancer?

“…However, several previous studies reported that bladder cancer shows clinical variations depending on its histological type [4,11,[23][24][25]. Furthermore, a recent study analyzing gene expression in bladder cancer showed that UC has different gene expression patterns, depending on the molecular or histological subtype [26]. Some studies have reported differences in the molecular characteristics of UC depending on the primary tumor site [27][28][29].…”