![Fig. 1 – Comparison of subtype calls in TCGA’s final dataset. Each group used TCGA’s normalized RNA-seq data to assign TCGA’s tumors to the UNC, MD Anderson, or Lund subtypes. Published calls made by a group at The Broad Institute [[5_TD$DIFF]18] and TCGA were also included for comparison. The top left panel provides a schematic overview of the relationships among the calls made by the five groups. The heat maps display the relative expression of the gene sets that characterize each group’s subtypes. The red and green colors correspond to high and low relative expression, respectively. GU = genomically unstable; MDA = MD Anderson; NA = not applicable; SCCL = squamous cell carcinoma like; TCGA = The Cancer Genome Atlas; UNC = University of North Carolina; uroA = urobasal A; uroB = urobasal B.](/figures/fig-1-comparison-of-subtype-calls-in-tcgas-final-dataset-i4ldego7.webp)
Q2. What have the authors stated for future works in "Genetic alterations in the molecular subtypes of bladder cancer: illustration in the cancer genome atlas dataset" ?
Biological effects of these alterations will need to be explored in future functional studies. The precise mechanisms that cause them to appear more ‘ ‘ basal ’ ’ ( at the molecular level, and also in terms of their enrichment with squamous histological features and lethality ) will be very interesting ; their relatively high content of RB1 and NFE2L2 mutations suggests possible mechanisms. The existence of uroB tumors also suggests that basal versus luminal subtype class ‘ ‘ switching ’ ’ is possible. Clinically, it will be interesting to determine whether the uroA and uroB tumors are equally sensitive to FGFR inhibitors.
Q3. What is the common cause of amplification of cyclin D1 in bladder cancer?
Amplification of cyclin D1 was reported in approximately 20% of NMIBCs and MIBCs [1], and amplification of E2F3 was observed in high-grade T1 lesions and MIBCs [[29_TD$DIFF]1,32].
Q4. What factors were implicated in the formation of these two major gene expression subtypes?
TP53 mutation frequencies and/or genomic instability to the formation of these two major gene expression subtypes [[52_TD$DIFF] 8].
Q5. What is the common mRNA subtype of bladder cancer?
Recent whole genome mRNA expression profiling studies revealed that bladder cancers can be grouped into molecular subtypes, some of which share clinical properties and gene expression patterns with the intrinsic subtypes of breast cancer and the molecular subtypes found in other solid tumors.
Q6. What were the common inactivating mutations in ERCC2?
The most prevalent were inactivating mutations in ERCC2 (12% of tumors) [ [5_TD$DIFF]18], which were linked to sensitivity to neoadjuvant cisplatin-based combination chemotherapy [ [32_TD$DIFF] 5].
Q7. What is the expensive tumor on a per patient basis?
papillary NMIBCs are rarely lethal but recur almost always, necessitating that patients receive lifelong surveillance; the repeated surgical procedures required to deal with recurrences cause significant anxiety, discomfort, and morbidity, making bladder cancer the most expensive tumor on a per patient basis.
Q8. What is the main reason why NMIBCs are prone to recurrence?
NMIBCs are prone to recurrence, and it will be important to perform longitudinal studies to determine how often subtype membership is maintained in these recurrences.
Q9. What are the biological consequences of APOBEC3B-mediated mutagenesis?
Although the biological consequences of these events have not been defined experimentally, they would be expected to lead to decreased RNA polymerase accessibility, gene silencing, and a less well-differentiated phenotype.
Q10. What is the effect of cisplatin on basal cancer?
Although the molecular mechanisms that underlie the benefit produced by chemotherapy in basal tumors are still under investigation, basal human bladder cancer cell lines are more sensitive to cisplatininduced apoptosis than are luminal cell lines (A. Ochoa, D.J. McConkey, unpublished observations).
Q11. What is the reason for the TCGA cluster IV tumors?
even though TCGA cluster IV tumors are heavily infiltrated with lymphocytes, the T cells appear to be more actively suppressed than are the T cells in the tumors that belong to TCGA cluster II luminal subtype [[66_TD$DIFF]76], which could explain why cluster IV tumors are somewhat less sensitive to immune checkpoint blockade.
Q12. What is the significance of the alterations in the luminal uroA subtype?
Although they cluster together with the squamous/basal tumors in the UNC, MD Anderson, and TCGA classifications, the genetic alterations in the uroB tumors more closely resemble those present in the luminal uroA subtype, supporting the conclusion that they represent progressed versions of the uroA cancers.
Q13. What is the common APOBEC gene in bladder cancer?
Among the APOBEC genes, APOBEC3B appears to be most commonly overexpressed in solidtumors, and bladder cancers stand out for expressing some of the highest levels of APOBEC3B among all solid malignancies [[20_TD$DIFF] 4].
Q14. What subtypes were found to be beneficial to patients with p53-like tumor?
In the phase II trial that led to Food and Drug Administration approval of the drug, patients whose tumors belonged to TCGA cluster II obtained somewhat more benefit than patients whose tumors belonged to the other subtypes, and patients with ‘‘papillary’’ (cluster I) tumors derived little benefit, if at all [ [65_TD$DIFF]75].
Q15. What is the significance of the uroA subtype?
In addition, as noted above, the uroB subtype may establish a precedent for luminal-to-basal subtype ‘‘switching’’ in bladder cancer.
Q16. What were the alterations that were enriched in the breast cancer intrinsic subtypes?
Included among them were alterations that were enriched in the breast cancer intrinsic subtypes (TP53, RB1, ERBB2, and PIK3CA), genes that displayed different mutation frequencies in NMIBCs versus MIBCs (FGFR3, KDM6A, and STAG2), and genes that encode for mRNAs that were enriched in basal or luminal MIBCs (EGFR, PPARG, GATA3, ELF3, and ERBB3).
Q17. What is the likely explanation for the differences in the molecular subtypes of bladder?
Given past observations in the molecular subtypes in other cancers, it seemed likely that the molecular subtypes of bladder cancer would contain distinct mutations and CNAs.