<p class="first" id="d37721097e282">Stage T1 bladder cancers have the highest progression
and recurrence rates of all
non-muscle-invasive bladder cancers (NMIBCs). Most T1 cancers are treated with bacillus
Calmette-Guérin (BCG), but many will progress or recur, and some T1 patients will
die from bladder cancer. Particularly aggressive tumors could be treated with early
cystectomy. To better understand the molecular heterogeneity of T1 cancers, we performed
transcriptome profiling and unsupervised clustering, and identified five consensus
subtypes of T1 tumors treated with repeat transurethral resection (reTUR) and induction
and maintenance BCG. The T1-LumGU subtype was associated with carcinoma in situ (CIS;
six/13, 46% of all CIS), had high E2F1 and EZH2 expression, and was enriched in E2F
target and G2M checkpoint hallmarks. The T1-Inflam subtype was inflamed and infiltrated
with immune cells. While most T1 tumors were classified as luminal papillary, the
T1-TLum subtype had the highest median luminal papillary score and FGFR3 expression,
no recurrence events, and the fewest copy number gains. T1-Myc and T1-Early subtypes
had the most recurrences (14/30 within 24 mo), the highest median MYC expression,
and, when combined, had significantly worse recurrence-free survival than the other
three subtypes. T1-Early had five (38%) recurrences within the first 6 mo of BCG,
and repressed IFN-α and IFN-γ hallmarks and inflammation. We developed a single-patient
T1 classifier and validated our subtype biology in a second cohort of T1 tumors. Future
research will be necessary to validate the proposed T1 subtypes and to determine if
therapies can be individualized for each subtype. PATIENT SUMMARY: We identified and
characterized expression subtypes of high-grade stage T1 bladder cancer that are biologically
heterogeneous and have variable responses to bacillus Calmette-Guérin treatment. We
validated the subtypes and describe a single-patient classifier.
</p>