MSKCC High-Grade Bladder Cancer 2012 (Solit)

Overview

Multi-platform integrated genomic study of 97 high-grade urothelial carcinomas of the bladder assembled at Memorial Sloan Kettering Cancer Center, published in 2013 by Iyer, Solit and colleagues. The dataset underpins the cBioPortal study blca_mskcc_solit_2012 and was built to catalogue potentially actionable genomic alterations across the RTK–RAS–RAF, PI3K/AKT/mTOR, and G1–S cell-cycle pathways. 61% of tumors harbored at least one such alteration.

Composition

  • Cancer type: BLCA — high-grade urothelial carcinoma of the bladder.
  • Samples: 97 tumors (94 cystectomy, 1 nephroureterectomy, 2 TURBT); macro-dissected to ≥60% tumor content.
  • Demographics: median age 73 (range 42–89); 72 male / 25 female.
  • Stage (95 evaluable): pTa/pTis 4, I 11, II 15, III 33, IV 32; 34 (35%) received neoadjuvant chemotherapy.
  • Histology: 57 (59%) TCC NOS; 30 (31%) TCC with minor variant components; 10 (10%) predominantly neuroendocrine.
  • Comparator: 285 consecutively treated MSKCC patients (cystectomy 2007–2010) with comparable median overall survival (38 vs 35.2 months; P=.19).
  • Reference genome: NCBI build 36.1 (hg18). PMID:23897969

Assays / panels (linked)

  • array-cgh-agilent-1m — Agilent 1M human oligonucleotide aCGH; co-hybridized with reference normal DNA; segmented by circular binary segmentation; analyzed with the RAE algorithm at FDR <1%.
  • sequenom-genotyping — mass-spectrometry iPLEX hotspot genotyping panel covering recurrent oncogene/tumor-suppressor hotspots.
  • sanger-sequencing — all coding exons of 15 selected oncogenes/tumor suppressors.
  • illumina-microarray — Illumina HumanHT-12 expression BeadChip, quantile-normalized.

Papers using this cohort

  • PMID:23897969 — Iyer G et al., “Prevalence and Co-Occurrence of Actionable Genomic Alterations in High-Grade Bladder Cancer”, J Clin Oncol 2013.

Notable findings derived from this cohort

  • 61% (59/97) of high-grade bladder tumors harbored at least one potentially actionable alteration — defined as a validated drug target in another tumor type or a target with an inhibitor in clinical investigation. PMID:23897969
  • Unsupervised hierarchical clustering of aCGH data identified two subsets (high-CNA-burden vs low-CNA-burden); high-burden bladder tumors ranked second only to serous ovarian in structural-aberration load across 14 reference tumor types (n=5,135). PMID:23897969
  • TP53 mutations (34%) and RB1 alterations (15%) were significantly enriched in high-CNA-burden tumors (P<.001 and P<.003). PMID:23897969
  • ERBB2 was focally amplified in 6.2% (6/97) with concordant mRNA up-regulation and 3+ HER2 IHC; E2F3 amplified in 21% (vs 4.9% across 1,932 non-urothelial epithelial tumors). PMID:23897969
  • RTK–RAS–RAF pathway altered in 35% of samples; PI3K/AKT/mTOR pathway in 30% — with TSC1-null tumors resistant to MK-2206 despite AKT inhibition. PMID:23897969

Sources

  • cBioPortal study: blca_mskcc_solit_2012
  • PMID:23897969 — primary publication

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