Genomic Predictors of Survival in Patients with High-Grade Urothelial Carcinoma of the Bladder

Authors

Philip H. Kim

Eugene K. Cha

John P. Sfakianos

Gopa Iyer

Emily C. Zabor

Sasinya N. Scott

Irina Ostrovnaya

Ricardo Ramirez

Arony Sun

Ronak Shah

Alyssa M. Yee

Victor E. Reuter

Dean F. Bajorin

Jonathan E. Rosenberg

Nikolaus Schultz

Michael F. Berger

Hikmat A. Al-Ahmadie

David B. Solit

Bernard H. Bochner

Doi

10.1016/j.eururo.2014.06.050

PMID: 25092538 · DOI: 10.1016/j.eururo.2014.06.050 · Journal: European Urology (2015)

TL;DR

Kim et al. performed capture-based, massively-parallel sequencing (MSK-IMPACT) on 109 high-grade urothelial carcinomas of the bladder (BLCA) to identify prognostic genomic markers. In the 89-patient subset treated with radical cystectomy, recurrent PIK3CA missense mutations were associated with improved recurrence-free and cancer-specific survival, while CDKN2A alterations independently predicted worse outcomes. TP53 mutations (57% of tumors) tracked with locally advanced and node-positive disease but did not retain prognostic significance after adjustment for stage. Chromatin-modifying gene mutations were highly prevalent (83%) but not prognostic.

Cohort & data

  • 109 patients with high-grade urothelial carcinoma of the bladder (BLCA); 89-patient subset analyzed for prognostic associations were those whose tumors were obtained at radical cystectomy.
  • Tumor + matched germline blood sequenced using MSK-IMPACT capture-based targeted DNA-seq.
  • Mean coverage 579× across targeted exons; average of 10 mutations per tumor (range 0–46).
  • Orthogonal sequencing of all coding exons of STAG2, KDM6A, ARID1A, and KMT2D (MLL2) confirmed 99.3% of MSK-IMPACT mutation calls.
  • Dataset: blca_mskcc_solit_2014.

Key findings

  • Mutations were detected in 240 genes total, with 23 genes mutated in ≥5% of cases PMID:25092538.
  • TP53 mutation was the most common alteration (62/109; 57%); more common in extravesical vs. organ-confined disease (69% vs. 32%, p=0.005) and in lymph node-positive vs. node-negative disease (77% vs. 56%, p=0.025).
  • Cell-cycle (S-phase entry) alterations present in 46% of tumors; chromatin-modifying gene mutations present in 83%.
  • KDM6A mutated in 45/109 (41%), 41/45 truncating.
  • ARID1A altered in 28% (30/31 truncating); mutually exclusive with SMARCA4 alterations.
  • CREBBP (13%) and EP300 (15%) showed mutually exclusive truncating mutation patterns.
  • PI3K/AKT pathway alterations identified in 38/109 (35%); PIK3CA recurrent missense mutations in 23/109 (21%), predominantly activating helical-domain mutations. Other PI3K/AKT pathway hits: PTEN 6%, AKT1 2%, TSC1 6%.
  • In the 89-patient radical cystectomy cohort, recurrent PIK3CA mutation was associated with improved recurrence-free survival (RFS; HR=0.35, p=0.014) and cancer-specific survival (CSS; HR=0.35, p=0.040).
  • Analyzing PI3K/AKT pathway as a functionally related group: RFS HR=0.34 (p=0.006); CSS HR=0.29 (p=0.01).
  • In multivariable analyses controlling for pT stage and nodal involvement: PIK3CA mutation HR=0.39, p=0.032 for RFS; PI3K/AKT pathway alteration HR=0.37, p=0.017 for RFS.
  • CDKN2A alterations independently associated with worse outcomes in multivariable analyses: RFS HR=5.76 (p<0.001); CSS HR=2.94 (p=0.029).
  • p53 pathway alterations: univariate RFS HR=1.92 (p=0.048) and CSS HR=2.94 (p=0.013), but not significant after adjustment for pT/pN.
  • Chromatin-modifying gene mutations highly prevalent (83%) but not associated with outcomes.
  • STAG2 mutations not associated with outcomes in this cohort.
  • Even among PIK3CA-mutant patients, 5-year disease recurrence rate was 44%.

Genes & alterations

  • PIK3CA — recurrent activating helical-domain missense mutations in 21% of tumors; associated with favorable RFS/CSS after radical cystectomy.
  • TP53 — mutation in 57% of tumors; enriched in extravesical and node-positive disease; worse univariate outcomes that did not survive stage adjustment.
  • CDKN2A — alterations independently associated with worse RFS (HR=5.76) and CSS (HR=2.94).
  • KDM6A — truncating mutations in 41% of tumors; not associated with outcomes.
  • ARID1A — truncating alterations in 28%; mutually exclusive with SMARCA4.
  • CREBBP and EP300 — mutually exclusive truncating mutations (13% and 15%).
  • STAG2 — mutations present, but no outcome association in this cohort (contradicts some prior reports, agrees with others).
  • KMT2D (MLL2) — included as one of four CMGs validated by orthogonal sequencing (99.3% concordance).
  • PTEN, AKT1, TSC1 — recurrent mutations in PI3K/AKT pathway (6%, 2%, 6% respectively).

Clinical implications

  • PIK3CA mutation / PI3K/AKT pathway alteration status may identify BLCA patients with favorable post-cystectomy outcomes, providing rationale for adjuvant trials of selective PI3-kinase inhibitors in this genetically defined subset (note: 44% 5-year recurrence rate even in PIK3CA-mutant patients).
  • CDKN2A alterations identify a high-risk genomic subgroup; authors propose rationale for studies of selective CDK4 inhibitors in this group.
  • TP53 mutation status reflects locally advanced/node-positive disease but does not provide independent prognostic information beyond pT/pN stage.
  • Genomic profiling may aid identification of UCB patients at highest risk following radical cystectomy.

Limitations & open questions

  • Sample size limited given the genomic heterogeneity of bladder cancer.
  • Single-site sampling per tumor may underestimate intratumoral genetic heterogeneity.
  • Targeted capture panel does not detect less frequently mutated genes, most structural alterations, epigenetic changes, or expression differences.
  • Findings pending validation in a larger and more comprehensive cohort.
  • Authors note that prior literature on STAG2 prognostic significance in UCB is contradictory (PMID:24121792 reported worse survival with STAG2 alterations; this study found no association).
  • Why are chromatin-modifying gene mutations near-universal in UCB (83%) yet not prognostic? Authors speculate they may be necessary early events in pathogenesis.

Citations from this paper used in the wiki

  • “Mutations were detected in 240 genes, with 23 genes mutated in ≥5% of cases.” (Abstract)
  • “The presence of a recurrent PIK3CA mutation was associated with improved recurrence-free survival (RFS; HR=0.35, p=0.014) and cancer-specific survival (CSS; HR=0.35, p=0.040) in patients treated with radical cystectomy.” (Abstract)
  • “In multivariable analyses controlling for pT and pN stages, PIK3CA mutation remained associated with RFS (HR=0.39, p=0.032).” (Abstract)
  • “The most frequent alteration, TP53 mutation (57%), was more common in extravesical (69% vs. 32%, p=0.005) and lymph node-positive (77% vs. 56%, p=0.025) disease.” (Abstract)
  • “Patients with CDKN2A altered tumors experienced worse RFS (HR=5.76, p<0.001) and CSS (HR=2.94, p=0.029) in multivariable analyses.” (Abstract / Results)
  • “KDM6A was mutated in 45 patients (41%), with 41/45 truncating mutations. ARID1A alterations (28%), similarly enriched for truncating mutations (30/31), were mutually exclusive with SMARCA4 alterations…” (Results)
  • “We identified PI3K/AKT pathway alterations in 38 patients (35%) … Recurrent missense mutations in PIK3CA … in 23 patients (21%)…” (Results)
  • “Although relatively favorable, UCB patients with PIK3CA mutant tumors still experienced a significant rate of disease recurrence (44% at 5 years).” (Discussion)
  • “Tissue samples and matched germline blood from 109 patients with high-grade UCB were sequenced using MSK-IMPACT…” (Methods, Results)

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