SUO 2017: Update on The Cancer Genome Atlas (TCGA)

Washington, DC ( Much of what we have learned about the genomic underpinnings of urothelial carcinoma (UCC) has come from analysis of The Cancer Genome Atlas. Dr. Seth Lerner presented a variety of updates on what we have learned from TCGA in the last year. Many of the points highlighted were very recently reported in a manuscript published in the journal Cell.

In the final comprehensive analysis of TCGA, we have learned that UCC is driven by 58 significantly mutated genes and 5 specific mutation signatures. Out of 412 patients in the muscle-invasive (MIBC) cohort, 31% had N+ disease, and 2.4% had M+ disease. Unfortunately, information on neoadjuvant chemotherapy is incomplete. Though this information would be very helpful in future studies, it certainly does not detract from the momentous genomic findings from the TCGA group.

5 specific subtypes have been defined based on mutation signatures. These are listed in order of increasing aggressiveness:

  1. Luminal papillary subtype – enriched with markers of cell differentiation (low CIS signature, high FGFR alteration, etc.)
  2. Luminal infiltrated – high lymphocytic infiltrate, immune marker expression, highest p53-like signature
  3. Luminal – highest uroplakins, umbrella cell origin
  4. Basal squamous – largest overall group, highest amount of squamous differentiation and most aggressive features
  5. Neuronal – Loss of p53 and RB1, neuronal differentiation and some NE tumors. WE need to better characterize this group; though it is the rarest it portents very poor outcomes.
Several groups have demonstrated that non-coding RNA may be a way to dissect differences within each of the subtypes.

Overall, TCGA analysis has demonstrated that MIBC outcomes are driven by mutation burden, mutational process, APOBEC mutation load (APOBEC is a cytidine deaminase that causes mutation clusters when overexpressed by tumors), and neoantigen load. Although these all relate to outcome, we still have much to learn regarding the biologic mechanisms by which they produce these outcomes. Identification of the genetic pathways, however, is the first step on the path to better understanding.

Lastly, Dr. Lerner presented a final slide that demonstrated an impressive number of newly-discovered biomarkers that can be used to diagnose, prognosticate, and follow patients who develop MIBC. This area is thus clearly open to future investigation. As these biomarkers continue to be defined and validated, we will hopefully have better tools to manage this disease in the near future.

Presented by: Seth Lerner, MD, Baylor College of Medicine, Waco, TX

Written by: Shreyas Joshi, MD, @ssjoshimd Fox Chase Cancer Center, Philadelphia, PA at the 18th Annual Meeting of the Society of Urologic Oncology, November 20-December 1, 2017 – Washington, DC