Emilie Lalonde received her PhD from the University of Toronto and completed ABMGG Molecular Genetics and Cytogenetics fellowships at the University of Pennsylvania and Children’s Hospital of Philadelphia. She is current a clinical molecular geneticist and cytogeneticist at the Detroit Medical Center. Her interests lie in the integration of molecular, cytogenetic and bioinformatics techniques for improved diagnostics of inherited and somatic diseases, and in assessing the clinical impact of molecular and cytogenetic markers on clinical outcomes in cancer.
Emilie Lalondea, Kathryn Ewensb, Jennifer Richards-Yutzb, Jessica Ebrahimzedehb, Mizue Teraic, Carin F. Gonsalvesc, Takami Satoc, Carol L. Shieldsd, Arupa Gangulyb
aDetroit Medical Center, Detroit, MI, USA; bUniversity of Pennsylvania, Philadelphia, PA, USA; cThomas Jefferson University, Philadelphia, PA, USA; dWills Eye Hospital, Thomas Jefferson University, Philadelphia, PA, USA
Background: Metastatic uveal melanoma (mUM) develops in 25-50% of uveal melanoma (UM) patients, followed rapidly by UM-mortality. UM is genetically heterogeneous and evaluation of copy number aberrations (CNAs) at diagnosis is used to predict metastatic risk. This study evaluated the genomic and clinical heterogeneity within established CNA subtypes of UM, and aimed to refine these subtypes based on CNA profiling in a large patient cohort.
Methods: Genome-wide CNAs were generated for primary tumors from 921 patients with a median time to metastasis of 4.5 years, and for 19 mUM to the liver. The prognostic effect of individual CNAs and multiple CNA clustering strategies, including more specific molecular subgroups with rare CNAs, were evaluated. The TCGA cohort was used to confirm findings.
Results: Genomic profiling demonstrated a strong association between chromosomal instability and patient prognosis, and confirmed a strong prognostic effect of 16q deletions. Using standard prognostic CNAs, six clusters were detected, while inclusion of 16q deletion revealed an additional cluster. Of these seven genomic clusters, there were five patient groups with distinct rates of metastasis. One ‘ultra-high-risk’ subtype, accounting for ~8% of patients, had a significantly higher rate of metastasis compared to even the second-highest risk group (88% vs. 45%) and was characterized by monosomy 3, 8q amplification, and deletion of 1p or 16q.
Conclusions: Deletions of 1p and 16q should be incorporated in clinical assays to assess prognosis at diagnosis, and to guide enrollment in clinical trials for adjuvant therapies.