Genomic testing for copy number aberrations (CNAs) at diagnosis is used to predict the risk of metastasis in patients with uveal melanoma (UM). However, UM is a rare disease, and small cohort sizes hinder the identification of infrequent CNAs that have prognostic ability. Researchers from the University of Pennsylvania performed a large-scale genome-wide analysis of CNAs and identified deletions in chromosomes 1p and 16q as low-frequency CNAs associated with an increased risk of metastasis in patients with UM.1
“Our findings suggest that, although 1p and 16q deletions are uncommon, they strongly increase the risk of metastasis in patients with UM,” said Arupa Ganguly, PhD. She added that testing for deletions in chromosomes 1p and 16q should be incorporated into clinical practice to identify patients who are at a high risk of metastasis. “Knowing this information is key for optimization of clinical management.”
Study rationale. CNAs in chromosomes 1p, 3, 6, and 8 can be used to assess prognosis in patients with UM. However, identifying low-frequency CNAs with prognostic value is challenging because of the rarity of UM. “To identify low-frequency CNAs with prognostic value, we conducted genome-wide CNA profiling of 921 primary tumors and 19 metastatic tumors from patients with UM,” Dr. Ganguly said. The patients were referred to the University of Pennsylvania for genetic testing between 2008 and 2016.
Low-frequency prognostic CNAs. “Although aberrations in 16q have been previously reported in UM, their prognostic ability remained unclear,” Dr. Ganguly pointed out. “By profiling CNAs in a large cohort of patients, we were able to confirm the prognostic significance of 16q deletion, which was associated with a high risk of metastasis.” Although 16q deletion was observed in only 9.3% of patients, patients with this CNA had the worst outcomes.1
New molecular subtypes. Traditionally, UMs are classified into four molecular subtypes using standard prognostic CNAs. However, inclusion of chromosome 16q deletion revealed a rare but clinically relevant molecular subtype that cannot be captured by standard CNAs. “Analyzing a large number of tumors enabled us to uncover additional genomic drivers of UM and improve the accuracy of molecular tumor subtypes,” Dr. Ganguly said.
Identification of an ultra–high-risk patient group. By analyzing outcomes in a large cohort of patients with UM, the researchers were able to identify a small subgroup of patients who had a very high rate of metastasis, Dr. Ganguly said. Primary tumors from these patients harbored chromosome 3 monosomy, chromosome 8q amplification, and 1p or 16q deletion. “Although this subpopulation of patients represents less than 10% of the entire cohort, the four-year metastasis rate in this group is nearly twice as high as the rate in the second-highest risk group,” she said.
Next steps. The findings need to be clinically validated in large multicenter studies, Dr. Ganguly said. “We also plan to conduct mechanistic studies to assess how CNAs contribute to metastasis in UM,” she added.
—Christos Evangelou, PhD
1 Lalonde E et al. Ophthalmol Sci. 2022;2:100121.
Relevant financial disclosures: Dr. Ganguly—None.
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Full Financial Disclosures
Dr. Acharya NEI: S.
Dr. Ganguly None.
Dr. Lin None.
Dr. Patel AbbVie: C; Aerie: P; Emmecell: C; GlaxoSmithKline: C; Iris Medicine: P.
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