Somatic immune system gene variants predict the survival time of patients with cutaneous melanoma, and might augment existing clinical and pathologic prognostic tools, report researchers at New York University’s Langone Medical Center and Perlmutter Cancer Center.
Somatic immune system gene variants predict the survival time of patients with cutaneous melanoma, and might augment existing clinical and pathologic prognostic tools, report researchers at New York University’s Langone Medical Center and Perlmutter Cancer Center. Their findings were reported online ahead of print in Clinical Cancer Research.
“There are gene variants that we inherit from our parents that don’t increase our susceptibility to developing melanoma, but once the disease strikes, they can alter outcome,” explained senior study author Tomas Kirchhoff, PhD, an assistant professor at the Department of Population Health at NYU Langone, in a NYU press release. “We hypothesized that if somebody inherits a certain genetic variant that suppresses immunity, there is a much higher chance that once melanoma strikes, it will progress faster.”
The researchers conducted whole-genome expression quantitative trait loci (eQTL) testing to identify 385 single nucleotide polymorphisms (SNPs) that impact expression of 268 immune-relevant genes, they reported. They then tested the 40 “most significant” lymphocyte-specific eQTLs variants-those variants exhibiting the strongest correlations with activation of immune pathway genes-in a prospective cohort of 1,221 patients diagnosed with cutaneous melanoma, to test how well these gene variants predict patient overall survival (OS) time.
“We identified highly significant associations with better melanoma OS for rs6673928, impacting IL19 expression (hazard ratio [HR] 0.56, 95% CI: .41-.77; P = .0002) and rs6695772, controlling the expression of BATF3 (HR 1.64, 95% CI: 1.19-2.24; P = .0019),” they reported in the journal.
Both variants are found in a region of chromosome 1 that also contains a cluster of interleukin genes known to regulate immune response, the team reported. They hypothesize that the SNPs “impact balanced activation” of interleukin genes IL10 and IL19, allowing melanoma to progress toward more aggressive and metastatic phenotypes.
“This imbalanced immunity determines, or modulates, melanoma survival,” Dr. Kirchhoff proposed.
The combined effect of rs6673928 and rs6695772 SNPs on melanoma OS “substantially enhanced reaching the level of clinical applicability (HR 1.92, 95% CI: 1.43-2.6; P = 2.38e-5),” the study team reported.
“Our unique approach to interrogating lymphocyte-specific eQTLs reveals novel and biologically-relevant immunomodulatory eQTL predictors of cutaneous melanoma prognosis that are independent of current histopathological markers,” they concluded. “The significantly enhanced combined effects of identified eQTLs suggests the personalized utilization of both SNPs in a clinical setting, strongly indicating the promise of the proposed design for the discovery of prognostic or risk germline markers in other cancers.”