Inherited genetic markers may predict melanoma survival

February 26, 2016

Abstract

Purpose
The identification of personalized germline markers with biological relevance for the prediction of cutaneous melanoma (CM) prognosis is highly demanded but to date it has been largely unsuccessful. As melanoma progression is controlled by host immunity, here we present a novel approach interrogating immunoregulatory pathways using the genome-wide maps of expression quantitative trait loci (eQTL) to reveal biologically relevant germline variants modulating CM outcomes.

Experimental design
Using whole genome eQTL data from a healthy population, we identified 385 variants -significantly impacting the expression of 268 immune-relevant genes. The 40 most significant eQTLs were tested in a prospective cohort of 1,221 CM patients for their association with overall (OS) and recurrence-free survival using Cox regression models.

Results
We identified highly significant associations with better melanoma OS for rs6673928, impacting IL19 expression (HR 0.56, 95% CI 0.41-0.77; P= 0.0002) and rs6695772, controlling the expression of BATF3 (HR 1.64, 95% CI 1.19-2.24; P= 0.0019). Both associations map in the previously suspected melanoma prognostic locus at 1q32. Furthermore, we show that their combined effect on melanoma OS is substantially enhanced reaching the level of clinical applicability (HR 1.92, 95% CI 1.43-2.60; P= 2.38e-5).

Conclusions
Our unique approach of interrogating lymphocyte-specific eQTLs reveals novel and biologically relevant immunomodulatory eQTL predictors of CM prognosis that are independent of current histopathological markers. The significantly enhanced combined effect 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.

Sources:

Vogelsang, M, et al. The expression quantitative trait loci in immune pathways and their effect on cutaneous melanoma prognosis. Clinical Cancer Research. Published Online First January 5, 2016; doi: 10.1158/1078-0432.CCR-15-2066 http://clincancerres.aacrjournals.org/content/earl...

New York University Media Release: Inherited genetic markers may predict melanoma survival -- and help plot course of disease http://www.eurekalert.org/pub_releases/2016-01/nlm...