One challenge in clinical management of cutaneous melanoma (CM) is the limited predictability of recurrence and hence the progression to advanced stages that associate with less favorable outcomes. Aggressive follow-up care and novel adjuvant therapy strategies in early-stage patients with high-risk of recurrence would likely improve CM-specific survival and reduce mortality. We developed a genome-wide approach to identify germline genetic determinants of melanoma prognosis as putative personalized biomarkers for patients at risk of CM recurrence.
Exploring both the coding and non-coding transcribed genome we performed germline whole genome sequencing (WGS) and tumor RNA-seq on 96 CM patients with tumor/blood matched specimens. All patients were of primary stages I-IIB and of Ashkenazi Jewish ancestry to reduce genetic heterogeneity. We compared 48 patients that recurred in < 4 years versus 48 patients with recurrence in > 6 years. Univariate and multivariate logistic regression, gene-burden analysis (SKAT), and differential expression analyses of both mRNA and lncRNAs were used to identify germline regions associated with melanoma recurrence.
Several gene regions were associated with melanoma recurrence, with NEGR1 and MGST3 both passing SKAT levels of significance (p < 1e-05), and logistic regression analysis on common WGS variants found over 100 variants with significance p < 1e-03. In addition, we found 200 differentially expressed putative lncRNAs (p < 0.05). The analysis of germline WGS found rs199818927, a 1bp insertion previously associated with both NEGR1 and lncRNA LINC01360, among our top 5 most significant regression results (OR = 9.107 p = 2.31e-05).
This initial phase of our large scale whole genome scan has uncovered germline variants in several coding loci and putative lncRNAs that associate with melanoma recurrence. Most notably, we identified germline variation in a lncRNA near NEGR1, a putative tumor suppressor that has been shown to be under-expressed in advanced cancers, indicating its putative role in cancer progression to metastatic stages. We are currently expanding the patient cohorts and validating these results.
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All authors have declared no conflicts of interest.