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. 2023 Jan 19:12:1050741.
doi: 10.3389/fonc.2022.1050741. eCollection 2022.

A genome-wide association study of germline variation and melanoma prognosis

Vylyny Chat  1   2   3 , Sasha Dagayev  1   2   3 , Una Moran  1   3 , Matija Snuderl  4 , Jeffrey Weber  1   3 , Robert Ferguson  1   2   3 , Iman Osman  1   3   5 , Tomas Kirchhoff  1   2   3
Affiliations

A genome-wide association study of germline variation and melanoma prognosis

Vylyny Chat et al. Front Oncol. .

Abstract

Background: The high mortality of cutaneous melanoma (CM) is partly due to unpredictable patterns of disease progression in patients with early-stage lesions. The reliable prediction of advanced disease risk from early-stage CM, is an urgent clinical need, especially given the recent expansion of immune checkpoint inhibitor therapy to the adjuvant setting. In our study, we comprehensively investigated the role of germline variants as CM prognostic markers.

Methods: We performed a genome-wide association analysis in two independent cohorts of N=551 (discovery), and N=550 (validation) early-stage immunotherapy-naïve melanoma patients. A multivariable Cox proportional hazard regression model was used to identify associations with overall survival in the discovery group, followed by a validation analysis. Transcriptomic profiling and survival analysis were used to elucidate the biological relevance of candidate genes associated with CM progression.

Results: We found two independent associations of germline variants with melanoma prognosis. The alternate alleles of these two SNPs were both associated with an increased risk of death [rs60970102 in MELK: HR=3.14 (2.05-4.81), p=1.48×10-7; and rs77480547 in SH3BP4: HR=3.02 (2.02-4.52), p=7.58×10-8, both in the pooled cohort]. The addition of the combined risk alleles (CRA) of the identified variants into the prognostic model improved the predictive power, as opposed to a model of clinical covariates alone.

Conclusions: Our study provides suggestive evidence of novel melanoma germline prognostic markers, implicating two candidate genes: an oncogene MELK and a tumor suppressor SH3BP4, both previously suggested to affect CM progression. Pending further validation, these findings suggest that the genetic factors may improve the prognostic stratification of high-risk early-stage CM patients, and propose putative biological insights for potential therapeutic investigation of these targets to prevent aggressive outcome from early-stage melanoma.

Keywords: cancer survival; cutaneous melanoma; genome-wide association study; prognostic biomarkers; single nucleotid polymorphisms.

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Conflict of interest statement

JW owns stock or other ownership at Altor BioScience, Biond, CytomX Therapeutics, received honoraria from Bristol-Myers Squibb, Merck, Genentech, AbbVie, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Eisai, Altor BioScience, Amgen, Roche, Ichor Medical Systems, Celldex, CytomX Therapeutics, Nektar, Novartis, Sellas, WindMIL, Takeda, has consulting/advisory role at Celldex, Ichor Medical Systems, Biond, Altor BioScience, Bristol-Myers Squibb, Merck, Genentech, Roche, Amgen, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo, AbbVie, Eisai, CytomX Therapeutics, Nektar, Novartis, Sellas, WindMIL, Takeda, and obtained research funding to the Institution from Bristol-Myers Squibb, Merck, GlaxoSmithKline, Genentech, Astellas Pharma, Incyte, Roche, Novartis and received funding for travel/accommodations/expenses from Bristol-Myers Squibb, GlaxoSmithKline, Daiichi Sankyo, Roche, Celldex, Amgen, Merck, AstraZeneca, Genentech, Novartis, WindMIL, Takeda. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Kaplan-Meir survival (KM) curves, percentage of overall mortality, and estimated Area under the Curve (AUC) of the combined effect of rs77480547 and rs60970102 on CM OS detected in the GWAS study. Panel (A) plotted the survival curves of patients stratified by low risk (CRA=0), medium risk (CRA=1) and high risk (CRA>1) groups. We noted a clear dosage pattern of CRA effect on OS, further illustrated in Panel (B) by the linear increase in proportion of death as the CRA increased, for both local (stage I-II) and regional (stage III) disease over the median 5.8 year follow-up time. Panel (C) showed a statistically significant improvement in the estimated 10-year AUC (pooled cohort) as we incorporated CRA into the predictive model compared to the model of demographic and clinical variables alone (p=0.007).
Figure 2
Figure 2
Transcriptomic profiling of the candidate gene expressions and melanoma progression. Panel (A+C) showed the expression of MELK and SH3BP4 comparing adjacent normal vs. primary vs. metastatic tumor tissues [adapted from tnmplot.com (45)]. Panel (B+D) plotted Kaplan-Meir survival curves [adapted from the Human Protein Atlas (46)] of early-stage CM patients with low vs. high expression of MELK and SH3BP4 in primary tumors. High expression of MELK was associated with worse OS (log-rank p=0.059), while the inverse trend was observed for SH3BP4 (albeit not statistically significant p=0.14), reflecting their roles as an oncogene and a tumor suppressor, respectively.
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