Chat Vylyny, Dagayev Sasha, Moran Una, Snuderl Matija, Weber Jeffrey, Ferguson Robert, Osman Iman, Kirchhoff Tomas
Perlmutter Cancer Center, New York University School of Medicine, New York, NY, United States.
Department of Population Health and Environmental Medicine, New York University School of Medicine, New York, NY, United States.
Front Oncol. 2023 Jan 19;12:1050741. doi: 10.3389/fonc.2022.1050741. eCollection 2022.
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.
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.
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; and rs77480547 in SH3BP4: HR=3.02 (2.02-4.52), p=7.58×10, 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.
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.
皮肤黑色素瘤（CM）的高死亡率部分归因于早期病变患者疾病进展模式的不可预测性。从早期CM可靠预测晚期疾病风险是一项紧迫的临床需求，特别是考虑到免疫检查点抑制剂疗法最近已扩展到辅助治疗领域。在我们的研究中，我们全面调查了种系变异作为CM预后标志物的作用。
我们在两个独立队列中进行了全基因组关联分析，一个队列有N = 551名（发现队列）、另一个队列有N = 550名（验证队列）未经免疫治疗的早期黑色素瘤患者。使用多变量Cox比例风险回归模型在发现队列中确定与总生存期的关联，随后进行验证分析。转录组分析和生存分析用于阐明与CM进展相关的候选基因的生物学相关性。
我们发现种系变异与黑色素瘤预后有两个独立关联。这两个单核苷酸多态性（SNP）的替代等位基因均与死亡风险增加相关[在MELK基因中的rs60970102：风险比（HR）= 3.14（2.05 - 4.81），p = 1.48×10；在SH3BP4基因中的rs77480547：HR = 3.02（2.02 - 4.52），p = 7.58×10，均在合并队列中]。与仅包含临床协变量的模型相比，将所鉴定变异的联合风险等位基因（CRA）纳入预后模型可提高预测能力。
我们的研究为新的黑色素瘤种系预后标志物提供了提示性证据，涉及两个候选基因：一个癌基因MELK和一个肿瘤抑制基因SH3BP4，此前均提示它们会影响CM进展。在进一步验证之前，这些发现表明遗传因素可能改善高危早期CM患者的预后分层，并为针对这些靶点进行潜在治疗研究以预防早期黑色素瘤的侵袭性结局提供假定的生物学见解。
