Page 95 - EJMO-9-3

Eurasian Journal of
Medicine and Oncology Novel senescence-based melanoma risk model

1. Introduction immune profiles and survival outcomes. 11,15 The Cancer
Genome Atlas (TCGA) database provides comprehensive
Skin cutaneous melanoma (SKCM), a highly lethal skin multi-omics data and clinical information across a broad
cancer originating from melanocytes, is a major global spectrum of tumor samples, including melanoma, and
health concern. Ultraviolet radiation and senescence are serves as a valuable resource for identifying potential
significant factors contributing to melanoma development, prognostic biomarkers and understanding the molecular
which has a higher incidence in males. In recent years, basis of cancer. 16,17 Several studies have used transcriptomic
incidence rates have been rising in both male and female data from TCGA to identify genes notably linked to SKCM
populations, with a low 5-year survival rate, highlighting survival outcomes through logistic regression algorithms.
the urgency of improving diagnostic and therapeutic Using these prognostic factors, risk models have been
strategies for this disease. 1-3 developed to predict patient survival effectively, offering
An increasing amount of research has highlighted potential clinical applications. 18,19 However, despite these
the pivotal role of the immune system in melanoma advances, an optimal and widely applicable risk model for
development and therapy. Compared to other cancers, melanoma has yet to be established, and further research
melanoma is characterized by high immunogenicity, is required to refine predictive models and improve their
with extensive immune cell infiltration in the tumor accuracy.
microenvironment (TME). Immune checkpoint inhibitors Cellular senescence, a process in which proliferating
(ICIs) have significantly improved patient survival and cells permanently cease dividing, is considered one of the
are the first-line treatment for melanoma. However, 40 – hallmarks of cancer. Senescent cells exhibit a senescence-
60% of patients are resistant to this treatment. A large associated secretory phenotype (SASP), which involves
4,5
multicenter clinical study on melanoma has shown that the secretion of pro-inflammatory cytokines, chemokines,
autologous tumor-infiltrating lymphocyte (TIL) therapy and extracellular matrix-degrading proteins. 20,21 The
can significantly extend survival in patients with recurrence SASP is a complex mixture of factors that can have both
after ICI treatment. TILs, including natural killer (NK) beneficial and detrimental effects on tumor progression,
6
cells and cluster of differentiation 8-positive (CD8 ) T cells, depending on the surrounding microenvironment. On
+
22
are known to exert anti-tumor effects. Activation of NK one hand, SASP factors can disrupt tissue repair, promote
7
cells and CD8 T cells has been shown to directly mediate chronic inflammation, and create a protumorigenic
+
tumor cell killing, which can result in favorable clinical microenvironment that supports cancer growth and
outcomes. 4,8,9 Conversely, excessive accumulation of progression. Through a paracrine mechanism, senescent
immunosuppressive cells, such as regulatory T cells (Tregs) cells can induce neighboring healthy cells to become
and myeloid-derived suppressor cells, suppresses immune senescent, thereby amplifying inflammation and further
function and contributes to tumor metastasis, recurrence, facilitating tumor progression. On the other hand, cellular
23
and resistance to therapy. The balance between pro- and senescence can also act as a tumor-suppressive mechanism.
4,10
anti-tumor immune responses is essential in determining In response to oncogenic stress, senescent cells prevent the
melanoma progression and therapeutic efficacy. proliferation of precancerous cells, effectively blocking
High-throughput RNA sequencing technologies offer early-stage cancer progression. Furthermore, SASP factors
valuable insights into immune activity in SKCM and help can activate immune surveillance by recruiting immune
reveal the prognostic potential of aberrantly expressed cells to the tumor site, enhancing immune-mediated
24
immune-related genes. 11,12 For example, high expression tumor clearance, and preventing further malignancy. To
levels of genes such as granzyme B, complement C1q A characterize cellular senescence, researchers have curated
chain (C1QA), and complement C1q B chain have been numerous senescence-related genes that serve as valuable
associated with significantly longer survival in melanoma resources for investigating their association with tumor
25-27
patients. In addition, upregulated chemokines have progression and cellular senescence.
13
been linked to favorable long-term outcomes, suggesting In this study, a panel of senescence-linked genes was
the presence of an immunoactivated TME that promotes retrieved from prior literature, 25-27 and TCGA SKCM
immune surveillance and tumor clearance. However, no transcriptome and survival data were obtained from the
14
clinically validated prognostic biomarkers are currently UCSC Xena database. The samples were divided into a
available. Recent studies have highlighted the high molecular training and validation set. In the training set, prognostic
heterogeneity of melanoma, which can complicate the senescence-related genes were identified, and cancer
identification of robust biomarkers and therapeutic targets. subtypes with significantly different survival outcomes
By analyzing the molecular features of melanoma, SKCM were determined based on these genes. Lasso regression
can be categorized into molecular subtypes with distinct followed by multivariate Cox regression was performed

Volume 9 Issue 3 (2025) 87 doi: 10.36922/ejmo.8574