Multicenter proteome-wide Mendelian randomization study identifies causal plasma proteins in melanoma and non-melanoma skin cancers

Sep 21, 2026

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A multicenter Mendelian randomization framework identifies circulating plasma proteins causally linked to malignant melanoma and non-melanoma skin cancer traits. Large-scale cis-MR estimates protein effects across MM, NMSC, squamous cell carcinoma, and basal cell carcinoma, with robustness supported by MR Steiger, Bayesian colocalization, and replication via meta-analytical methods. Tissue-level validation uses Transcriptome-Wide Association Study analyses, followed by protein-protein interaction profiling to connect prioritized proteins with existing cancer drug targets. The MR results implicate 13 proteins for BCC, 2 for SCC, and 1 for MM, nominating ASIP, KRT5, CTSS, and TNFSF8 as diagnostic and therapeutic candidates.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

Introduction

Background and clinical challenges

Rationale for protein biomarkers

Methods

Mendelian randomization framework

Validation and druggability analyses

Results

Causal proteins by cancer subtype

communications biology Article [https://doi.org/10.1038/s42003-024-06538-2](https://doi.org/10.1038/s42003-024-06538-2) Multicenter proteome-wide Mendelian randomization study identiﬁes causal plasma proteins in melanoma and non-melanoma skin cancers Check for updates Yajia Li 1,2, Qiangxiang Li2, Ziqin Cao 2,3,4 & Jianhuang Wu 2,3,4 This study addresses the diagnostic and therapeutic challenges in malignant melanoma (MM) and non-melanoma skin cancers(NMSC). We aim to identify circulating proteins causally linked toMMand NMSC traits using a multicenter Mendelian randomization (MR) framework. We utilized large-scale cis-MR to estimatethe impact of numerous plasma proteins on MM, NMSC, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC). To ensure robustness, additional analyses like MR Steiger and Bayesian colocalization are conducted, followed by replication through meta-analytical methods. The associations between identiﬁed proteins and outcomes are also validated at the tissue level using Transcriptome-Wide Association Study methods. Furthermore, a protein-protein interaction analysis is conducted to explore the relationship between identiﬁed proteins and existing cancer medication targets. The MR analysis has identiﬁed associations of 13 plasma proteins with BCC, 2 with SCC, and 1 with MM. Speciﬁcally, ASIP and KRT5 are associated with BCC, with ASIP also potentially targeting MM. CTSS and TNFSF8 are identiﬁed as promising druggability candidates for BCC. This multidimensional approach nominates ASIP, KRT5, CTSS, and TNFSF8 as potential diagnostic and therapeutic targets for skin cancers. Skin cancer is the ﬁfth most common cancer type and rates are predicted to rise sharply over the next 20 years1–4. Malignant melanoma (MM) arises when mutations occur in melanocytes. It is highly invasive and metastatic and accounts for around 75% of skin cancer-related deaths despite representing only 4% of all skin cancers5,6. Non-melanoma skin cancer (NMSC) develops from the epidermis and may be subdivided into squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). It is the most frequently occurring form of skin cancer and is considered curable at an early stage, although the identiﬁcation of novel drugs, clinical success, and drug resistance present challenges7. On the one hand, traditionally, screening via imaging and pathology tests has had limited effectiveness in early-stage detection. On the other hand, until date, the main treatments for MM and NMSC, including surgery, chemotherapy, radiotherapy, photothermal therapy, etc, are often painful and can have negative consequences, rarely resulting in cancer eradication8,9. Current treatments often fail to speciﬁcally target cancer cells, resulting in only modest extensions in survival for advanced MM or NSMC patients1, 10–13. Such therapies frequently impact healthy cells without adequately targeting cancerous ones13–15. Skin cancer’s complexity and cellular heterogeneity lead to varied progression and metastasis, driven by the dysregulation at multiple targeting sites. Recent advancements in targeted therapies offer promising alternatives, utilizing drugs that directly inhibit speciﬁc molecules or pathways critical to cancer cells, like BRAF16. However, the myriad skin cancer subtypes and emerging drug resistances continue to complicate achieving a comprehensive cure with a single therapeutic approach17, 18. Therefore, developing innovative strategies for early detection and treatment remains critical to addressing these challenges in managing MM and NSMC. Plasma proteins mediate signaling, transportation, growth, repair, and defense against infections. Many are also cancer biomarkers, enabling early diagnosis, prognostic evaluation, and treatment monitoring19,20. Immune checkpoint inhibitors (ICIs) are effective in treating MM and NMSC but only a small proportion of patients respond to them21–24. Biomarkers, such as 1Department of Dermatology,

FAQs

What is the main goal of the multicenter Mendelian randomization study?

To identify circulating plasma proteins that are causally associated with traits of malignant melanoma and non-melanoma skin cancers using integrated GWAS and pQTL data.

How is causal evidence strengthened in the study?

By using large-scale cis-MR and performing additional robustness analyses such as MR Steiger and Bayesian colocalization, then replicating findings through meta-analytical methods.

Which plasma proteins are highlighted as potential diagnostic and therapeutic targets?

ASIP, KRT5, CTSS, and TNFSF8 are nominated as potential targets based on the multidimensional analyses, including protein-protein interaction and druggability considerations.

Sep 21, 2026

Uploaded by Aria