Yoshikawa Masahiro, Nakayama Tomohiro, Asaba Kensuke
Division of Laboratory Medicine, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan.
Department of Computational Diagnostic Radiology and Preventive Medicine, The University of Tokyo Hospital, Tokyo, Japan.
Commun Biol. 2024 Dec 19;7(1):1681. doi: 10.1038/s42003-024-07403-y.
Skin cancer is one of the most common cancers worldwide. Some risk factors including sun exposure and MC1R variants are recognized; however, the identification of additional genetic factors is essential for the development of novel therapeutic strategies. Here, we conducted a proteome-wide Mendelian randomization (MR) using plasma protein quantitative trait loci (pQTLs) from a published study and the UK Biobank genome-wide association study (GWAS) of skin cancers. We replicated the published result of ASIP, which was significantly associated with increased risks of basal cell carcinoma (BCC) and malignant melanoma. Moreover, we newly identified CTSS, which was significantly associated with a decreased risk of BCC. A series of replication analyses using the DeCODE pQTLs and the FinnGen GWAS, and sensitivity analyses including Steiger filtering, reverse MR, and Bayesian colocalization, supported our primary results. Our findings highlighted the possibility of prioritizing proteins for novel therapeutic or preventive targets and biomarkers for skin cancers.
皮肤癌是全球最常见的癌症之一。一些风险因素，包括阳光暴露和黑素皮质素受体1（MC1R）基因变异已为人所知；然而，识别其他遗传因素对于开发新的治疗策略至关重要。在此，我们利用一项已发表研究中的血浆蛋白定量性状位点（pQTL）以及英国生物银行皮肤癌全基因组关联研究（GWAS）进行了全蛋白质组孟德尔随机化（MR）分析。我们重复了已发表的阿黑皮素原（ASIP）研究结果，该基因与基底细胞癌（BCC）和恶性黑色素瘤风险增加显著相关。此外，我们新发现了组织蛋白酶S（CTSS），它与BCC风险降低显著相关。使用迪科德（DeCODE）pQTL和芬兰基因库（FinnGen）GWAS进行的一系列重复分析，以及包括斯泰格（Steiger）过滤、反向MR和贝叶斯共定位在内的敏感性分析，均支持了我们的主要结果。我们的研究结果凸显了将蛋白质优先作为皮肤癌新治疗或预防靶点以及生物标志物的可能性。
