Rashid Sarem, Usoltsev Dmitrii, Gupta Sameer, Artomov Mykyta, Tsao Hensin
Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, 02114 MA, USA.
Boston University School of Medicine, Boston, 02118 MA, USA.
Mol Clin Oncol. 2025 Jul 10;23(3):83. doi: 10.3892/mco.2025.2878. eCollection 2025 Sep.
Limited and conflicting data have been available regarding the association between inflammatory bowel disease and skin cancer. It was hypothesized that inflammatory bowel diseases [Crohn's disease (CD) and ulcerative colitis (UC)] harbor a genetically increased risk of skin cancer [skin cutaneous melanoma (SKCM), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] and performed two-sample mendelian randomization (MR) analysis using genome-wide association (GWAS) studies of European ancestry retrieved from FinnGen R8. The inverse variance weighted method was used to approximate MR effects. Sensitivity analyses including weighted median, MR-Egger and MR-pleiotropy residual sum and outlier were performed to estimate pleiotropy and heterogeneity . MR results suggest a significant causal association between UC and SKCM, (beta=0.097, P=0.0138) and UC and SCC (beta=0.171, P=0.0014). These findings were then validated using summary-level GWAS from the UK Biobank and an independent meta-analysis which demonstrated a suggestive or causal genetic association between UC and SCC (beta=0.065, P=0.036), UC and BCC (beta=0.056, P=0.002), but not UC and SKCM (beta=0.02, P=0.432). Due to limited sample size for CD instruments, only 5 significant single nucleotide polymorphisms were found with no significant causal effects on skin cancer. These results provide evidence for a causal genetic association between UC and skin cancer through shared polymorphisms involving the IL-23/Th17 axis, which may inform preventative counseling and precision medicine in the future.
关于炎症性肠病与皮肤癌之间的关联,现有数据有限且相互矛盾。研究假设炎症性肠病(克罗恩病(CD)和溃疡性结肠炎(UC))在遗传上会增加患皮肤癌(皮肤黑色素瘤(SKCM)、基底细胞癌(BCC)和鳞状细胞癌(SCC))的风险,并使用从FinnGen R8中检索到的欧洲血统全基因组关联(GWAS)研究进行了两样本孟德尔随机化(MR)分析。采用逆方差加权法来近似MR效应。进行了包括加权中位数、MR-Egger以及MR多效性残差总和与离群值分析在内的敏感性分析,以估计多效性和异质性。MR结果表明UC与SKCM之间存在显著因果关联(β = 0.097,P = 0.0138),以及UC与SCC之间存在显著因果关联(β = 0.171,P = 0.0014)。然后使用英国生物银行的汇总水平GWAS和一项独立的荟萃分析对这些发现进行了验证,该分析表明UC与SCC之间存在提示性或因果性遗传关联(β = 0.065,P = 0.036),UC与BCC之间存在提示性或因果性遗传关联(β = 0.056,P = 0.002),但UC与SKCM之间不存在提示性或因果性遗传关联(β = 0.02,P = 0.432)。由于CD工具的样本量有限,仅发现5个显著的单核苷酸多态性,对皮肤癌没有显著的因果效应。这些结果为UC与皮肤癌之间通过涉及IL-23/Th17轴的共享多态性存在因果遗传关联提供了证据,这可能为未来的预防性咨询和精准医学提供参考。