Wang Sabrina E, Tan Vanessa Y, Yarmolinsky James, Zheng Yadi, O'Mara Tracy A, Timpson Nicholas J, Gunter Marc J, Dossus Laure, Lee Matthew A
International Agency for Research on Cancer, World Health Organization, Lyon, France.
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.
Cancer Epidemiol Biomarkers Prev. 2025 Sep 2;34(9):1534-1543. doi: 10.1158/1055-9965.EPI-25-0165.
Proteomics could enhance our understanding of endometrial carcinogenesis. However, addressing confounding in traditional observational studies remains challenging, especially given the strong impact of adiposity on the plasma proteome and endometrial cancer risk.
Using Mendelian randomization (MR) and colocalization analyses, we examined the causal association between 2,751 unique proteins from the UK Biobank (N proteins = 2,031; N = 52,363) and deCODE (N proteins = 1,667; N = 35,559) with endometrial cancer risk [overall (N cases = 12,270; N controls = 46,126), endometrioid (N cases = 8,758), and nonendometrioid (N cases = 1,230)]. We performed enrichment analyses to explore pathways overrepresented among plasma proteins in endometrioid and nonendometrioid cancer subtypes. We assessed whether circulating proteins mediated the effect of body mass index on endometrial cancer risk using uni- and multivariable MR.
Twenty proteins were associated with endometrial cancer risk in MR and colocalization analyses. GSTO1-1 and SKAP1 were positively and MMP10 was negatively associated with overall and endometrioid endometrial cancer; DTYMK and ABO were positively and TSSC4 was negatively associated with overall endometrial cancer; IGF2R was positively associated with endometrioid cancer; and MAPK9 was positively and DNAJB14, IFI16, LCN2, and SCT were negatively associated with nonendometrioid endometrial cancer. Distinct pathways were overrepresented in endometrioid (e.g., platelet-derived growth factor signaling and PTEN gene regulation) and nonendometrioid (e.g., noncanonical NF-κB signaling) cancer subtypes. There was weak evidence of associated proteins mediating the relationship between body mass index and endometrial cancer risk.
We identified distinct plasma proteins and pathways associated with endometrioid and nonendometrioid endometrial cancer risk.
Prioritized proteins may support noninvasive methods to differentiate endometrial cancer subtypes.
蛋白质组学有助于加深我们对子宫内膜癌发生机制的理解。然而，在传统观察性研究中解决混杂因素仍然具有挑战性，尤其是考虑到肥胖对血浆蛋白质组和子宫内膜癌风险的强烈影响。
我们使用孟德尔随机化（MR）和共定位分析，研究了来自英国生物银行（N蛋白 = 2031；N = 52363）和 deCODE（N蛋白 = 1667；N = 35559）的2751种独特蛋白质与子宫内膜癌风险之间的因果关联[总体（N病例 = 12270；N对照 = 46126）、子宫内膜样癌（N病例 = 8758）和非子宫内膜样癌（N病例 = 1230）]。我们进行了富集分析，以探索在子宫内膜样癌和非子宫内膜样癌亚型中血浆蛋白中过度富集的途径。我们使用单变量和多变量MR评估循环蛋白是否介导了体重指数对子宫内膜癌风险的影响。
在MR和共定位分析中，20种蛋白质与子宫内膜癌风险相关。GSTO1-1和SKAP1与总体和子宫内膜样子宫内膜癌呈正相关，MMP10与它们呈负相关；DTYMK和ABO与总体子宫内膜癌呈正相关，TSSC4与总体子宫内膜癌呈负相关；IGF2R与子宫内膜样癌呈正相关；MAPK9与非子宫内膜样子宫内膜癌呈正相关，而DNAJB14、IFI16、LCN2和SCT与非子宫内膜样子宫内膜癌呈负相关。不同的途径在子宫内膜样癌（如血小板衍生生长因子信号传导和PTEN基因调控）和非子宫内膜样癌（如非经典NF-κB信号传导）亚型中过度富集。有微弱证据表明相关蛋白介导了体重指数与子宫内膜癌风险之间的关系。
我们确定了与子宫内膜样癌和非子宫内膜样癌风险相关的不同血浆蛋白和途径。
优先考虑的蛋白质可能支持区分子宫内膜癌亚型的非侵入性方法。
