PO.PS01.01 · 人群科学
按组织学亚组评估子宫内膜癌病因
Assessing endometrial cancer etiology by histologic subgroups
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言:在过去二十年中,子宫内膜癌发病率大幅上升,增幅主要发生在预后不良的非子宫内膜样组织学肿瘤中。关于这一增长起源的证据稀少。我们试图确定具有特定内源性和外源性暴露分子特征的女性是否具有更高的非子宫内膜样组织学(尤其是浆液性肿瘤)风险。
方法:我们研究了癌症基因组图谱(TCGA)外显子组测序数据中的单碱基替换(SBS)特征。应用了突变特征评估的标准算法。在连续尺度上评估特征,并使用由最大选择秩统计量确定的高/低切点进行评估。计算了49种特征的相对风险(RR)和95%置信区间(CI),比较浆液性相对于子宫内膜样组织学的风险。还在Cox比例风险模型中评估了疾病特异性生存(DSS),计算了风险比(HR)和95% CI。通过Schoenfeld残差验证了比例风险假设。所有分析均对癌症诊断时的年龄进行了校正,DSS分析还对分期进行了校正。
结果:纳入了n=414名子宫内膜样肿瘤女性和n=134名浆液性非子宫内膜样肿瘤女性。如文献所预期,高错配修复缺陷(dMMR)(SBS6和SBS15)和聚合酶ε突变(POLE)(SBS10a;SBS10b)特征在浆液性肿瘤中比子宫内膜样肿瘤中更少见(dMMR:SBS6 RR 0.21;95% CI 0.12-0.39;SBS15 0.22;95% CI 0.12-0.40;SBS26 0.21;95% CI 0.12-0.40);SBS15 RR 0.22;95% CI 0.12-0.40以及POLE SBS10a RR 0.23;95% CI 0.10-0.54和SBS10b 0.33;95% CI 0.19-0.58)。与烟草使用相关的特征(SBS4)在浆液性肿瘤中也较少见(RR 0.32;95% CI 0.15-0.71)。具有高dMMR(SBS6:HR 0.06;95%CI 0.01-0.47;SBS15 HR 0.23;95%CI 0.08-0.64;SBS26:HR 0.42;95% CI 0.21-0.84)或高POLE(SBS10a HR 0.06;95% CI 0.01-0.46;SBS10b HR 0.13;0.03-0.54)特征的女性,其子宫内膜癌特异性死亡风险降低。
讨论:子宫内膜样肿瘤和浆液性肿瘤在突变特征上存在差异。dMMR和POLE特征在浆液性肿瘤和DSS方面均呈现风险降低,这与其他研究发现一致。我们的结果为探索浆液性肿瘤病因开辟了新的前景。
查看英文原文 English abstract
Introduction: Endometrial cancer incidence has increased substantially in the past two decades, with the increases occurring primarily in tumors of non-endometrioid histology, which have a poor prognosis. Evidence regarding the origin(s) of the increase is sparse. We sought to determine whether women who had particular molecular signatures of endogenous and exogenous exposures had an increased risk of non-endometrioid histology, particularly serous tumors.
Methods: We investigated single-base substitution (SBS) signatures in exome sequencing data from The Cancer Genome Atlas (TCGA). Standard algorithms for mutational signature assessment were applied. Signatures were evaluated on a continuous scale, and also using a high/low cut point determined by maximally selected rank statistics. Relative risks (RR) and 95% confidence intervals (CI) were computed for 49 signatures, comparing risk for serous in relation to endometrioid histology. Disease-specific survival (DSS) was also evaluated in Cox proportional hazard models, with calculation of hazard ratios (HR) and 95% CI. The proportional hazards assumption was verified by Schoenfeld residuals. All analyses were adjusted for age at cancer diagnosis, and DSS analyses were also adjusted for stage.
Results: Included were n=414 women with endometrioid and n= 134 with serous non-endometrioid tumors. High Mismatch Repair defective (dMMR) (SBS6 and SBS15) and Polymerase Epsilon mutation (POLE) (SBS10a; SBS10b) signatures were less common in serous than endometrioid tumors, as expected from the literature (dMMR: SBS6 RR 0.21;95% CI 0.12-0.39; SBS15 0.22;95% CI 0.12-0.40;SBS26 0.21;95% CI 0.12-0.40); SBS15 RR 0.22;95% CI 0.12-0.40 and POLE SBS10a RR 0.23;95% CI 0.10-0.54 and SBS10b 0.33; 95% CI 0.19-0.58). A signature related to tobacco use (SBS4) was also less common in serous tumors (RR 0.32;95% CI 0.15-0.71). Women with high dMMR (SBS6: HR 0.06;95%CI 0.01-0.47; SBS15 HR 0.23;95%CI 0.08-0.64; SBS26: HR 0.42;95% CI 0.21-0.84)) or high POLE (SBS10a HR 0.06;95% CI 0.01-0.46; SBS10b HR 0.13; 0.03-0.54) signatures had a reduced risk of endometrial cancer-specific mortality.
Discussion: Endometrioid and serous tumors differ in mutational signatures. The reduced dMMR and POLE signature risk in relation to both serous tumors and DSS are in agreement with other findings. Our results open up new prospects for exploration of serous tumor etiology
利益披露 Disclosure
D. A. Hill, None..
C. Y. Muller, None..
K. K. Leslie, None..
D. G. Mutch, None.