PO.CL01.16 · 临床研究
研究遗传性基因变异作为黑色素瘤患者接受免疫检查点抑制剂（ICI）治疗后免疫介导性结肠炎的预测因子
Investigation of inherited genetic variation for predictors of immune mediated colitis following immune checkpoint inhibitor (ICI) therapy of patients (pts) with melanoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：免疫介导性结肠炎是黑色素瘤ICI治疗后常见的毒性反应，可危及生命。因此，预测发生结肠炎的风险可为治疗方案和临床随访提供参考。我们推测，遗传性基因变异是使患者易发生这一免疫相关不良事件（irAE）的重要因素。
方法：我们对入组ECOG-ACRIN E1609试验（NCT01274338，评估ipilimumab）的744例知情同意患者的样本进行了全基因组基因分型。我们使用Illumina Infinium Global Screening Array v.3.0 + Multi-Disease BeadChip，包含730059个设计位点。基因型经过质量控制，与1000 Genomes第3阶段（1KGP3）基因型协调统一，并使用Michigan Imputation Server 2（流程v2.0.6）针对hrc-r1.1参考面板进行填补。我们使用plink（v2.00a4LM glm，采用firth回退）实现的逻辑回归，估计遗传标志物与结肠炎发生之间的关联，并校正遗传谱系。我们还计算了PGS-Catalog v20240318中列出的5个已发表的炎症性肠病（IBD）多基因风险评分（PRS）的数值，并在E1609患者中检验其与结肠炎的关联，将irAE分级作为分类变量（Kruskal-Wallis检验）和二分变量（Wilcoxon秩和检验）处理。irAE采用CTCAE v.4进行分级。
结果：5个PRS中，任何一个PRS在不同结肠炎分级间的分布均无显著差异（Kruskal-Wallis）。然而，当irAE分级以>3 vs 其他进行二分时，所有PRS均显示出更强的差异。PRS PGS004253与4-5级结肠炎的关联最为显著（P = 0.01；AUC 0.73）。该PRS（Medha. Nature Commun 2024）在一个非黑色素瘤欧洲人群中训练，其遗传谱系与我们的黑色素瘤研究队列相似（Tarhini. AACR 2025），且该PRS中的所有标志物在我们的数据集中均可获得。通过全基因组关联分析，我们鉴定出10个与结肠炎irAE显著相关的独立SNP。当以log(OR)为权重进行组合时，这些SNP与irAE分级的严重程度显著相关，无论是在不同irAE分级间（Kruskal-Wallis P = 2.5e-26），还是二分为任何结肠炎irAE vs 无（Wilcoxon P = 8.9e-30）时均如此。在校正原发状态（已知、未知）和性别（男、女）的多变量生存分析中，我们的10-SNP PGS呈现出与生存结局关联的趋势。
结论：我们的结果支持遗传性基因变异与ICI治疗后结肠炎风险之间存在关联，包括基于与训练PRS所用人群的遗传相似性而选择的IBD PRS，以及采用我们GWAS分析所鉴定的10个SNP计算得出的新型PRS评分。
查看英文原文 English abstract
Background: Immune mediated colitis is a common toxicity following ICI therapy of melanoma and can be life threatening. Therefore, predicting the risk of developing colitis may inform the treatment plan and clinical follow up. We hypothesize that inherited genetic variation is an important factor in predisposing pts to this immune related adverse event (irAE).
Methods: We conducted genome-wide genotyping on samples from 744 consenting pts enrolled in ECOG-ACRIN E1609 trial (NCT01274338) that tested ipilimumab. We used Illumina Infinium Global Screening Array v.3.0 + Multi-Disease BeadChip with 730059 designed loci. Genotypes were quality controlled, harmonized with the 1000 Genomes Phase 3 (1KGP3) genotypes, and imputed against the hrc-r1.1 reference panel using the Michigan Imputation Server 2, pipeline v2.0.6. We used logistic regression implemented in plink (v2.00a4LM glm with firth fallback) to estimate associations between inherited genetic markers and the occurrence of colitis, adjusting for genetic ancestry. We also calculated the value for 5 published polygenic risk scores (PRS) for inflammatory bowel disease (IBD) listed in PGS-Catalog v20240318 and tested the association with colitis in E1609 pts treating irAE grades as categorical (Kruskal-Wallis test) and as dichotomous (Wilcoxon rank-sum test) variables. IrAEs were graded using CTCAE v.4.
Results: There was no significant difference in distribution of the PRS across grade of colitis (Kruskal-Wallis) with any of the 5 PRS. However, all demonstrated stronger differences when irAE grades were dichotomized at >3 vs. other. PRS PGS004253 was most significant in association with grades 4-5 colitis (P = 0.01; AUC 0.73). This PRS ( Medha. Nature Commun 2024 ) was trained in a non-melanoma European population that has a genetic ancestry similar to our melanoma study cohort ( Tarhini. AACR 2025 ) and for which all markers in the PRS were available in our dataset. From our genome-wide association analysis, we identified 10 independent SNPs that were significantly associated with colitis irAE. When combined using log(OR) as weights, these SNPs were significantly associated with the severity of irAE grades, both across irAE grades (Kruskal-Wallis P = 2.5e-26) and when dichotomized as any colitis irAE vs. none (Wilcoxon P = 8.9e-30). In multivariable survival analysis adjusting for primary status (known, unknown) and sex (male, female), our 10-SNP PGS trended towards an association with survival outcomes.
Conclusion: Our results support an association between inherited genetic variation and the risk of colitis following ICI, including PRS for IBD selected based on inherited genetic similarity with the population used to train the PRS as well as a novel PRS score computed using 10 SNPs identified from our GWAS analysis.
利益披露 Disclosure
A. A. Tarhini,
Bristol Myers Squibb Other, Consulting or advisory role.
Merck Other, Consulting or advisory role.
Genentech Other, Consulting or advisory role.
Novartis Other, Consulting or advisory role.
Sanofi Other, Consulting or advisory role.
Regeneron Other, Consulting or advisory role.
Partner Therapeutics Other, Consulting or advisory role.
Clinigen Group Other, Consulting or advisory role.
Eisai Other, Consulting or advisory role.
Bayer Other, Consulting or advisory role.
Instil Bio Other, Consulting or advisory role.
ConcertAI Other, Consulting or advisory role.
OncoSec ).
InflaRx ).
Acrotech Biopharma ).
Pfizer ).
Agenus ).
Scholar Rock ).
Z. Chen, None..
M. Khaksar, None..
S. J. Lee, None.
F. Hodi,
Bristol Myers Squibb ).
Merck ).
Novartis ).
compass Therapeutics ).
Apricity ).
Puretech ).
Curis ).
Bicara ).
Checkpoint Therapeutics ).
Astra Zeneca ).
Bioentre ).
Gossamer ).
Iovance ).
Catalym ).
Immunocore ).
Kairos ).
Rheos ).
Bayer ).
Zumutor ).
Corner Therapeutics ).
T. Li, None..
H. Streicher, None.
V. K. Sondak,
Neogene Therapeutics ).
SkylineDx ).
Turnstone Biologics ).
Bristol Myers Squibb Other, Consultant.
Merck Other, Consultant.
Mural Oncology Other, Consultant.
Regeneron Other, Consultant.
J. M. Kirkwood,
Ankyra Therapeutics Other, Consulting/advisory boards under 10,000 per year.
Axio Research, LLC Other, Consulting/advisory boards under 10,000 per year.
Bristol Myers Squibb Other, Consulting/advisory boards under 10,000 per year.
Boxer Capital Other, Consulting/advisory boards under 10,000 per year.
Cytom X Therapeutics Other, Consulting/advisory boards under 10,000 per year.
Daiichi Sankyo Inc Other, Consulting/advisory boards under 10,000 per year.
Derm Tech Other, Consulting/advisory boards under 10,000 per year.
Engage Health Media Other, Consulting/advisory boards under 10,000 per year.
GE Healthcare Inc Other, Consulting/advisory boards under 10,000 per year.
iOnctura Other, Consulting/advisory boards under 10,000 per year.
Iovance Biotherapeutics Other, Consulting/advisory boards under 10,000 per year.
IQVIA Other, Consulting/advisory boards under 10,000 per year.
Takeda Other, Consulting/advisory boards under 10,000 per year.
Pfizer Other, Consulting/advisory boards under 10,000 per year.
Magnolia Innovations, LLC Other, Consulting/advisory boards under 10,000 per year.
Mural Oncology Other, Consulting/advisory boards under 10,000 per year.
Merck Other, Consulting/advisory boards under 10,000 per year.
Istari Oncology Other, Consulting/advisory boards under 10,000 per year.
Jazz Pharmaceuticals, Inc Other, Consulting/advisory boards under 10,000 per year.
Lytix Biopharma AS Other, Consulting/advisory boards under 10,000 per year.
X. Wang, None..
P. A. Kanetsky, None.