PO.MCB08.01 · 分子与细胞生物学

基因融合与微卫星不稳定性（MSI）的共存定义了结直肠癌一个临床上独特的亚型

Co-occurrence of gene fusions and microsatellite instability (MSI) defines a clinically distinct subtype of colorectal cancer

编号 500 展板 12 时间 4/19 02:00–05:00 区域 Section 20 主讲 Scott Kulm

分会场 Genomic Dissection to Define Novel Therapeutic Strategies

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作者与单位 Authors & Affiliations

Scott Kulm, Sebastià Franch-Expósito, Paul Fields, Catherine Igartua

Tempus, Chicago, IL

摘要 Abstract

中文摘要

背景：微卫星不稳定性（MSI）是结直肠癌中一个已确立的生物标志物。基因融合也可能影响预后，但其与 MSI 共存的临床意义仍不甚明了。方法：我们分析了一个结直肠癌患者队列（N = 29,099），全部使用 Tempus AI 的 xT 平台进行检测。采用 Fisher 检验评估致病性和可能致病性基因融合在微卫星稳定性分组内的富集情况。采用 Cox 模型评估 MSI 状态与基因融合对自活检采集起真实世界总生存期的独立效应及交互效应，并校正年龄、分期、治疗线数、肿瘤纯度、肿瘤突变负荷及 PD-L1 联合阳性评分。我们检验了所有融合、激酶融合（NTRK1、NTRK3、RET、ALK、FGFR2、BRAF）以及 NTRK 融合（NTRK1、NTRK3）的富集情况。结果：临床相关基因融合的比例在 MSI 型结直肠癌肿瘤中高于 MSS 型（5.9% 对 1.8%）：NTRK1（2.2% 对 0.048%）、NTRK3（1.2% 对 0.14%）、RET（0.87% 对 0.096%）以及 TPM3（1.0% 对 0.0074%）。生存分析显示，所有融合和激酶融合均与显著更差的总生存期相关（表 1）。这些趋势在各亚队列中持续存在。在纳入所有融合、激酶融合和 NTRK 融合的模型中，MSI 与总生存期延长相关。在任何模型中我们均未检测到 MSI 与基因融合之间的显著交互作用，这可能是由于样本量较小所致。然而，当限定于 MSS 肿瘤时，我们确认所有基因融合和激酶融合仍与不良总生存期相关。针对接受特定疗法（如免疫治疗）患者拟合的其他模型未能收敛。结论：MSI 型与 MSS 型结直肠肿瘤之间的基因融合率存在差异。虽然多数融合总体上与更差的生存相关，但在 MSI 病例中该效应可能逆转。表 1：结直肠癌中融合与 MSI 的总生存期关联结果。限定条件融合类别融合 MSI N 风险比 P N 风险比 P 全部全部 274 1.261 0.015 575 0.643 3.51E-05 分期 3/4 全部 234 1.253 0.025 426 0.677 0.002 治疗前全部 201 1.297 0.019 417 0.631 5.30E-04 MSS 全部 226 1.260 0.015 MSI 全部 48 0.927 0.763 全部 NTRK 52 0.564 0.13 575 0.652 4.53E-05 分期 3/4 NTRK 40 0.692 0.368 426 0.693 0.003 治疗前 NTRK 42 0.630 0.223 417 0.633 4.67E-04 MSS NTRK 22 0.564 0.130 MSI NTRK 30 0.684 0.297 全部激酶 136 1.427 0.010 575 0.648 4.65E-05 分期 3/4 激酶 117 1.518 0.004 426 0.685 0.003 治疗前激酶 99 1.545 0.005 417 0.640 7.74E-04 MSI 激酶 89 1.426 0.010 MSS 激酶 47 0.860 0.593

查看英文原文 English abstract

Background : Microsatellite instability (MSI) is a well-established biomarker in colorectal cancer. Gene fusions may also influence prognosis, but the clinical significance of their co-occurrence with MSI remains poorly understood. Methods : We analyzed a cohort of colorectal (N = 29,099) cancer patients, all profiled with Tempus AIs xT platform. Fishers tests assessed the enrichment of pathogenic and likely pathogenic gene fusions within microsatellite stability groups. Cox models evaluated the independent and interaction effects of MSI status and gene fusions on real-world overall survival from at biopsy collection, adjusting for age, stage, line of therapy, tumor purity, tumor mutation burden, and PD-L1 combined positive score. We tested for enrichment of all fusions, kinase fusions ( NTRK1 , NTRK3 , RET , ALK , FGFR2 , BRAF ), and NTRK fusions ( NTRK1 , NTRK3 ). Results : The proportion of clinically relevant gene fusions was higher in MSI versus MSS colorectal cancer tumors (5.9% vs 1.8%): NTRK1 (2.2% vs. 0.048%), NTRK3 (1.2% vs. 0.14%), RET (0.87% vs. 0.096%), and TPM3 (1.0% vs. 0.0074%). Survival analyses revealed that all fusions and kinase fusions were both associated with significantly worse overall survival (Table 1). These trends persisted in sub-cohorts. MSI was associated with increased overall survival in models including all fusions, kinase fusions, and NTRK fusions. We did not detect a significant interaction between MSI and gene fusions across any of the models, likely due to smaller sample sizes. However, we confirmed fusions remained associated with poor overall survival when restricting to MSS tumors for all gene fusions and kinase fusions. Additional models fit to patients treated with specific therapies, such as immunotherapy, did not converge. Conclusion : Gene fusion rates differ between MSI and MSS colorectal tumors. While most fusions are generally associated with worse survival, this effect may be reversed in MSI cases. Table 1: Overall Survival Association Results with fusions and MSI in Colorectal Cancer. Restricted To Fusion Class Fusion MSI N Hazard Ratio P N Hazard Ratio P All All 274 1.261 0.015 575 0.643 3.51E-05 Stage 3/4 All 234 1.253 0.025 426 0.677 0.002 Pre-Treatment All 201 1.297 0.019 417 0.631 5.30E-04 MSS All 226 1.260 0.015 MSI All 48 0.927 0.763 All NTRK 52 0.564 0.13 575 0.652 4.53E-05 Stage 3/4 NTRK 40 0.692 0.368 426 0.693 0.003 Pre-Treatment NTRK 42 0.630 0.223 417 0.633 4.67E-04 MSS NTRK 22 0.564 0.130 MSI NTRK 30 0.684 0.297 All Kinase 136 1.427 0.010 575 0.648 4.65E-05 Stage 3/4 Kinase 117 1.518 0.004 426 0.685 0.003 Pre-Treatment Kinase 99 1.545 0.005 417 0.640 7.74E-04 MSI Kinase 89 1.426 0.010 MSS Kinase 47 0.860 0.593

利益披露 Disclosure

S. Kulm, Tempus Employment, Stock Option. S. Franch-Expósito, Tempus Employment, Stock. P. Fields, Tempus Employment, Stock. Adaptive Biotechnologies Stock. C. Igartua, Tempus Employment, Stock.

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