PO.BCS01.04 · 生物信息与计算

杯状细胞阑尾腺癌在分子层面上区别于其他组织学亚型：来自大规模基因组、转录组和类器官建模的见解

Goblet cell appendiceal adenocarcinoma is molecularly distinct from other histologic subtypes: Insights from large-scale genomic, transcriptomic, and organoid modeling

编号 4125 展板 5 时间 4/21 09:00–12:00 区域 Section 2 主讲 Saikat Chowdhury, BS;MS;PhD

分会场 Application of Bioinformatics to Cancer Biology 4

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作者与单位 Authors & Affiliations

Saikat Chowdhury¹, Ichiaki Ito¹, Samuel Rivero-Hinojosa², Chia-Mei Young¹, Eleanor A. Fallon³, Beth A. Helmink¹, Taylor Neilson¹, Vasily Aushev², Sacha El Khoury¹, Abdelrahman MG Yousef⁴, Mahmoud Mohamad Gamal Yousef⁵, Shruti Sharma², Robert Lentz², Adham Jurdi², Paul F. Mansfield¹, Keith Fournier¹, Yuan-Hung Lo¹, Michael G. White¹, John Paul Shen¹

¹UT MD Anderson Cancer Center, Houston, TX,²Natera, Inc., Austin, TX,³Roswell Park Comprehensive Cancer Center, Buffalo, NY,⁴University of New Mexico Health Sciences Center, Albuquerque, NM,⁵Upstate Medical University, New York, NY

摘要 Abstract

中文摘要

背景：阑尾腺癌（AA）是一种罕见癌症，但近期数据表明其发病率呈上升趋势，目前每年每 10 万人中超过 1 例。阑尾杯状细胞腺癌（GCA）约占所有 AA 的 15%，其生存率较非杯状细胞 AA 更差。为阐明 GCA 独特的肿瘤生物学特性，我们系统性地比较了 GCA 与非 GCA AA 的基因组和转录组图谱，识别出将 GCA 与其他 AA 组织学亚型区分开来的 GCA 特异性驱动突变和失调通路。方法：作为个体化、肿瘤指导性循环肿瘤 DNA 检测（Signatera™）标准流程的一部分，我们对 1,202 例 AA 肿瘤生成了全外显子组测序（WES）数据，其中包括 385 例 GCA 患者、450 例黏液性、206 例肠型和 161 例印戒细胞组织学患者。63 例肿瘤（n=25 例 GCA，38 例非 GCA）使用 Altera™ 肿瘤基因组分析检测（Natera, Inc.）获得了转录组分析数据。在 KRAS/GNAS 共突变小鼠肿瘤中，使用 CRISPR/Cas9 生成了带有基因敲除（KO）的同基因型类器官。结果：GCA 与非 GCA 肿瘤在体细胞突变图谱上存在显著差异，非 GCA 肿瘤中 KRAS（73.4%）、TP53（39.5%）和 GNAS（36%）频繁突变。相比之下，GCA 中没有任何单一基因在超过 20% 的队列中发生突变。在 GCA 中，最常见的突变基因是 ZFP36L2（18%），这是一种可结合并稳定 mRNA 转录本的锌指蛋白，此前有报道称其可抑制细胞增殖。GCA 中其他常见突变基因包括 TP53（17%）和 SMAD4（10%），仅有 10% 的肿瘤携带 KRAS 突变。转录调控因子如 WTAP（9%）、SOX9（8%）、ARID1A（7%）、MLLT4（7%）、KMT2D（7%）和 KMT2B（4%）也频繁发生改变。对 GCA 与非 GCA 肿瘤间差异表达基因进行基因集富集分析（GSEA），发现胆汁酸和脂肪生成通路在 GCA 中上调。生存分析显示 GCA 相较于非 GCA AA 的总生存（OS）更差（94.7 个月 vs 未达到；HR 3.51，95% CI 2.67-4.63；p < 0.0001）。为探索 ZFP36L2 的潜在意义，源自 ZFP36L2 KO 的类器官表现出倍增时间缩短，并允许在不使用强力霉素诱导表达 GNAS R201C（AA 中一种已知的致癌驱动因子）的情况下传代培养。将 ZFP36L2 KO 与亲本细胞系进行比较的转录组分析显示，雄激素反应、EMT、TNFalpha、Wnt、Hedgehog、KRAS 和 TGFbeta 信号通路富集。结论：观察到 GCA 与更常见的黏液性 AA 之间存在明确的分子差异。显然，开发 AA 新药的策略必须将 GCA 视为一个独立的实体，而不应像以往常见的做法那样将这些患者与其他组织学亚型合并。

查看英文原文 English abstract

Background: Appendiceal Adenocarcinoma (AA) is a rare cancer, though recent data indicate a rising incidence, now exceeding 1 per 100,000 individuals annually. Goblet cell adenocarcinoma (GCA) of the appendix, which accounts for ~15% of all AA, is associated with worse survival than non-goblet AA. To elucidate the unique tumor biology of GCA, we systematically compared the genomic and transcriptomic landscapes of GCA versus non-GCA AA, identifying GCA-specific driver mutations and dysregulated pathways that distinguish GCA from other AA histologic subtypes. Methods: Whole-exome sequencing (WES) data from 1,202 AA tumors were generated as part of the standard workflow for personalized, tumor informed circulating tumor DNA testing (Signatera TM ), including 385 patients with GCA, 450 with mucinous, 206 with enteric-type, and 161 with signet ring cell histology. Transcriptomic profiling was available for 63 tumors (n=25 GCA, 38 non-GCA) using Altera TM tumor genomic profiling test (Natera, Inc.). Isogenic organoids with gene knock-out (KO) were generated using CRISPR/Cas9 in a KRAS/GNAS co-mutant murine tumor. Results: There were striking differences in the somatic mutation landscapes between GCA and non-GCA tumors, with frequent mutations in KRAS (73.4%), TP53 (39.5%), and GNAS (36%) in non-GCA tumors. In contrast, GCA did not harbor a single gene mutation in more than 20% of the cohort. In GCA, the most commonly mutated gene was ZFP36L2 (18%), a zinc finger protein that binds and stabilizes mRNA transcripts, and has previously been reported to inhibit cell proliferation. Other commonly mutated genes in GCA included TP53 (17%) and SMAD4 (10%), with only 10% of tumors harboring KRAS mutations. Transcriptional regulators such as WTAP (9%), SOX9 (8%), ARID1A (7%), MLLT4 (7%), KMT2D (7%), and KMT2B (4%) were also frequently altered. Performing Gene Set Enrichment Analysis (GSEA) on the differentially expressed genes between GCA and non-GCA tumors revealed that the bile acid and adipogenesis pathways were upregulated in GCA. Survival analysis showed worse OS in GCA vs non-GCA AA (94.7 months vs not reached; HR 3.51, 95% CI 2.67-4.63; p < 0.0001). To explore the potential significance of ZFP36L2, organoids derived from ZFP36L2 KO showed decreased doubling time and allowed propagation of the organoid culture without doxycycline-induced expression of GNAS R201C , a known oncogenic driver in AA. Transcriptomic analysis comparing ZFP36L2 KO to parental lines showed enrichment for androgen response, EMT, TNFalpha, Wnt, Hedgehog, KRAS, and TGFbeta signaling. Conclusion: Clear molecular differences between GCA and the more common mucinous AA were observed. It is clear that strategies for developing new drugs for AA must treat GCA as a distinct entity and not merge these patients with other histological subtypes, as has frequently been done previously.

利益披露 Disclosure

S. Chowdhury, None.. I. Ito, None. S. Rivero-Hinojosa, Natera, Inc. Employment, Stock, Stock Option. C. Young, None.. B. A. Helmink, None.. T. Neilson, None. V. Aushev, Natera Inc. Employment, Stock, Stock Option. S. Khoury, None.. A. M. Yousef, None.. M. Yousef, None. S. Sharma, Natera, Inc. Employment, Stock, Stock Option. R. Lentz, Natera, Inc. Employment, Stock, Stock Option. A. Jurdi, Natera, Inc. Employment, Stock, Stock Option. P. Mansfield, None.. K. Fournier, None.. Y. Lo, None.. M. White, None. J. Shen, Agios Stock. Syndax Stock. Engine Biosciences Consulting or Advisory Role. NaDeNo Nanosciences Consulting or Advisory Role. BostonGene ). Ikena Oncology (Inst) ).

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