PO.CL12.02 · 临床研究

新型Rho-GTP酶调控蛋白基因家族变异在急性髓系白血病（AML）患者（pts）中频发，并与不良生存相关

Novel Rho-GTPase regulatory protein gene family variants are frequent and associate with poor survival in patients (pts) with acute myeloid leukemia (AML)

编号 7897 展板 2 时间 4/22 09:00–12:00 区域 Section 48 主讲 Ethan Hamp, BS

分会场 Translational Biomarkers and Emerging Molecular Approaches

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作者与单位 Authors & Affiliations

Ethan Hamp¹, Lorenz Oelschläger², Bailee N. Kain³, Deedra Nicolet⁴, Krzysztof Mrozek¹, Katherine E. Miller⁵, Audrey Bollas⁵, Michael C. Walker⁴, Christopher J. Walker¹, Jill Buss¹, Andrea Laganson¹, Andrew J. Carroll⁶, William G. Blum⁷, Bayard L. Powell⁸, Geoffrey L. Uy⁹, Wendy Stock¹⁰, Marina Y. Konopleva¹¹, Richard M. Stone¹², John C. Byrd¹³, Martin Carroll¹⁴, Tanmoy Sarkar¹⁴, Akmaljon Salimov¹⁴, Benjamin J. Kelly⁵, Electra D. Paskett¹, Jesse J. Plascak¹, Shannon McWeeney¹⁵, Jeffrey W. Tyner¹⁵, Jeffery Klco¹⁶, Nathan Salomonis³, H. Leighton Grimes³, Elaine R. Mardis⁵, Ann-Kathrin Eisfeld¹

¹Ohio State University Comprehensive Cancer Center, Columbus, OH,²University Hospital Schleswig-Holstein, Lübeck, Germany,³Cincinnati Children's Hospital Medical Center, Cincinnati, OH,⁴Clara D. Bloomfield Center for Leukemia Outcomes Research, Columbus, OH,⁵Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH,⁶University of Alabama, Birmingham, AL,⁷Emory University, Atlanta, GA,⁸Wake Forest University, Winston-Salem, NC,⁹Division of Oncology, Washington University School of Medicine, Saint Louis, MO,¹⁰College of Medicine, University of Chicago, Chicago, IL,¹¹Department of Oncology, Albert Einstein College of Medicine, New York City, NY,¹²Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA,¹³Department of Internal Medicine, University of Cincinnati, Cincinnati, OH,¹⁴University of Pennsylvania, Philadelphia, PA,¹⁵OHSU Knight Cancer Institute, Portland, OR,¹⁶St. Jude Children's Research Hospital, Memphis, TN

摘要 Abstract

中文摘要

引言：AML是一种分子异质性疾病，依据反复出现的细胞遗传学异常和基因突变进行分类。近期研究显示，若干遗传畸变的频率因遗传学血统及自我报告的种族/族裔而存在差异，凸显出扩大测序工作以纳入更多样化患者群体的必要性。方法：我们对271例血统和/或族裔多样化的患者[包括100例非裔美国人（AA）和71例自我认定为西班牙裔的患者；CALGB/Alliance]进行了配对肿瘤/正常全外显子组测序（WES）和转录组测序，并纳入一个由45例AA患者组成的验证队列（宾夕法尼亚大学）。结果：我们鉴定出>20个在3-8%患者中发生突变的基因，这些基因在此前以非西班牙裔白人/欧洲血统（EA）患者为主的测序工作中未被发现。值得注意的是，编码Rho-GTP酶调控蛋白的基因（ARHG家族，属于RAS基因超家族）变异在12%的患者中被检出，使这些基因位居该患者队列中反复突变基因的前5位。这一频率在第二个AA患者队列中得到证实（n=7/45，15%）。相比之下，对805例具有WES数据的EA成人（BeatAML 2022）和877例儿童AML患者（TARGET）的分析发现，ARHG基因家族变异分别见于26/805（3%）和17/877（1.9%）的EA AML患者。ARHG突变（m）患者中位年龄为41岁，倾向于更年轻（P=.16），且更常被诊断为核心结合因子AML（39% vs 19%，P=.02）。ARHG突变常与NRAS和FLT3突变共存（二者各见于35%的ARHG m患者）。值得注意的是，ARHG m患者的生存较差，中位总生存期（OS）<12个月，从而与2022年欧洲白血病网（ELN）不良风险组的OS相当。在血统多样化队列的2022 ELN良好风险组中，ARHG m患者的OS短于ARHG野生型（wt）患者（P=.02）。临床结局在青少年及青年成人（AYA，18-39岁）中尤为不良（突变 vs 野生型；3年无病生存率，10% vs 50%，P<.001；3年OS，20% vs 55%，P=.008）。对17例ARHG m患者的RNAseq显示转录组RAS通路激活，其中52%表现出RAS相关特征，即使在无其他RAS突变的情况下亦是如此。此外，对1250例AML患者的批量转录组分析鉴定出120个预测的RAS特征基因，上调基因富集于金属肽酶、MAP激酶磷酸酶和ARHG基因。结论：我们鉴定出ARHG家族基因突变是AML中频发但迄今未被识别的RAS通路激活因子，与不良生存相关，且尚未纳入临床检测panel。其未被识别的原因可能在于受突变影响的ARHG家族基因的异质性、在AYA患者中的富集以及在非欧洲血统患者中的高频率——这两类患者群体在此前的测序工作中均代表性不足。

查看英文原文 English abstract

Introduction: AML is a molecularly heterogeneous disease that is classified by recurrent cytogenetic abnormalities and gene mutations. Recent studies have shown divergent frequencies of several genetic aberrations depending on genetic ancestry and self-reported race/ethnicity, highlighting the need to broaden sequencing efforts to include more diverse pts. Methods: We performed paired tumor/normal whole exome sequencing (WES) and transcriptome sequencing on 271 ancestry and/or ethnically diverse pts [including 100 African American (AA) and 71 self-identified Hispanic pts; CALGB/Alliance], and a validation cohort of 45 AA pts (University of Pennsylvania). Results: We identified >20 genes to be mutated in 3-8% of pts that were not seen in previous sequencing efforts of predominantly non-Hispanic White/European ancestry (EA) pts. Notably, variants in genes encoding Rho-GTPase regulatory proteins ( ARHG family, belonging to the RAS gene superfamily) were identified in 12% of pts, placing these genes in the top 5 of recurrently mutated genes in this pt cohort. This frequency was confirmed in the second cohort of AA pts (n=7/45, 15%). In contrast, analysis of 805 EA adults with WES data (BeatAML 2022) and 877 pediatric AML pts (TARGET) found ARHG gene family variants in 26/805 (3%) and 17/877 (1.9%) of EA AML pts, respectively. With a median age of 41y, ARHG -mutated(m) pts tended to be younger (P=.16) and more often diagnosed with core-binding factor AML (39% vs 19%, P=.02). ARHG mutations frequently co-occurred with NRAS and FLT3 mut (each found in 35% of ARHG m pts). Notably, survival of ARHG m pts was poor, with a median overall survival (OS) of <12 months, thereby mirroring OS of the 2022 European LeukemiaNet (ELN) Adverse risk group. Within the 2022 ELN Favorable risk group in the ancestry diverse cohort, ARHG m pts had shorter OS than ARHG wt pts (P=.02). The clinical outcome was especially poor in young adolescents and adults (AYA, 18-39y) (mut vs wt; 3y disease-free survival, 10% vs 50%, P<.001; 3y OS, 20% vs 55%, P=.008). RNAseq of 17 ARHG m pts showed transcriptomic RAS pathway activation, with 52% displaying a RAS-associated signature, also in the absence of other RAS mutations. Furthermore, bulk transcriptomic analyses of 1250 AML pts identified 120 predicted RAS signature genes, with the upregulated genes being enriched in metallopeptidases, MAP kinase phosphatases, and ARHG genes. Conclusion: We identified mutations in ARHG family genes as frequent yet thus far unrecognized RAS pathway activators in AML associated with poor survival that are not yet included in clinical testing panels. Their lack of recognition is likely due to the heterogeneity of mutationally affected ARHG family genes, enrichment in AYA pts and the high frequency in pts of non-European ancestry, both of which are pt populations that were underrepresented in previous sequencing efforts.

利益披露 Disclosure

E. Hamp, None.. L. Oelschläger, None.. B. N. Kain, None.. D. Nicolet, None.. K. Mrozek, None.. K. E. Miller, None.. A. Bollas, None.. M. C. Walker, None.. C. J. Walker, None.. J. Buss, None.. A. Laganson, None.. A. J. Carroll, None.. W. G. Blum, None.. B. L. Powell, None.. W. Stock, None.. M. Y. Konopleva, None.. R. M. Stone, None.. J. C. Byrd, None.. M. Carroll, None.. T. Sarkar, None.. A. Salimov, None.. B. J. Kelly, None.. E. D. Paskett, None.. J. J. Plascak, None.. N. Salomonis, None.. E. R. Mardis, None.. A. Eisfeld, None.

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