Newman Haley, Lee Shawn H R, Pölönen Petri, Shraim Rawan, Li Yimei, Liu Hongyan, Aplenc Richard, Bandyopadhyay Shovik, Chen Changya, Devidas Meenakshi, Diorio Caroline, Dunsmore Kimberly, Elghawy Omar, Elhachimi Amira, Fuller Tori, Gupta Sumit, Hall Junior, Hughes Andrew D, Hunger Stephen P, Loh Mignon L, Martinez Zachary, McCoy Michael F, Mullen Cassidy G, Pounds Stanley B, Raetz Elizabeth, Seffernick Anna Eames, Shi Gongping, Sussman Jonathan, Tan Kai, Uppuluri Lahari, Vincent Tiffaney L, Wang'ondu Ruth, Winestone Lena E, Winter Stuart S, Wood Brent L, Wu Gang, Xu Jason, Yang Wenjian, Mullighan Charles G, Yang Jun J, Bona Kira, Teachey David T
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Blood Cancer Discov. 2025 Aug 8:OF1-OF13. doi: 10.1158/2643-3230.BCD-25-0049.
The influence of genetic ancestry on genomics in T-cell acute lymphoblastic leukemia (T-ALL) has not been fully explored. We examined the impact of genetic ancestry on multiomic alterations, survival outcomes, and risk stratification. Among 1,309 children and young adults with T-ALL treated on the Children's Oncology Group trial AALL0434, the prognostic value of five commonly altered T-ALL genes varied by ancestry-including NOTCH1, which was associated with superior overall survival for patients of European ancestry but was nonprognostic among patients of African ancestry. Integrating genetic ancestry with published T-ALL risk classifiers, we identified that an X01 penalized Cox regression classifier stratified patients regardless of ancestry, whereas a European multigene classifier misclassified patients of certain ancestries. Overall, 80% of patients harbored a genomic alteration in at least one gene with differential prognostic impact in an ancestry-specific manner. These data demonstrate the importance of incorporating genetic ancestry into genomic risk classification.
There is a lack of studies examining the prognostic significance of genomic features by genetic ancestry in T-ALL, especially in non-European ancestral groups. In this study, we demonstrate how the prognostic value of individual alterations differs by genetic ancestry, warranting future studies to identify germline alleles affecting these associations. See related commentary by de Smith, p. xxx.
遗传血统对T细胞急性淋巴细胞白血病（T-ALL）基因组学的影响尚未得到充分研究。我们研究了遗传血统对多组学改变、生存结果和风险分层的影响。在儿童肿瘤学组试验AALL0434中接受治疗的1309例T-ALL儿童和青年患者中，五个常见的T-ALL基因的预后价值因血统而异，包括NOTCH1，它与欧洲血统患者的总体生存率较高相关，但在非洲血统患者中无预后价值。将遗传血统与已发表的T-ALL风险分类器相结合，我们发现X01惩罚Cox回归分类器无论血统如何都能对患者进行分层，而欧洲多基因分类器对某些血统的患者进行了错误分类。总体而言，80%的患者至少有一个基因发生了基因组改变，这些改变在特定血统中具有不同的预后影响。这些数据证明了将遗传血统纳入基因组风险分类的重要性。
缺乏研究探讨遗传血统在T-ALL中对基因组特征的预后意义，尤其是在非欧洲祖先群体中。在本研究中，我们证明了个体改变的预后价值如何因遗传血统而异，这需要未来的研究来确定影响这些关联的种系等位基因。见de Smith的相关评论，第xxx页。
