Yao Song, Zhu Qianqian, Cole Peter D, Stevenson Kristen, Harris Marian H, Schultz Emily, Kahn Justine M, Ladas Elena J, Athale Uma H, Clavell Luis A, Laverdiere Caroline, Leclerc Jean-Marie, Michon Bruno, Schorin Marshall A, Welch Jennifer J G, Sallan Stephen E, Silverman Lewis B, Kelly Kara M
Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY.
Jacob School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY.
Blood Adv. 2021 Jan 26;5(2):451-458. doi: 10.1182/bloodadvances.2020003060.
Hispanic children have a higher incidence of acute lymphoblastic leukemia (ALL) and inferior treatment outcomes relative to non-Hispanic White children. We previously reported that Hispanic children with ALL had lower risk of fracture and osteonecrosis. To unravel the genetic root of such ethnic differences, we genotyped 449 patients from the DFCI 05-001 cohort and analyzed their ancestry. Patients with discordant clinical and genetic ancestral groups were reclassified, and those with unknown ancestry were reassigned on the basis of genetic estimates. Both clinical and genetic ancestries were analyzed in relation to risk of bone toxicities and survival outcomes. Consistent with clinically reported race/ethnicity, genetically defined Hispanic and Black patients had significantly lower risk of fracture (Hispanic: subdistribution hazard ratio [SHR], 0.42; 95% confidence interval [CI], 0.22-0.81; P = .01; Black: SHR, 0.28; 95% CI, 0.10-0.75; P = .01), and osteonecrosis (Hispanic: SHR, 0.12; 95% CI, 0.02-0.93; P = .04; Black: SHR, 0.24; 95% CI, 0.08-0.78; P = .02). The lower risk was driven by African but not Native American or Asian ancestry. In addition, patients with a higher percentage of Native American ancestry had significantly poorer overall survival and event-free survival. Our study revealed that the lower risk of bone toxicities among Black and Hispanic children treated for ALL was attributed, in part, to the percentage of African ancestry in their genetic admixture. The findings provide suggestive evidence for the protective effects of genetic factors associated with African decent against bone damage caused by ALL treatment and clues for future studies to identify underlying biological mechanisms.
与非西班牙裔白人儿童相比，西班牙裔儿童急性淋巴细胞白血病（ALL）的发病率更高，治疗效果更差。我们之前报道过，患ALL的西班牙裔儿童发生骨折和骨坏死的风险较低。为了揭示这种种族差异的遗传根源，我们对DFCI 05-001队列中的449名患者进行了基因分型，并分析了他们的血统。对临床和遗传祖先群体不一致的患者进行了重新分类，对血统不明的患者根据基因估计进行了重新分配。分析了临床和遗传血统与骨毒性风险和生存结果的关系。与临床报告的种族/族裔一致，基因定义的西班牙裔和黑人患者骨折风险显著较低（西班牙裔：亚分布风险比[SHR]，0.42；95%置信区间[CI]，0.22-0.81；P = 0.01；黑人：SHR，0.28；95% CI，0.10-0.75；P = 0.01），骨坏死风险也显著较低（西班牙裔：SHR，0.12；95% CI，0.02-0.93；P = 0.04；黑人：SHR，0.24；95% CI，0.08-0.78；P = 0.02）。较低的风险是由非洲血统而非美洲原住民或亚洲血统驱动的。此外，美洲原住民血统比例较高的患者总生存率和无事件生存率显著较差。我们的研究表明，接受ALL治疗的黑人和西班牙裔儿童骨毒性风险较低，部分原因是其基因混合中非洲血统的比例。这些发现为与非洲血统相关的遗传因素对ALL治疗引起的骨损伤的保护作用提供了提示性证据，并为未来研究确定潜在生物学机制提供了线索。
