The landscape of rare genetic variants in familial Waldenström macroglobulinemia

Blood Neoplasia Pub Date : 2024-06-01 DOI:10.1016/j.bneo.2024.100013

Alexander Pemov , Jung Kim , Wen Luo , Jia Liu , Cole Graham , Kristine Jones , Delphine DeMangel , Neal D. Freedman , Charles Dumontet , Bin Zhu , Mary L. McMaster , Douglas R. Stewart

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Abstract

Waldenström macroglobulinemia (WM) is a rare hematological malignancy. Risk for WM is elevated 20-fold among first-degree relatives of patients with WM. However, the list of variants and genes that cause WM remains incomplete. In this study we analyzed exomes from 64 WM pedigrees for evidence of genetic susceptibility for this malignancy. We determined the frequency of pathogenic (P) or likely pathogenic (LP) variants among patients with WM; performed variant- and gene-level association analyses with the set of 166 WM cases and 681 unaffected controls; and examined the segregation pattern of deleterious variants among affected members in each pedigree. We identified P/LP variants in TREX1 and SAMHD1 (genes that function at the interface between innate immune response, genotoxic surveillance, and DNA repair) segregating in patients with WM from 2 pedigrees. There were additional P/LP variants in cancer-predisposing genes (eg, POT1, RECQL4, PTPN11, PMS2). In variant- and gene-level analyses, no associations were statistically significant after multiple testing correction. On a pathway level, we observed involvement of genes that play a role in telomere maintenance (q-value = 0.02), regulation of innate immune response (q-value = 0.05), and DNA repair (q-value = 0.08). Affected members of each pedigree shared multiple deleterious variants (median, n = 18), but the overlap between the families was modest. In summary, P/LP variants in highly penetrant genes constitute a modest proportion of the deleterious variants; each pedigree is largely unique in its genetic architecture, and multiple genes are likely involved in the etiology of WM.

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家族性沃登斯特伦巨球蛋白血症的罕见基因变异情况

摘要瓦尔登斯特伦巨球蛋白血症（WM）是一种罕见的血液恶性肿瘤。在WM患者的一级亲属中，罹患WM的风险增加了20倍。然而，导致 WM 的变异和基因列表仍不完整。在这项研究中，我们分析了 64 个 WM 血统的外显子组，以寻找这种恶性肿瘤遗传易感性的证据。我们确定了 WM 患者中致病（P）变异或可能致病（LP）变异的频率；对 166 例 WM 病例和 681 例未受影响的对照进行了变异和基因水平的关联分析；并研究了每个血统中受影响成员之间有害变异的分离模式。我们在两个血统的 WM 患者中发现了 TREX1 和 SAMHD1（在先天免疫反应、基因毒性监控和 DNA 修复之间起作用的基因）的 P/LP 变异。癌症易感基因（如 POT1、RECQL4、PTPN11 和 PMS2）中也存在其他 P/LP 变异。在变异和基因水平的分析中，经多重检验校正后，没有发现有统计学意义的关联。在通路水平上，我们观察到参与端粒维持（q 值 = 0.02）、先天性免疫反应调节（q 值 = 0.05）和 DNA 修复（q 值 = 0.08）的基因。每个血统中受影响的成员都有多个有害变体（中位数，n = 18），但家族间的重叠率不高。总之，高渗透性基因中的 P/LP 变异在有害变异中所占比例不大；每个血统的遗传结构基本上都是独特的，多个基因可能参与了 WM 的病因学研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Blood Neoplasia

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