背景:自然杀伤/T细胞淋巴瘤(NKTCL)是一种临床和遗传异质性疾病,预后不良。基因组测序和突变表征为患者分层提供了一种强大的方法,治疗目标发现,和病因鉴定。然而,以前的研究主要集中在原发性NKTCL的碱基水平突变,而NKTCL的大规模基因组改变和复发/难治性NKTCL的突变景观仍未被探索。
方法:这里,我们收集了来自163例原发性或复发/难治性NKTCL患者的全基因组测序和全外显子组测序数据,并在核苷酸和结构水平比较了他们的体细胞突变情况.
结果:我们的研究不仅证实了先前报道的常见NKTCL突变靶标,如STAT3,TP53和DDX3X,而且还揭示了一些新的高频突变靶标,如PRDM9,DST,和RBMX。就整体突变景观而言,我们观察到原发性和复发/难治性NKTCL患者组之间存在显著差异,后者表现出更高水平的肿瘤突变负担,拷贝数变体(CNVs),和结构变体(SV),表明基因组不稳定的强烈信号。在复发/难治性NKTCL患者中,复杂的结构重排(如色素沉着和局灶性扩增)也显着富集。对预后产生重大影响。因此,我们设计了一种新颖的分子分型系统(即,C0-C4)通过在核苷酸和结构水平上整合潜在的驱动突变而具有不同的预后,这进一步为靶向这些特定驱动突变和整个基因组不稳定性的新治疗提供了信息指导。
结论:原发性和复发/难治性NKTCL患者之间突变景观的显著差异突出了基因组不稳定在驱动NKTCL进展中的重要性。在精准医学时代,我们新提出的分子分型系统在帮助患者分层和新颖的治疗设计以实现更好的预后方面具有重要价值。
Natural killer/T cell lymphoma (NKTCL) is a clinically and genetically heterogeneous disease with poor prognosis. Genome sequencing and mutation characterization provides a powerful approach for patient stratification, treatment target discovery, and etiology identification. However, previous studies mostly concentrated on base-level mutations in primary NKTCL, whereas the large-scale genomic alterations in NKTCL and the mutational landscapes in relapsed/refractory NKTCL remain largely unexplored.
Here, we assembled whole-genome sequencing and whole-exome sequencing data from 163 patients with primary or relapsed/refractory NKTCL and compared their somatic mutational landscapes at both nucleotide and structure levels.
Our study not only confirmed previously reported common NKTCL mutational targets like STAT3, TP53, and DDX3X but also unveiled several novel high-frequency mutational targets such as PRDM9, DST, and RBMX. In terms of the overall mutational landscape, we observed striking differences between primary and relapsed/refractory NKTCL patient groups, with the latter exhibits higher levels of tumor mutation burden, copy number variants (CNVs), and structural variants (SVs), indicating a strong signal of genomic instability. Complex structural rearrangements such as
chromothripsis and focal amplification are also significantly enriched in relapsed/refractory NKTCL patients, exerting a substantial impact on prognosis. Accordingly, we devised a novel molecular subtyping system (i.e., C0-C4) with distinct prognosis by integrating potential driver mutations at both nucleotide and structural levels, which further provides an informative guidance for novel treatments that target these specific driver mutations and genome instability as a whole.
The striking differences underlying the mutational landscapes between the primary and relapsed/refractory NKTCL patients highlight the importance of genomic instability in driving the progression of NKTCL. Our newly proposed molecular subtyping system is valuable in assisting patient stratification and novel treatment design towards a better prognosis in the age of precision medicine.