通过333个癌症基因检测分析骨髓增殖性肿瘤中非驱动基因的分子图谱：巴基斯坦的研究启示

Molecular landscape of non-driver genes in myeloproliferative neoplasms through 333 cancer genes panel: Insights to reveal in Pakistan.

作者信息

Rashid Munazza, Ahmed Rifat Zubair, Usmani Muhammad Asad, Mukry Samina Naz, Zaidi Uzma, Asghar Muhammad Nadeem

机构信息

National Institute of Blood Disease and Bone Marrow Transplantation, Karachi, Pakistan.

Department of Genetics, University of Karachi, Karachi, Pakistan.

出版信息

BMC Med Genomics. 2025 Aug 4;18(1):125. doi: 10.1186/s12920-025-02159-8.

DOI:10.1186/s12920-025-02159-8

PMID:40760728

Abstract

BACKGROUND

Discoveries of driver mutations in myeloproliferative neoplasms (MPNs) have filled the diagnostic gap however there are non-driver genes which play an important role in the phenotype of the disease. This study is the first to evaluate the molecular landscape of non-driver genes in MPNs patients from Pakistan.

METHODS

A sample of fourteen MPNs patients (eight essential thrombocythemia, five primary myelofibrosis and one polycythemia vera) was investigated by the next generation sequencing, using 333 cancer genes panel. Chi square test was run in SPSS 22.0 to check association of non-driver genes with sub categories of MPNs.

RESULT

Among 333 oncology related genes, possible pathogenic variations were identified in 2.1% of analyzed genes (7/333). TP53 and KIT were the only known frequent non-driver genes in MPNs which were found mutated in this study. The highest frequency (85.7%) was found of UGT1 A1 gene variant *28 with 71.4% heterozygous (*1/*28) and 14.2% homozygous genotype (*28/*28). Second most common (64.2%) detected gene variants were of MTHFR with WT/c.1298A > C, c.1298A > C/c.1298A > C and c.677C > T/c.1298A > C genotypes 28.5%, 28.5% and 7.1%, respectively. Frequency of TP53 substitution c.215C > G was 57.1% and XRCC1 c.1196 A > G was 42.8%. KIT CNV was 42.8% whereas KIT substitution c.1924A > G was 7.1%. The frequency of DPYD *9A/c.496A > G/ IVS1 0-15 T > C and *2A/*9A/c.496A > G was 21.4%. The lowest frequency (7.1%) was observed of CYP2D6 *4/*41. KIT was significantly (P = 0.026) frequently mutated in primary myelofibrosis patients (4/5).

CONCLUSION

A distinct molecular landscape of non-driver genes was observed in MPNs from Pakistan and most of the genes detected belonged to drug metabolizing pathways.

摘要

背景

骨髓增殖性肿瘤（MPNs）中驱动基因突变的发现填补了诊断空白，然而，有一些非驱动基因在该疾病的表型中发挥着重要作用。本研究首次评估了巴基斯坦MPNs患者中非驱动基因的分子格局。

方法

使用包含333个癌症基因的检测板，通过下一代测序对14例MPNs患者（8例原发性血小板增多症、5例原发性骨髓纤维化和1例真性红细胞增多症）的样本进行研究。在SPSS 22.0中进行卡方检验，以检查非驱动基因与MPNs亚类的相关性。

结果

在333个与肿瘤学相关的基因中，在2.1%的分析基因（7/333）中鉴定出可能的致病变异。TP53和KIT是MPNs中仅有的已知常见非驱动基因，在本研究中发现它们发生了突变。UGT1 A1基因变体*28的频率最高（85.7%），杂合子（*1/*28）为71.4%，纯合子基因型（*28/*28）为14.2%。第二常见（64.2%）的检测到的基因变体是MTHFR，其WT/c.1298A＞C、c.1298A＞C/c.1298A＞C和c.677C＞T/c.1298A＞C基因型分别为28.5%、28.5%和7.1%。TP53替换c.215C＞G的频率为57.1%，XRCC1 c.1196 A＞G的频率为42.8%。KIT拷贝数变异（CNV）为42.8%，而KIT替换c.1924A＞G为7.1%。DPYD 9A/c.496A＞G/IVS1 0-15 T＞C和2A/*9A/c.496A＞G的频率为21.4%。观察到CYP2D6 *4/*41的频率最低（7.1%）。KIT在原发性骨髓纤维化患者中显著（P = 0.026）频繁突变（4/5）。