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Background <p>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.</p> Methods <p>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.</p> Result <p>Among 333 oncology related genes, possible pathogenic variations were identified in 2.1% of analyzed genes (7/333). <i>TP</i>53 and <i>KIT</i> 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 <i>UGT1 A1</i>&#xa0;gene variant <i>*28</i> with 71.4% heterozygous (*1/*28) and 14.2% homozygous genotype (*28/*28). Second most common (64.2%) detected gene variants were of <i>MTHFR</i> with WT/c.1298A &gt; C, c.1298A &gt; C/c.1298A &gt; C and c.677C &gt; T/c.1298A &gt; C genotypes 28.5%, 28.5% and 7.1%, respectively. Frequency of <i>TP</i>53 substitution c.215C &gt; G was 57.1% and <i>XRCC1 c.1196 A</i> &gt; <i>G</i> was 42.8%. <i>KIT</i> CNV was 42.8% whereas <i>KIT</i> substitution c.1924A &gt; G was 7.1%. The frequency of <i>DPYD</i> *9A/c.496A &gt; G/ IVS1 0-15&#xa0;T &gt; C and *2A/*9A/c.496A &gt; G was 21.4%. The lowest frequency (7.1%) was observed of <i>CYP</i>2D6 *4/*41. <i>KIT</i> was significantly (<i>P</i> = 0.026) frequently mutated in primary myelofibrosis patients (4/5).</p> Conclusion <p>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.</p>

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

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  • 发表日期：

    2025年8月4日

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

摘要

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.