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Background <p>Molecular profiling has transformed risk stratification in myelodysplastic neoplasms (MDS). However, the independent prognostic value of specific genomic alterations beyond comprehensive molecular scoring remains unclear. We investigated whether <i>CUX1</i> copy-number loss (haploinsufficiency) adds prognostic value and its association with other mutations. Given its correlation with chromosome 7 abnormality, we examined its independent significance within the current MDS molecular framework.</p> Methods <p>A cohort of 501 MDS patients with available <i>CUX1</i> copy-number data (CNACS gene-level calls) and complete clinical follow-up was analyzed from cBioPortal. We assessed associations with clinical characteristics, co-occurring alterations, and survival. Cox proportional hazards models evaluated independence adjusting for IPSS-R and IPSS-M.</p> Results <p><i>CUX1</i> loss occurred in 129/501 patients (26%), nearly always with − 7/del(7q) (98%). Patients with <i>CUX1</i> loss had higher marrow blasts (median 7% vs. 4%, <i>P</i> &lt; 0.001), IPSS-R scores (6.9 vs. 4.6), and IPSS-M scores (2.33 vs. 0.79). <i>CUX1</i> loss strongly associated with <i>EZH2</i> alterations (OR 223.8) and complex karyotype (60%). In univariable analysis, <i>CUX1</i> loss predicted inferior overall survival (OS; median 11.8 vs. 27.1 months; HR 2.39, 95%CI 1.85–3.08, <i>P</i> &lt; 0.001) and leukemia-free survival (LFS; HR 2.30, 95%CI 1.78–2.98, <i>P</i> &lt; 0.001). After IPSS-M adjustment, associations were non-significant (OS HR 1.27, <i>P</i> = 0.11; LFS HR 1.23, <i>P</i> = 0.15) with negligible incremental discrimination. Within the − 7/del(7q) subgroup, no survival difference was detected (OS <i>P</i> = 0.41; LFS <i>P</i> = 0.31).</p> Conclusion <p><i>CUX1</i> loss identifies high-risk MDS with − 7/del(7q) and <i>EZH2</i> co-alterations but provides no independent prognostic information beyond IPSS-M. Isolated <i>CUX1</i> deletions are rare. <i>CUX1</i> loss reflects − 7/del(7q) biology rather than independent prognostic significance.</p>

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Prognostic significance of CUX1 genomic deletion in myelodysplastic neoplasms

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月13日

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  • Mohamed M. Khamis,
  • Aleksandar Babic,
  • Aref Al-Kali,
  • Omar Alkharabsheh

摘要

Background

Molecular profiling has transformed risk stratification in myelodysplastic neoplasms (MDS). However, the independent prognostic value of specific genomic alterations beyond comprehensive molecular scoring remains unclear. We investigated whether CUX1 copy-number loss (haploinsufficiency) adds prognostic value and its association with other mutations. Given its correlation with chromosome 7 abnormality, we examined its independent significance within the current MDS molecular framework.

Methods

A cohort of 501 MDS patients with available CUX1 copy-number data (CNACS gene-level calls) and complete clinical follow-up was analyzed from cBioPortal. We assessed associations with clinical characteristics, co-occurring alterations, and survival. Cox proportional hazards models evaluated independence adjusting for IPSS-R and IPSS-M.

Results

CUX1 loss occurred in 129/501 patients (26%), nearly always with − 7/del(7q) (98%). Patients with CUX1 loss had higher marrow blasts (median 7% vs. 4%, P < 0.001), IPSS-R scores (6.9 vs. 4.6), and IPSS-M scores (2.33 vs. 0.79). CUX1 loss strongly associated with EZH2 alterations (OR 223.8) and complex karyotype (60%). In univariable analysis, CUX1 loss predicted inferior overall survival (OS; median 11.8 vs. 27.1 months; HR 2.39, 95%CI 1.85–3.08, P < 0.001) and leukemia-free survival (LFS; HR 2.30, 95%CI 1.78–2.98, P < 0.001). After IPSS-M adjustment, associations were non-significant (OS HR 1.27, P = 0.11; LFS HR 1.23, P = 0.15) with negligible incremental discrimination. Within the − 7/del(7q) subgroup, no survival difference was detected (OS P = 0.41; LFS P = 0.31).

Conclusion

CUX1 loss identifies high-risk MDS with − 7/del(7q) and EZH2 co-alterations but provides no independent prognostic information beyond IPSS-M. Isolated CUX1 deletions are rare. CUX1 loss reflects − 7/del(7q) biology rather than independent prognostic significance.