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Background <p>Endometrial cancer represents a significant global health challenge, with undifferentiated and dedifferentiated endometrial carcinoma (UDEC) being a particularly aggressive subset.</p> Methods <p>We employed whole-exome sequencing (WES) to comprehensively characterize the molecular landscape of 29 UDECs in a single institution cohort. We analyzed driver mutations, molecular subgroups, SWI/SNF complex, DNA mismatch repair (MMR) pathways, and somatic copy number alterations (SCNAs).</p> Results <p>We identified 5 (17%) ultramutated tumors, 14 (48%) DNA mismatch repair (MMR)-deficient tumors, and 10 (35%) mutation-low tumors in this cohort. Mutations in the SWI/SNF family and other driver genes are common, including <i>PTEN</i>, <i>ARID1A</i>, <i>KMT2B</i>, <i>ARID1B</i>, <i>SMARCA4</i>, and <i>PIK3CA</i>. Genomic inactivation of SWI/SNF complex genes occurred in 19 of 29 (66%) of cases, highlighting the frequent chromatin remodeling dysfunction in UDEC. We observed frequent homopolymer mutations in UDECs with MMR deficiency, with <i>RPL22</i><sup><i>K15Rfs*5</i></sup> mutation found in 10 of 14 (71%) MMR-deficient tumors. Notably, ultramutated tumors demonstrated superior survival compared to the other two subtypes.</p> Conclusions <p>Our analysis revealed distinct architectures and actionable alterations in UDEC. The identification of molecular subgroups provides a promising framework for prognostic stratification. Collectively, our findings not only advance our understanding of UDEC biology but also illuminate potential translational applications.</p>

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Distinct genomic subgroups and mutational patterns in undifferentiated/dedifferentiated endometrial carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月9日

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  • Chen-Yang Huang,
  • Angel Chao,
  • Chiao-Yun Lin,
  • Steven G. Rozen,
  • An-Shine Chao,
  • Chen-Bin Chang,
  • Hsiu-Jung Tung,
  • Ren-Chin Wu,
  • Chyong-Huey Lai

摘要

Background

Endometrial cancer represents a significant global health challenge, with undifferentiated and dedifferentiated endometrial carcinoma (UDEC) being a particularly aggressive subset.

Methods

We employed whole-exome sequencing (WES) to comprehensively characterize the molecular landscape of 29 UDECs in a single institution cohort. We analyzed driver mutations, molecular subgroups, SWI/SNF complex, DNA mismatch repair (MMR) pathways, and somatic copy number alterations (SCNAs).

Results

We identified 5 (17%) ultramutated tumors, 14 (48%) DNA mismatch repair (MMR)-deficient tumors, and 10 (35%) mutation-low tumors in this cohort. Mutations in the SWI/SNF family and other driver genes are common, including PTEN, ARID1A, KMT2B, ARID1B, SMARCA4, and PIK3CA. Genomic inactivation of SWI/SNF complex genes occurred in 19 of 29 (66%) of cases, highlighting the frequent chromatin remodeling dysfunction in UDEC. We observed frequent homopolymer mutations in UDECs with MMR deficiency, with RPL22K15Rfs*5 mutation found in 10 of 14 (71%) MMR-deficient tumors. Notably, ultramutated tumors demonstrated superior survival compared to the other two subtypes.

Conclusions

Our analysis revealed distinct architectures and actionable alterations in UDEC. The identification of molecular subgroups provides a promising framework for prognostic stratification. Collectively, our findings not only advance our understanding of UDEC biology but also illuminate potential translational applications.