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Background <p>The molecular mechanisms of colorectal cancer (CRC)–ovarian metastasis (OM) remain unclear, and this study aimed to identify the genetic determinants.</p> Methods <p>We retrospectively included 81 CRC patients developing OM. Treatment-naïve primary and metastatic lesion tissue samples underwent DNA sequencing to identify gene-level and global genomic OM determinants. Two external CRC cohorts (MSKCC cohort, <i>N</i> = 643; TCGA cohort, <i>N</i> = 448) were analyzed for mechanism exploration.</p> Results <p>Copy number variations (CNVs) of <i>SMAD4</i> (<i>p</i> &lt; 0.01) and <i>SMAD2</i> (<i>p</i> &lt; 0.01) were more common in metastatic lesions than in primary lesions, with similar findings (<i>SMAD4</i>, <i>p</i> = 0.05; <i>SMAD4</i>, <i>p</i> = 0.02) in 28 pairs of matched samples. Unfavorable overall survival was associated with <i>SMAD4</i> (<i>p</i> &lt; 0.001) and <i>SMAD2</i> (<i>p</i> = 0.09) CNV loss. RNA sequencing data demonstrated an upregulated angiogenesis pathway related to <i>SMAD4</i> (<i>q</i> = 0.03) and <i>SMAD2</i> (<i>q</i> &lt; 0.001) CNV loss. Metastatic lesions exhibited higher chromosome instability scores than primary lesions (<i>p</i> &lt; 0.01), consistent with findings in the MSKCC cohort (<i>p</i> &lt; 0.001). Compared to metachronous metastasis, the primary (<i>p</i> = 0.04) and metastatic (<i>p</i> = 0.01) lesions of synchronous metastasis showed a heavier APOBEC signature burden. <i>FLT1</i> (17.6%) and <i>ZNF217</i> (17.6%) CNV gains were exclusively detected in metastatic lesions of synchronous metastasis, whereas primary lesions of metachronous metastasis exhibited higher whole-genome doubling fraction (<i>p</i> = 0.04) and ploidy (<i>p</i> = 0.02).</p> Conclusions <p><i>SMAD4/2</i> CNV loss and chromosome instability are enriched in ovarian metastases of colorectal cancer. Synchronous and metachronous ovarian metastases also show distinct genomic features. Further mechanistic studies are needed to clarify the biological roles of these alterations.</p>

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Gene-level and global genomic insights into colorectal cancer ovarian metastasis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月29日

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  • Ying Fang,
  • Yan Sun,
  • Ningyou Li,
  • Xiaotian Zhao,
  • Xiaoying Wu,
  • Jiaohui Pang,
  • Qiuxiang Ou,
  • Hua Bao,
  • Che Chen,
  • Ziwei Xu

摘要

Background

The molecular mechanisms of colorectal cancer (CRC)–ovarian metastasis (OM) remain unclear, and this study aimed to identify the genetic determinants.

Methods

We retrospectively included 81 CRC patients developing OM. Treatment-naïve primary and metastatic lesion tissue samples underwent DNA sequencing to identify gene-level and global genomic OM determinants. Two external CRC cohorts (MSKCC cohort, N = 643; TCGA cohort, N = 448) were analyzed for mechanism exploration.

Results

Copy number variations (CNVs) of SMAD4 (p < 0.01) and SMAD2 (p < 0.01) were more common in metastatic lesions than in primary lesions, with similar findings (SMAD4, p = 0.05; SMAD4, p = 0.02) in 28 pairs of matched samples. Unfavorable overall survival was associated with SMAD4 (p < 0.001) and SMAD2 (p = 0.09) CNV loss. RNA sequencing data demonstrated an upregulated angiogenesis pathway related to SMAD4 (q = 0.03) and SMAD2 (q < 0.001) CNV loss. Metastatic lesions exhibited higher chromosome instability scores than primary lesions (p < 0.01), consistent with findings in the MSKCC cohort (p < 0.001). Compared to metachronous metastasis, the primary (p = 0.04) and metastatic (p = 0.01) lesions of synchronous metastasis showed a heavier APOBEC signature burden. FLT1 (17.6%) and ZNF217 (17.6%) CNV gains were exclusively detected in metastatic lesions of synchronous metastasis, whereas primary lesions of metachronous metastasis exhibited higher whole-genome doubling fraction (p = 0.04) and ploidy (p = 0.02).

Conclusions

SMAD4/2 CNV loss and chromosome instability are enriched in ovarian metastases of colorectal cancer. Synchronous and metachronous ovarian metastases also show distinct genomic features. Further mechanistic studies are needed to clarify the biological roles of these alterations.