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Purpose <p>Lynch syndrome (LS), the most common hereditary colorectal cancer (CRC), is caused by germline mutations in mismatch repair (MMR) genes, resulting in microsatellite instability-high (MSI-H) tumors. Lynch-like syndrome (LL) exhibits MSI-H and MMR deficiency, but lacks identifiable germline MMR mutations. Although LS/LL CRCs share clinical and molecular features, they are distinct from sporadic MSI-H (SM) CRCs, emphasizing the need for refined molecular classification. This study investigated the somatic alterations that distinguish LS/LL CRC from SM CRC.</p> Methods <p>Whole-exome sequencing (WES) was performed on 49 LS/LL CRC and 96 SM CRC samples. Tumor-normal paired data were analyzed using GATK and MuTect2 to detect somatic variants. Mutation frequencies were compared using Fisher’s exact test (<i>p</i> &lt; 0.005). Logistic regression and receiver operating characteristic (ROC) curve analyses were used to evaluate the discriminatory performance.</p> Results <p>We identified 11 gene regions that were significantly enriched in LS/LL CRC, including KRAS, ITGB3BP, CLEC16A, ARHGEF28, PIK3CA, and RBM26. A variant panel based on these alterations showed an area under the curve (AUC) of 0.85 and an Akaike information criterion of 129.81.</p> Conclusions <p>These findings support the utility of LS/LL-specific somatic variants in stratifying MSI-H CRCs and identifying hereditary cases for personalized management.</p>

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Identification of the Lynch syndrome and Lynch-like syndrome specific somatic mutations in microsatellite instability-high colorectal cancer cases

  • 期刊论文

  • 发表日期：

    2025年12月24日

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  • Takashi Ofuchi,
  • Kosuke Hirose,
  • Kiyotaka Hosoda,
  • Tomohiko Ikehara,
  • Satoshi Higuchi,
  • Akinori Tsujimoto,
  • Aoi Wada,
  • Yuta Tamaoka,
  • Yasuo Tsuda,
  • Hajime Otsu,
  • Yusuke Yonemura,
  • Masaaki Iwatsuki,
  • Koshi Mimori

摘要

Purpose

Lynch syndrome (LS), the most common hereditary colorectal cancer (CRC), is caused by germline mutations in mismatch repair (MMR) genes, resulting in microsatellite instability-high (MSI-H) tumors. Lynch-like syndrome (LL) exhibits MSI-H and MMR deficiency, but lacks identifiable germline MMR mutations. Although LS/LL CRCs share clinical and molecular features, they are distinct from sporadic MSI-H (SM) CRCs, emphasizing the need for refined molecular classification. This study investigated the somatic alterations that distinguish LS/LL CRC from SM CRC.

Methods

Whole-exome sequencing (WES) was performed on 49 LS/LL CRC and 96 SM CRC samples. Tumor-normal paired data were analyzed using GATK and MuTect2 to detect somatic variants. Mutation frequencies were compared using Fisher’s exact test (p < 0.005). Logistic regression and receiver operating characteristic (ROC) curve analyses were used to evaluate the discriminatory performance.

Results

We identified 11 gene regions that were significantly enriched in LS/LL CRC, including KRAS, ITGB3BP, CLEC16A, ARHGEF28, PIK3CA, and RBM26. A variant panel based on these alterations showed an area under the curve (AUC) of 0.85 and an Akaike information criterion of 129.81.

Conclusions

These findings support the utility of LS/LL-specific somatic variants in stratifying MSI-H CRCs and identifying hereditary cases for personalized management.