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<p>In recent years, new cases of thyroid cancer (TC) in China have accounted for about 10% of all newly diagnosed malignant tumors, ranking as the third most common cancer. Familial papillary thyroid carcinoma (fPTC) is a hereditary subtype for which large-scale clinical cohort studies are lacking and definitive susceptibility genes remain elusive. A large fPTC clinical cohort (171 cases), 490 sporadic papillary thyroid carcinoma (sPTC) patients, and 500 healthy blood samples from physical examination were collected in the study. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) were used to screen for susceptibility genes. Three <i>MCM2</i> gene mutations (c.1092 C &gt; G, p.N364K; c.1975A&gt;G, p.I659V; and c. 2379 G &gt; A, p.M793I) in 8 patients from 4 distinct families were identified as candidate susceptibility variants. These mutations disrupt the interaction of <i>MCM2</i> with its partner proteins (<i>MCM3</i>-7), leading to ubiquitination of free MCM monomers. Levels of DNA damage, <b>γ</b>-H2AX foci, RPA foci, and micronucleus formation were significantly elevated in <i>MCM2</i>-deficient cells. Cell-derived xenograft (CDX) modeling, combined with WES and RNA-seq analyses, revealed that <i>MCM2</i>-deficient tumors exhibited significantly faster growth rates and increased chromosomal instability (CIN). MAPK signaling and the PI3K-AKT pathway were significantly over-activated in <i>MCM2</i>-deficient tumors. In our study, based on the fPTC cohort, germline variants of <i>MCM2</i> predispose to fPTC. The variants disrupt the MCM complex, leading to ubiquitination of free monomeric MCM proteins. <i>MCM2</i> deficiency induces cell cycle arrest, DNA damage, and CIN, ultimately accelerating tumorigenesis through oncogenic pathway activation. These findings identify <i>MCM2</i> as a low-frequency, moderately penetrant susceptibility gene for fPTC and underscore the clinical value of <i>MCM2</i> testing in informing early detection, preventive management, and precision treatment strategies for familial papillary thyroid carcinoma.</p>

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MCM2 germline variants predispose to familial papillary thyroid carcinoma due to genomic instability caused by MCM complex disruption

  • 期刊论文

  • 发表日期：

    2026年6月18日

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  • Shiyu Cao,
  • Tengyun Ma,
  • Long Zhao,
  • Lin Xiao,
  • Peichuan Zhang,
  • Yuze Han,
  • Yichen Liu,
  • Yong Jiang,
  • Feng Ye

摘要

In recent years, new cases of thyroid cancer (TC) in China have accounted for about 10% of all newly diagnosed malignant tumors, ranking as the third most common cancer. Familial papillary thyroid carcinoma (fPTC) is a hereditary subtype for which large-scale clinical cohort studies are lacking and definitive susceptibility genes remain elusive. A large fPTC clinical cohort (171 cases), 490 sporadic papillary thyroid carcinoma (sPTC) patients, and 500 healthy blood samples from physical examination were collected in the study. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) were used to screen for susceptibility genes. Three MCM2 gene mutations (c.1092 C > G, p.N364K; c.1975A>G, p.I659V; and c. 2379 G > A, p.M793I) in 8 patients from 4 distinct families were identified as candidate susceptibility variants. These mutations disrupt the interaction of MCM2 with its partner proteins (MCM3-7), leading to ubiquitination of free MCM monomers. Levels of DNA damage, γ-H2AX foci, RPA foci, and micronucleus formation were significantly elevated in MCM2-deficient cells. Cell-derived xenograft (CDX) modeling, combined with WES and RNA-seq analyses, revealed that MCM2-deficient tumors exhibited significantly faster growth rates and increased chromosomal instability (CIN). MAPK signaling and the PI3K-AKT pathway were significantly over-activated in MCM2-deficient tumors. In our study, based on the fPTC cohort, germline variants of MCM2 predispose to fPTC. The variants disrupt the MCM complex, leading to ubiquitination of free monomeric MCM proteins. MCM2 deficiency induces cell cycle arrest, DNA damage, and CIN, ultimately accelerating tumorigenesis through oncogenic pathway activation. These findings identify MCM2 as a low-frequency, moderately penetrant susceptibility gene for fPTC and underscore the clinical value of MCM2 testing in informing early detection, preventive management, and precision treatment strategies for familial papillary thyroid carcinoma.