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Background <p>Pathogenic/likely pathogenic variants (P/LPVs) in DNA damage response (DDR) genes are known ovarian cancer (OC) risk factors, but gene-specific risk estimates in Han Chinese remain unclear.</p> Objective <p>To accurately assess the risk associated with DDR genes in the Han Chinese population to facilitate personalized risk management and enhance clinical decision-making.</p> Methods <p>We performed next-generation sequencing of 45 DDR genes in 666&#xa0;OC patients from Henan, China. Associations between P/LPVs and clinical features were assessed using chi-squared tests. Variant frequencies were compared with population controls (gnomAD and ChinaMAP databases) to estimate gene-specific odds ratios (ORs) using Fisher’s test.</p> Results <p>In Henan Ovarian Cancer patients, the median disease onset age was 53 years (range: 24–81), with 7.7% diagnosed before 40. Most patients had advanced disease (56.5% Stage III, 18.9% Stage IV), and 75.8% had high-grade serous carcinoma (HGSC). P/LPVs in <i>BRCA1/2</i> were significantly associated with the HGSC subtype and a positive family history (<i>p</i> &lt; 0.001 for both). Beyond <i>BRCA1</i> (OR = 125.5/146.1) and <i>BRCA2</i> (OR = 17.9/20.2), significantly elevated ovarian cancer risks were observed for <i>RAD51D</i>, <i>RAD51C</i>, and <i>MSH2</i> (OR: 10.1–35.4, all <i>p</i> &lt; 0.05).</p> Conclusions <p>This study provides the first gene-specific ovarian cancer risk estimates for DDR genes in Han Chinese, expanding the high-risk gene spectrum. By defining population-specific risk magnitudes, our findings provide a framework for clinical risk stratification, and underscore the need to tailor screening and prevention strategies to China’s distinct genetic landscape.</p>

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Mutational landscape and risk estimates of DDR genes in Chinese ovarian cancer patients

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月10日

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  • Cuiyun Zhang,
  • Bing Wei,
  • Xia Xue,
  • Qingxin Xia,
  • Yi Wang,
  • Lanwei Guo,
  • Tingjie Wang,
  • Li Wang,
  • Junli Deng,
  • Yuping Guan,
  • Xiaoyan Wang,
  • Lu Feng,
  • Rui Wu,
  • Ziqing Hu,
  • Klaas Kok,
  • Anke van den Berg,
  • Yongjun Guo,
  • Jun Li

摘要

Background

Pathogenic/likely pathogenic variants (P/LPVs) in DNA damage response (DDR) genes are known ovarian cancer (OC) risk factors, but gene-specific risk estimates in Han Chinese remain unclear.

Objective

To accurately assess the risk associated with DDR genes in the Han Chinese population to facilitate personalized risk management and enhance clinical decision-making.

Methods

We performed next-generation sequencing of 45 DDR genes in 666 OC patients from Henan, China. Associations between P/LPVs and clinical features were assessed using chi-squared tests. Variant frequencies were compared with population controls (gnomAD and ChinaMAP databases) to estimate gene-specific odds ratios (ORs) using Fisher’s test.

Results

In Henan Ovarian Cancer patients, the median disease onset age was 53 years (range: 24–81), with 7.7% diagnosed before 40. Most patients had advanced disease (56.5% Stage III, 18.9% Stage IV), and 75.8% had high-grade serous carcinoma (HGSC). P/LPVs in BRCA1/2 were significantly associated with the HGSC subtype and a positive family history (p < 0.001 for both). Beyond BRCA1 (OR = 125.5/146.1) and BRCA2 (OR = 17.9/20.2), significantly elevated ovarian cancer risks were observed for RAD51D, RAD51C, and MSH2 (OR: 10.1–35.4, all p < 0.05).

Conclusions

This study provides the first gene-specific ovarian cancer risk estimates for DDR genes in Han Chinese, expanding the high-risk gene spectrum. By defining population-specific risk magnitudes, our findings provide a framework for clinical risk stratification, and underscore the need to tailor screening and prevention strategies to China’s distinct genetic landscape.