Allen-Brady Kristina, Moore Barry, Verrilli Lauren E, Alvord Margaret A, Kern Marina, Camp Nicola, Kelley Kristen, Letourneau Joseph, Cannon-Albright Lisa, Yandell Mark, Johnstone Erica B, Welt Corrine K
Division of Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108, USA.
Utah Center for Genetic Discovery, Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.
J Clin Endocrinol Metab. 2025 Apr 22;110(5):e1678-e1686. doi: 10.1210/clinem/dgae480.
DNA damage/repair gene variants are associated with both primary ovarian insufficiency (POI) and cancer risk.
We hypothesized that a subset of women with POI and family members would have increased risk for cancer.
Case-control population-based study using records from 1995 to 2022.
Two major Utah academic health care systems serving 85% of the state.
Women with POI (n = 613) were identified using International Classification of Diseases codes and reviewed for accuracy. Relatives were linked using the Utah Population Database.
Cancer diagnoses were identified using the Utah Cancer Registry.
The relative risk of cancer in women with POI and relatives was estimated by comparison to population rates. Whole genome sequencing was performed on a subset of women.
Breast cancer was increased in women with POI (OR, 2.20; 95% CI, 1.30-3.47; P = .0023) and there was a nominally significant increase in ovarian cancer. Probands with POI were 36.5 ± 4.3 years and 59.5 ± 12.7 years when diagnosed with POI and cancer, respectively. Causal and candidate gene variants for cancer and POI were identified. Among second-degree relatives of these women, there was an increased risk of breast (OR, 1.28; 95% CI, 1.08-1.52; P = .0078) and colon cancer (OR, 1.50; 95% CI, 1.14-1.94; P = .0036). Prostate cancer was increased in first- (OR, 1.64; 95% CI, 1.18-2.23; P = .0026), second- (OR, 1.54; 95% CI, 1.32-1.79; P < .001), and third-degree relatives (OR, 1.33; 95% CI, 1.20-1.48; P < .001).
Data suggest common genetic risk for POI and reproductive cancers. Tools are needed to predict cancer risk in women with POI and potentially to counsel about risks of hormone replacement therapy.
DNA损伤/修复基因变异与原发性卵巢功能不全（POI）和癌症风险均相关。
我们假设患有POI的女性及其家庭成员患癌症的风险会增加。
基于病例对照的人群研究，使用1995年至2022年的记录。
犹他州两个主要的学术医疗系统，覆盖该州85%的人口。
使用国际疾病分类代码识别出患有POI的女性（n = 613），并对其准确性进行审核。通过犹他州人口数据库将亲属关联起来。
使用犹他州癌症登记处识别癌症诊断情况。
通过与总体发病率比较，估计患有POI的女性及其亲属患癌症的相对风险。对一部分女性进行全基因组测序。
患有POI的女性患乳腺癌的风险增加（比值比[OR]，2.20；95%置信区间[CI]，1.30 - 3.47；P = 0.0023），卵巢癌也有明显增加。患有POI的先证者在被诊断为POI和癌症时的年龄分别为36.5±4.3岁和59.5±12.7岁。确定了癌症和POI的因果及候选基因变异。在这些女性的二级亲属中，患乳腺癌（OR，1.28；95% CI，1.08 - 1.52；P = 0.0078）和结肠癌（OR，1.50；95% CI，1.14 - 1.94；P = 0.0036）的风险增加。在一级（OR，1.64；95% CI，1.18 - 2.23；P = 0.0026）、二级（OR，1.54；95% CI，1.32 - 1.79；P < 0.001）和三级亲属中，前列腺癌的发病风险增加（OR，1.33；95% CI，1.20 - 1.48；P < 0.001）。
数据表明POI和生殖系统癌症存在共同的遗传风险。需要工具来预测患有POI的女性患癌症的风险，并可能就激素替代疗法的风险提供咨询。
