Abstract：
Hereditary uterine cancer (UC) is traditionally associated with pathogenic/likely pathogenic germline variants (PGVs) in Lynch syndrome genes or PTEN; however, growing evidence supports a role for other genes that may reveal new clinical management options. In this study we assessed the prevalence and potential clinical impact of PGVs identified in UC patients referred for comprehensive germline genetic testing that combined testing for Lynch syndrome, PTEN, and other cancer predisposition genes.
Prevalence of PGVs in patients referred to a single clinical lab for germline genetic testing with an indication of uterine or endometrial cancer were retrospectively assessed and compared by syndrome type, patient age at testing, and self-reported ancestry. Potential clinical actionability of PGVs was based on established guidelines for clinical management, targeted therapies, and clinical trial eligibility.
PGVs were detected in 13.6% of the cohort (880/6490). PGVs were most frequently observed in Lynch syndrome genes (60.4%) and PTEN (1.5%), with 38.1% in another cancer predisposition gene (i.e., CHEK2, BRCA1/BRCA2). PGV prevalence was similar for patients <50 years and those ≥50 years (15.1% vs 13.2%). Nearly all PGVs (97.2%) were associated with guideline-recommended management, including cascade testing; 60.5% were associated with FDA-approved therapies; and 35.2% were associated with clinical trials.
Focusing germline testing on Lynch syndrome genes and PTEN and limiting testing to patients <50 years of age at diagnosis may overlook a substantial proportion of UC patients who harbor actionable PGVs. Universal comprehensive genetic testing of UC patients could benefit many patients and at-risk family members.
Prevalence of PGVs in patients referred to a single clinical lab for germline genetic testing with an indication of uterine or endometrial cancer were retrospectively assessed and compared by syndrome type, patient age at testing, and self-reported ancestry. Potential clinical actionability of PGVs was based on established guidelines for clinical management, targeted therapies, and clinical trial eligibility.
PGVs were detected in 13.6% of the cohort (880/6490). PGVs were most frequently observed in Lynch syndrome genes (60.4%) and PTEN (1.5%), with 38.1% in another cancer predisposition gene (i.e., CHEK2, BRCA1/BRCA2). PGV prevalence was similar for patients <50 years and those ≥50 years (15.1% vs 13.2%). Nearly all PGVs (97.2%) were associated with guideline-recommended management, including cascade testing; 60.5% were associated with FDA-approved therapies; and 35.2% were associated with clinical trials.
Focusing germline testing on Lynch syndrome genes and PTEN and limiting testing to patients <50 years of age at diagnosis may overlook a substantial proportion of UC patients who harbor actionable PGVs. Universal comprehensive genetic testing of UC patients could benefit many patients and at-risk family members.
摘要：
遗传性子宫癌（UC）传统上与Lynch综合征基因或PTEN中的致病性/可能致病性种系变异体（PGV）相关；然而，越来越多的证据支持其他基因的作用，这些基因可能揭示新的临床管理选择。在这项研究中，我们评估了在UC患者中确定的PGV的患病率和潜在的临床影响，这些患者被称为综合种系基因检测，联合检测Lynch综合征。PTEN,和其他癌症易感性基因。
回顾性评估了在单一临床实验室进行生殖系基因检测的患者中PGV的患病率，并根据综合征类型进行了比较。患者年龄在测试，和自我报告的祖先。PGV的潜在临床可操作性是基于既定的临床管理指南，靶向治疗,和临床试验资格。
在13.6%的队列中检测到PGV(880/6490)。PGV在Lynch综合征基因（60.4％）和PTEN（1.5％）中最常见，在另一个癌症易感性基因中有38.1%(即，CHEK2，BRCA1/BRCA2）。<50岁和≥50岁患者的PGV患病率相似（15.1%vs13.2%）。几乎所有PGV(97.2%)都与指南推荐的管理相关，包括级联测试;60.5%与FDA批准的治疗相关;35.2%与临床试验相关.
将种系检测集中在Lynch综合征基因和PTEN上，并将检测限制在诊断时年龄<50岁的患者，可能会忽略相当大比例的携带可操作PGV的UC患者。UC患者的通用综合基因检测可以使许多患者和高危家庭成员受益。
回顾性评估了在单一临床实验室进行生殖系基因检测的患者中PGV的患病率，并根据综合征类型进行了比较。患者年龄在测试，和自我报告的祖先。PGV的潜在临床可操作性是基于既定的临床管理指南，靶向治疗,和临床试验资格。
在13.6%的队列中检测到PGV(880/6490)。PGV在Lynch综合征基因（60.4％）和PTEN（1.5％）中最常见，在另一个癌症易感性基因中有38.1%(即，CHEK2，BRCA1/BRCA2）。<50岁和≥50岁患者的PGV患病率相似（15.1%vs13.2%）。几乎所有PGV(97.2%)都与指南推荐的管理相关，包括级联测试;60.5%与FDA批准的治疗相关;35.2%与临床试验相关.
将种系检测集中在Lynch综合征基因和PTEN上，并将检测限制在诊断时年龄<50岁的患者，可能会忽略相当大比例的携带可操作PGV的UC患者。UC患者的通用综合基因检测可以使许多患者和高危家庭成员受益。
