Abstract：
Endometrial serous carcinoma (ESC) and tubo-ovarian high-grade serous carcinoma (HGSC) are characterized by late-stage presentation and high mortality. Current guidelines for prevention recommend risk-reducing salpingo-oophorectomy (RRSO) in patients with hereditary mutations in cancer susceptibility genes. However, HGSC displays extensive genetic heterogeneity with alterations in 168 genes identified in TCGA study, but current germline testing panels are often limited to the handful of recurrently mutated genes, leaving families with rare hereditary gene mutations potentially at-risk.
To determine if there are rare germline mutations that may aid in early identification of more patients at-risk for ESC and/or HGSC by evaluating patients with concurrent ESC, HGSC or precursor lesions, and endometrial atypical hyperplasia (CAH) or low-grade endometrial endometrioid adenocarcinoma (LGEEA).
We performed targeted next-generation sequencing using TSO 500, a 523 gene panel, on formalin-fixed paraffin-embedded tumor and matched benign non-tumor tissue blocks from 5 patients with concurrent ESC, HGSC or precursor lesions, and CAH or LGEEA.
We identified germline pathogenic, likely pathogenic or uncertain significance variants in cancer susceptibility genes in 4 of 5 patients - affected genes included GLI1, PIK3R1, FOXP1, FANCD2, INPP4B and H3F3C. Notably, none of these genes were included in the commercially available germline testing panels initially used to evaluate the patients at the time of their diagnoses.
Comprehensive germline testing of patients with concurrent LGEEA or CAH and ESC, HGSC or precursor lesions may aid in early identification of relatives at-risk for cancer who may be candidates for RRSO with hysterectomy.
To determine if there are rare germline mutations that may aid in early identification of more patients at-risk for ESC and/or HGSC by evaluating patients with concurrent ESC, HGSC or precursor lesions, and endometrial atypical hyperplasia (CAH) or low-grade endometrial endometrioid adenocarcinoma (LGEEA).
We performed targeted next-generation sequencing using TSO 500, a 523 gene panel, on formalin-fixed paraffin-embedded tumor and matched benign non-tumor tissue blocks from 5 patients with concurrent ESC, HGSC or precursor lesions, and CAH or LGEEA.
We identified germline pathogenic, likely pathogenic or uncertain significance variants in cancer susceptibility genes in 4 of 5 patients - affected genes included GLI1, PIK3R1, FOXP1, FANCD2, INPP4B and H3F3C. Notably, none of these genes were included in the commercially available germline testing panels initially used to evaluate the patients at the time of their diagnoses.
Comprehensive germline testing of patients with concurrent LGEEA or CAH and ESC, HGSC or precursor lesions may aid in early identification of relatives at-risk for cancer who may be candidates for RRSO with hysterectomy.
摘要：
背景：子宫内膜浆液性癌（ESC）和输卵管卵巢高级别浆液性癌（HGSC）的特征是晚期表现和高死亡率。当前的预防指南建议对具有癌症易感基因遗传突变的患者进行降低风险的输卵管卵巢切除术（RRSO）。然而,HGSC表现出广泛的遗传异质性，在TCGA研究中鉴定出的168个基因发生了改变，但是目前的种系测试小组通常仅限于少数反复突变的基因，使具有罕见遗传性基因突变的家庭可能处于危险之中。
目的：通过评估并发ESC的患者，确定是否存在可能有助于早期识别更多ESC和/或HGSC风险患者的罕见种系突变，HGSC或前病变，子宫内膜非典型增生（CAH）或低度子宫内膜样腺癌（LGEEA）。
方法：我们使用TSO500（一种523基因组）进行了靶向下一代测序，在5例并发ESC患者的福尔马林固定石蜡包埋的肿瘤和匹配的良性非肿瘤组织块上，HGSC或前病变，和CAH或LGEA。
结果：我们确定了种系致病性，5例患者中4例的癌症易感基因中可能的致病或不确定的显著性变异包括GLI1,PIK3R1,FOXP1,FANCD2,INPP4B和H3F3C.值得注意的是,这些基因均未包括在最初用于在诊断时评估患者的市售种系测试组中.
结论：对合并LGEEA或CAH和ESC的患者进行综合种系测试，HGSC或前体病变可能有助于早期识别有癌症风险的亲属，这些亲属可能是子宫切除术后RRSO的候选人。
目的：通过评估并发ESC的患者，确定是否存在可能有助于早期识别更多ESC和/或HGSC风险患者的罕见种系突变，HGSC或前病变，子宫内膜非典型增生（CAH）或低度子宫内膜样腺癌（LGEEA）。
方法：我们使用TSO500（一种523基因组）进行了靶向下一代测序，在5例并发ESC患者的福尔马林固定石蜡包埋的肿瘤和匹配的良性非肿瘤组织块上，HGSC或前病变，和CAH或LGEA。
结果：我们确定了种系致病性，5例患者中4例的癌症易感基因中可能的致病或不确定的显著性变异包括GLI1,PIK3R1,FOXP1,FANCD2,INPP4B和H3F3C.值得注意的是,这些基因均未包括在最初用于在诊断时评估患者的市售种系测试组中.
结论：对合并LGEEA或CAH和ESC的患者进行综合种系测试，HGSC或前体病变可能有助于早期识别有癌症风险的亲属，这些亲属可能是子宫切除术后RRSO的候选人。
