Abstract：
OBJECTIVE: The treatment for stage IB grade 3 endometrioid endometrial adenocarcinoma is challenging with variable practice. Molecular characterization may help identify adjuvant therapy strategies beyond stage. We aimed to better understand the molecular features of these tumors by characterizing them by ProMisE classification, mutational signature, and commonly mutated genes.
METHODS: Patients with stage IB grade 3 EEC at two institutions were included. Immunohistochemistry and whole exome sequencing were performed on archival FFPE tissue sections to determine ProMisE classification. Personal Cancer Genome Reporter was used for somatic variant annotation, and mutational signatures were generated based on COSMIC single base substitution mutational signatures.
RESULTS: 46 patients were included with variable adjuvant treatment. Nine patients recurred (19.6%), most with extra-abdominal disease (n = 5, or 55.6%). 10 had POLE mutations (21.7%), 18 were MMR deficient (39.1%), 6 had abnormal p53 (13.0%), and 12 were p53 wildtype (26.1%). There were no recurrences in the POLE subgroup. A dominant mutational signature was identified in 38 patients: 17 SBS5 signature (44.7%), 10 SBS15 or SBS44 signature (26.3%), 7 SBS10a or SBS10b signature (18.4%), 3 SBS14 signature (7.9%), and 1 SBS40 signature (2.6%). The six patients that recurred had a SBS5 signature. Frequently mutated genes included ARID1A (n = 30, 65%), PTEN (n = 28, 61%), MUC16 (n = 27, 59%), and PIK3CA (n = 25, 54%).
CONCLUSIONS: This comprehensive evaluation found a molecularly diverse cohort of tumors, despite the same histology, stage and grade. Mutational signature SBS5 correlated with a high risk of recurrence. Further refining of endometrial cancer classification may enable more precise patient stratification and personalized treatment approaches.
METHODS: Patients with stage IB grade 3 EEC at two institutions were included. Immunohistochemistry and whole exome sequencing were performed on archival FFPE tissue sections to determine ProMisE classification. Personal Cancer Genome Reporter was used for somatic variant annotation, and mutational signatures were generated based on COSMIC single base substitution mutational signatures.
RESULTS: 46 patients were included with variable adjuvant treatment. Nine patients recurred (19.6%), most with extra-abdominal disease (n = 5, or 55.6%). 10 had POLE mutations (21.7%), 18 were MMR deficient (39.1%), 6 had abnormal p53 (13.0%), and 12 were p53 wildtype (26.1%). There were no recurrences in the POLE subgroup. A dominant mutational signature was identified in 38 patients: 17 SBS5 signature (44.7%), 10 SBS15 or SBS44 signature (26.3%), 7 SBS10a or SBS10b signature (18.4%), 3 SBS14 signature (7.9%), and 1 SBS40 signature (2.6%). The six patients that recurred had a SBS5 signature. Frequently mutated genes included ARID1A (n = 30, 65%), PTEN (n = 28, 61%), MUC16 (n = 27, 59%), and PIK3CA (n = 25, 54%).
CONCLUSIONS: This comprehensive evaluation found a molecularly diverse cohort of tumors, despite the same histology, stage and grade. Mutational signature SBS5 correlated with a high risk of recurrence. Further refining of endometrial cancer classification may enable more precise patient stratification and personalized treatment approaches.
摘要：
目的：IB期3级子宫内膜样腺癌的治疗具有挑战性。分子表征可能有助于识别超出阶段的辅助治疗策略。我们旨在通过ProMisE分类来更好地了解这些肿瘤的分子特征，突变签名，和常见的突变基因。
方法：纳入两个机构的IB期3级EEC患者。在存档的FFPE组织切片上进行免疫组织化学和全外显子组测序以确定ProMisE分类。个人癌症基因组报告用于体细胞变异注释，和突变签名是基于COSMIC单碱基替换突变签名生成的。
结果：46例患者接受可变辅助治疗。9例患者复发（19.6%），大多数患有腹外疾病(n=5，或55.6%)。10个有POLE突变（21.7%），18人缺乏MMR(39.1%)，6例p53异常（13.0%），12例为p53野生型(26.1%)。POLE亚组没有复发。在38例患者中确定了显性突变特征：17个SBS5特征（44.7％），10SBS15或SBS44签名（26.3%），7SBS10a或SBS10b签名（18.4%），3SBS14签名（7.9%），和1个SBS40签名（2.6%）。复发的6名患者具有SBS5特征。频繁突变的基因包括ARID1A（n=30，65%），PTEN（n=28，61%），MUC16（n=27，59%），和PIK3CA(n=25,54%)。
结论：这项综合评估发现了一个分子多样性的肿瘤队列，尽管组织学相同，阶段和等级。突变特征SBS5与高复发风险相关。子宫内膜癌分类的进一步细化可以实现更精确的患者分层和个性化治疗方法。
方法：纳入两个机构的IB期3级EEC患者。在存档的FFPE组织切片上进行免疫组织化学和全外显子组测序以确定ProMisE分类。个人癌症基因组报告用于体细胞变异注释，和突变签名是基于COSMIC单碱基替换突变签名生成的。
结果：46例患者接受可变辅助治疗。9例患者复发（19.6%），大多数患有腹外疾病(n=5，或55.6%)。10个有POLE突变（21.7%），18人缺乏MMR(39.1%)，6例p53异常（13.0%），12例为p53野生型(26.1%)。POLE亚组没有复发。在38例患者中确定了显性突变特征：17个SBS5特征（44.7％），10SBS15或SBS44签名（26.3%），7SBS10a或SBS10b签名（18.4%），3SBS14签名（7.9%），和1个SBS40签名（2.6%）。复发的6名患者具有SBS5特征。频繁突变的基因包括ARID1A（n=30，65%），PTEN（n=28，61%），MUC16（n=27，59%），和PIK3CA(n=25,54%)。
结论：这项综合评估发现了一个分子多样性的肿瘤队列，尽管组织学相同，阶段和等级。突变特征SBS5与高复发风险相关。子宫内膜癌分类的进一步细化可以实现更精确的患者分层和个性化治疗方法。
