PDF(Pubmed)
Abstract：
Mismatch-repair (MMR)/microsatellite instability (MSI) status has therapeutic implications in endometrial cancer (EC). The authors evaluated the concordance of testing and factors contributing to MMR expression heterogeneity.
Six hundred sixty-six ECs were characterized using immunohistochemistry (IHC), MSI testing, and mut-L homolog 1 (MLH1) methylation. Select samples underwent whole-transcriptome analysis and next-generation sequencing. MMR expression of metastatic/recurrent sites was evaluated.
MSI testing identified 27.3% of cases as MSI-high (n = 182), MMR IHC identified 25.1% cases as MMR-deficient (n = 167), and 3.8% of cases (n = 25) demonstrated discordant results. A review of IHC staining explained discordant results in 18 cases, revealing subclonal loss of MLH1/Pms 1 homolog 2 (PMS2) (n = 10) and heterogeneous MMR IHC (mut-S homolog 6 [MSH6], n = 7; MLH1/PMS2, n = 1). MSH6-associated Lynch syndrome was diagnosed in three of six cases with heterogeneous expression. Subclonal or heterogeneous cases had a 38.9% recurrence rate (compared with 16.7% in complete MMR-deficient cases and 9% in MMR-proficient cases) and had abnormal MMR IHC results in all metastatic recurrent sites (n = 7). Tumors with subclonal MLH1/PMS2 demonstrated 74 differentially expressed genes (determined using digital spatial transcriptomics) when stratified by MLH1 expression, including many associated with epithelial-mesenchymal transition.
Subclonal/heterogeneous MMR IHC cases showed epigenetic loss in 66.7%, germline mutations in 16.7%, and somatic mutations in 16.7%. MMR IHC reported as intact/deficient missed 21% of cases of Lynch syndrome. EC with subclonal/heterogeneous MMR expression demonstrated a high recurrence rate, and metastatic/recurrent sites were MMR-deficient. Transcriptional analysis indicated an increased risk for migration/metastasis, suggesting that clonal MMR deficiency may be a driver for tumor aggressiveness. Reporting MMR IHC only as intact/deficient, without reporting subclonal and heterogeneous staining, misses opportunities for biomarker-directed therapy.
Endometrial cancer is the most common gynecologic cancer, and 20%-40% of tumors have a defect in DNA proofreading known as mismatch-repair (MMR) deficiency. These results can be used to guide therapy. Tests for this defect can yield differing results, revealing heterogeneous (mixed) proofreading capabilities. Tumors with discordant testing results and mixed MMR findings can have germline or somatic defects in MMR genes. Cells with deficient DNA proofreading in tumors with mixed MMR findings have DNA expression profiles linked to more aggressive characteristics and cancer spread. These MMR-deficient cells may drive tumor behavior and the risk of spreading cancer.
Six hundred sixty-six ECs were characterized using immunohistochemistry (IHC), MSI testing, and mut-L homolog 1 (MLH1) methylation. Select samples underwent whole-transcriptome analysis and next-generation sequencing. MMR expression of metastatic/recurrent sites was evaluated.
MSI testing identified 27.3% of cases as MSI-high (n = 182), MMR IHC identified 25.1% cases as MMR-deficient (n = 167), and 3.8% of cases (n = 25) demonstrated discordant results. A review of IHC staining explained discordant results in 18 cases, revealing subclonal loss of MLH1/Pms 1 homolog 2 (PMS2) (n = 10) and heterogeneous MMR IHC (mut-S homolog 6 [MSH6], n = 7; MLH1/PMS2, n = 1). MSH6-associated Lynch syndrome was diagnosed in three of six cases with heterogeneous expression. Subclonal or heterogeneous cases had a 38.9% recurrence rate (compared with 16.7% in complete MMR-deficient cases and 9% in MMR-proficient cases) and had abnormal MMR IHC results in all metastatic recurrent sites (n = 7). Tumors with subclonal MLH1/PMS2 demonstrated 74 differentially expressed genes (determined using digital spatial transcriptomics) when stratified by MLH1 expression, including many associated with epithelial-mesenchymal transition.
Subclonal/heterogeneous MMR IHC cases showed epigenetic loss in 66.7%, germline mutations in 16.7%, and somatic mutations in 16.7%. MMR IHC reported as intact/deficient missed 21% of cases of Lynch syndrome. EC with subclonal/heterogeneous MMR expression demonstrated a high recurrence rate, and metastatic/recurrent sites were MMR-deficient. Transcriptional analysis indicated an increased risk for migration/metastasis, suggesting that clonal MMR deficiency may be a driver for tumor aggressiveness. Reporting MMR IHC only as intact/deficient, without reporting subclonal and heterogeneous staining, misses opportunities for biomarker-directed therapy.
Endometrial cancer is the most common gynecologic cancer, and 20%-40% of tumors have a defect in DNA proofreading known as mismatch-repair (MMR) deficiency. These results can be used to guide therapy. Tests for this defect can yield differing results, revealing heterogeneous (mixed) proofreading capabilities. Tumors with discordant testing results and mixed MMR findings can have germline or somatic defects in MMR genes. Cells with deficient DNA proofreading in tumors with mixed MMR findings have DNA expression profiles linked to more aggressive characteristics and cancer spread. These MMR-deficient cells may drive tumor behavior and the risk of spreading cancer.
摘要：
背景：错配修复（MMR）/微卫星不稳定性（MSI）状态在子宫内膜癌（EC）中具有治疗意义。作者评估了测试和导致MMR表达异质性的因素的一致性。
方法：使用免疫组织化学（IHC）对66个ECs进行了表征，MSI测试,和mut-L同源物1(MLH1)甲基化。选择样品进行全转录组分析和下一代测序。评估转移/复发部位的MMR表达。
结果：MSI测试发现27.3%的病例为MSI高（n=182），MMRIHC确定25.1％的病例为MMR缺陷（n=167），3.8%的病例(n=25)表现出不一致的结果。IHC染色的回顾解释18例结果不一致，揭示MLH1/Pms1同源物2（PMS2）（n=10）和异质MMRIHC（mut-S同源物6[MSH6]，n=7；MLH1/PMS2，n=1）。在6例表达异质性的病例中，有3例诊断出MSH6相关的Lynch综合征。亚克隆或异质病例的复发率为38.9％（完全MMR缺陷病例为16.7％，MMR精通病例为9％），并且在所有转移性复发部位均具有异常的MMRIHC结果（n=7）。当通过MLH1表达分层时，具有亚克隆MLH1/PMS2的肿瘤显示74个差异表达基因（使用数字空间转录组学确定），包括许多与上皮-间质转化相关的。
结论：亚克隆/异质性MMRIHC病例显示66.7％的表观遗传丢失，种系突变占16.7%，体细胞突变占16.7%。MMRIHC报告为完整/缺陷错过了21％的Lynch综合征病例。具有亚克隆/异质MMR表达的EC表现出高复发率，转移/复发部位为MMR缺陷。转录分析表明迁移/转移的风险增加，提示克隆MMR缺乏可能是肿瘤侵袭性的驱动因素。仅报告MMRIHC完整/缺陷，没有报告亚克隆和异质染色，错过了生物标志物导向治疗的机会。
结论：子宫内膜癌是最常见的妇科肿瘤，20%-40%的肿瘤有DNA校对缺陷，称为错配修复(MMR)缺陷。这些结果可用于指导治疗。这个缺陷的测试可以产生不同的结果，揭示异构(混合)校对能力。具有不一致的测试结果和混合的MMR发现的肿瘤可能在MMR基因中具有种系或体细胞缺陷。具有混合MMR发现的肿瘤中DNA校对缺陷的细胞具有与更具侵略性的特征和癌症扩散相关的DNA表达谱。这些缺乏MMR的细胞可能驱动肿瘤行为和癌症扩散的风险。
方法：使用免疫组织化学（IHC）对66个ECs进行了表征，MSI测试,和mut-L同源物1(MLH1)甲基化。选择样品进行全转录组分析和下一代测序。评估转移/复发部位的MMR表达。
结果：MSI测试发现27.3%的病例为MSI高（n=182），MMRIHC确定25.1％的病例为MMR缺陷（n=167），3.8%的病例(n=25)表现出不一致的结果。IHC染色的回顾解释18例结果不一致，揭示MLH1/Pms1同源物2（PMS2）（n=10）和异质MMRIHC（mut-S同源物6[MSH6]，n=7；MLH1/PMS2，n=1）。在6例表达异质性的病例中，有3例诊断出MSH6相关的Lynch综合征。亚克隆或异质病例的复发率为38.9％（完全MMR缺陷病例为16.7％，MMR精通病例为9％），并且在所有转移性复发部位均具有异常的MMRIHC结果（n=7）。当通过MLH1表达分层时，具有亚克隆MLH1/PMS2的肿瘤显示74个差异表达基因（使用数字空间转录组学确定），包括许多与上皮-间质转化相关的。
结论：亚克隆/异质性MMRIHC病例显示66.7％的表观遗传丢失，种系突变占16.7%，体细胞突变占16.7%。MMRIHC报告为完整/缺陷错过了21％的Lynch综合征病例。具有亚克隆/异质MMR表达的EC表现出高复发率，转移/复发部位为MMR缺陷。转录分析表明迁移/转移的风险增加，提示克隆MMR缺乏可能是肿瘤侵袭性的驱动因素。仅报告MMRIHC完整/缺陷，没有报告亚克隆和异质染色，错过了生物标志物导向治疗的机会。
结论：子宫内膜癌是最常见的妇科肿瘤，20%-40%的肿瘤有DNA校对缺陷，称为错配修复(MMR)缺陷。这些结果可用于指导治疗。这个缺陷的测试可以产生不同的结果，揭示异构(混合)校对能力。具有不一致的测试结果和混合的MMR发现的肿瘤可能在MMR基因中具有种系或体细胞缺陷。具有混合MMR发现的肿瘤中DNA校对缺陷的细胞具有与更具侵略性的特征和癌症扩散相关的DNA表达谱。这些缺乏MMR的细胞可能驱动肿瘤行为和癌症扩散的风险。
