目的:尽管早期发现的宫颈癌与良好的生存率相关,晚期疾病的预后较差,治疗方案稀少.错配修复缺陷(MMR-D)已成为几种癌症类型的预后和对免疫检查点抑制剂反应的预测因子。但其在宫颈癌中的价值尚不清楚。本研究旨在确定MMR-D在宫颈癌中的患病率,并评估MMR蛋白表达的预后价值。
方法:在前瞻性收集的宫颈癌队列(n=508)中,通过免疫组织化学染色研究了MMR蛋白MLH-1,PMS-2,MSH-2和MSH-6的表达,并获得相应的临床病理和随访数据。切片被评分为缺失或完整表达以定义MMR-D,通过染色指数,根据染色强度和面积,评估预后潜力。RNA和全外显子组测序数据可用于72和75名患者,并用于基因集富集和突变分析。分别。
结果:有5例(1%)肿瘤缺乏MMR,其中三个是神经内分泌组织学。MMR状态不能预测生存(HR1.93,p=0.17)。MSH-2低(n=48)与低生存率相关(HR1.94,p=0.02),也在调整肿瘤分期时,肿瘤类型,和患者年龄(HR2.06,p=0.013)。MSH-2低肿瘤具有较高的肿瘤突变负荷(p=0.003)和双链断裂修复基因RAD50中(移码)突变的频率较高(p<0.01)。
结论:MMR-D在宫颈癌中罕见,然而,低MSH-2表达是生存不良的独立预测因素。
OBJECTIVE: Although early-detected cervical cancer is associated with good survival, the prognosis for late-stage disease is poor and treatment options are sparse. Mismatch repair deficiency (MMR-D) has surfaced as a predictor of prognosis and response to immune checkpoint inhibitor(s) in several cancer types, but its value in cervical cancer remains unclear. This study aimed to define the prevalence of MMR-D in cervical cancer and assess the prognostic value of MMR protein expression.
METHODS: Expression of the MMR proteins MLH-1, PMS-2, MSH-2, and MSH-6 was investigated by immunohistochemical staining in a prospectively collected cervical cancer cohort (n=508) with corresponding clinicopathological and follow-up data. Sections were scored as either loss or intact expression to define MMR-D, and by a staining index, based on staining intensity and area, evaluating the prognostic potential. RNA and whole exome sequencing data were available for 72 and 75 of the patients and were used for gene set enrichment and mutational analyses, respectively.
RESULTS: Five (1%) tumors were MMR-deficient, three of which were of neuroendocrine histology. MMR status did not predict survival (HR 1.93, p=0.17). MSH-2 low (n=48) was associated with poor survival (HR 1.94, p=0.02), also when adjusting for tumor stage, tumor type, and patient age (HR 2.06, p=0.013). MSH-2 low tumors had higher tumor mutational burden (p=0.003) and higher frequency of (frameshift) mutations in the double-strand break repair gene RAD50 (p<0.01).
CONCLUSIONS: MMR-D is rare in cervical cancer, yet low MSH-2 expression is an independent predictor of poor survival.