Table_1_Rare Germline DICER1 Variants in Pediatric Patients With Cushing's Disease: What Is Their Role?.DOCX

Context: The DICER1 syndrome is a multiple neoplasia disorder caused by germline mutations in the DICER1 gene. In DICER1 patients, aggressive congenital pituitary tumors lead to neonatal Cushing's disease (CD). The role of DICER1 in other corticotropinomas, however, remains unknown.
Objective: To perform a comprehensive screening for DICER1 variants in a large cohort of CD patients, and to analyze their possible contribution to the phenotype.
Design, setting, patients, and interventions: We included 192 CD cases: ten young-onset (age <30 years at diagnosis) patients were studied using a next generation sequencing panel, and 182 patients (170 pediatric and 12 adults) were screened via whole-exome sequencing. In seven cases, tumor samples were analyzed by Sanger sequencing.
Results: Rare germline DICER1 variants were found in seven pediatric patients with no other known disease-associated germline defects or somatic DICER1 second hits. By immunohistochemistry, DICER1 showed nuclear localization in 5/6 patients. Variant transmission from one of the parents was confirmed in 5/7 cases. One patient had a multinodular goiter; another had a family history of melanoma; no other patients had a history of neoplasms.
Conclusions: Our findings suggest that DICER1 gene variants may contribute to the pathogenesis of non-syndromic corticotropinomas. Clarifying whether DICER1 loss-of-function is disease-causative or a mere disease-modifier in this setting, requires further studies.
Clinical trial registration:ClinicalTrials.gov: NCT00001595.

背景：DICER1综合征是一种由DICER1基因生殖系突变引发的多发性肿瘤疾病。在DICER1综合征患者中，侵袭性先天性垂体肿瘤可导致新生儿库欣病（Cushing's disease, CD）。然而，DICER1在其他类型促肾上腺皮质激素腺瘤中的作用仍有待阐明。
研究目的：针对大队列库欣病患者开展DICER1基因变异的全面筛查，并分析其对疾病表型的潜在贡献。
研究设计、研究场所、研究对象与干预措施：本研究共纳入192例库欣病病例：其中10例早发型患者（确诊年龄<30岁）采用下一代测序（next generation sequencing, NGS）检测panel进行检测，182例患者（170例儿童及12例成人）采用全外显子测序进行筛查；另有7例病例的肿瘤样本通过桑格测序完成分析。
研究结果：在7例无其他已知疾病相关生殖系缺陷或体细胞DICER1二次打击的儿科患者中，检出罕见生殖系DICER1变异。免疫组化检测显示，5/6例患者的DICER1蛋白呈核定位。7例病例中的5例经证实存在来自父母一方的变异传递。1例患者合并多结节性甲状腺肿，另1例存在黑色素瘤家族史，其余患者均无肿瘤病史。
研究结论：本研究结果提示，DICER1基因变异可能参与非综合征性促肾上腺皮质激素腺瘤的发病机制。明确在此类病例中DICER1功能缺失变异是致病因素还是仅为疾病修饰因子，仍需开展进一步研究。
临床试验注册：ClinicalTrials.gov: NCT00001595