Lack of pathogenic germline DICER1 variants in males with testicular germ-cell tumors,Cancer Genetics

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Lack of pathogenic germline DICER1 variants in males with testicular germ-cell tumors
Cancer Genetics ( IF 1.9 ) Pub Date : 2020-10-24 , DOI: 10.1016/j.cancergen.2020.10.002
Lauren M Vasta ₁ , Mary L McMaster ₂ , Laura A Harney ₃ , Alexander Ling ₄ , Jung Kim ₅ , Anne K Harris ₆ , Ann G Carr ₇ , Scott M Damrauer ₈ , Daniel J Rader ₉ , Rachel L Kember ₁₀ , Peter A Kanetsky ₁₁ , Katherine L Nathanson ₁₂ , Louise C Pyle ₁₃ , Mark H Greene ₅ , Kris Ann Schultz ₁₄ , Douglas R Stewart ₅ ,

Affiliation

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA; National Capital Consortium, Walter Reed National Military Medical Center, Bethesda, MD, USA.
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA; Commissioned Corps of the United States Public Health Service.
Westat, Inc, Rockville, MD, USA.
Radiology and Imaging Sciences, National Institutes of Health, Bethesda, MD, USA.
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA.
International Pleuropulmonary Blastoma/DICER1 Registry, Minneapolis, MN, USA.
Commissioned Corps of the United States Public Health Service.
Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
International Pleuropulmonary Blastoma/DICER1 Registry, Minneapolis, MN, USA; Cancer and Blood Disorders, Children's Minnesota, International Pleuropulmonary Blastoma/DICER1 Registry, Minneapolis, MN, USA; International Ovarian and Testicular Stromal Tumor Registry, Children's Minnesota, Minneapolis, MN, USA.

Background

Several studies have reported conflicting evidence on the inclusion of testicular germ cell tumors (TGCT) in the DICER1 tumor-predisposition phenotype. We evaluated the relationship between DICER1 and TGCT by reviewing scrotal ultrasounds of males with pathogenic germline variants in DICER1 and queried exome data from TGCT-affected men for DICER1 variants.

Methodology

Fifty-four male DICER1-carriers and family controls (n=41) enrolled in the National Cancer Institute (NCI) DICER1 Natural History Study were offered scrotal ultrasounds. These studies were examined by a single radiologist for abnormalities. In parallel, DICER1 variants from two large exome-sequenced TGCT cohorts were extracted. We used previously published AMG-AMP criteria to characterize rare DICER1 variants.

Results

There was no observed difference in frequency of testicular cystic structures in DICER1-carriers versus controls. DICER1 variation was not associated with TGCT in the NCI DICER1-carriers. In 1,264 exome-sequenced men with TGCT, none harbored ClinVar- or InterVar-determined pathogenic or likely pathogenic variants in DICER1. Three DICER1 variants of uncertain significance (one case and two controls) were predicted “damaging” based on a priori criteria.

Conclusion

Using two complementary approaches, we found no evidence of an association between pathogenic DICER1 variants and TGCT.

中文翻译：

睾丸生殖细胞肿瘤男性缺乏致病性生殖系 DICER1 变异

背景

几项研究报告了在DICER1肿瘤易感表型中包含睾丸生殖细胞肿瘤 (TGCT) 的相互矛盾的证据。我们评估之间的关系DICER1和睾丸生殖细胞通过审查男性阴囊超声致病性生殖细胞在多个变DICER1和查询从睾丸生殖细胞肿瘤，受影响的人外显子组数据DICER1变种。

方法

向美国国家癌症研究所 (NCI) DICER1自然历史研究中登记的54 名男性DICER1携带者和家庭对照 (n=41)提供了阴囊超声检查。这些研究由一名放射科医生检查异常。同时，提取了来自两个大型外显子组测序 TGCT 队列的DICER1变体。我们使用先前发布的 AMG-AMP 标准来表征罕见的DIcer1变体。

结果

在DICER1携带者与对照中睾丸囊性结构的频率没有观察到差异。DICER1变异与 NCI DICER1携带者中的 TGCT无关。在 1,264 名外显子组测序的 TGCT 男性中，没有人在DICER1 中携带 ClinVar 或 InterVar 确定的致病性或可能致病性变异。根据先验标准预测三个意义不确定的DICER1变体（一个病例和两个对照）是“破坏性的” 。