Michaela Kuhlen, Mariola Monika Golas, Tina Schaller, Nicole Stadler, Felicitas Maier, Olaf Witt, Michael C Frühwald
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引用次数: 0
摘要
背景:Lynch综合征(LS)不被认为是儿童癌症易感综合征的一部分。病例介绍:对一例儿童骨肉瘤(OS)的分析显示出高突变(16.8)、端粒选择性延长(ALT)、PMS2在肿瘤组织中的表达缺失(保留在非肿瘤细胞中)、PMS2杂合性缺失(LOH)和PCR检测的高度微卫星不稳定性(MSI)。外周血SNV分析检测到NM_000535.6:PMS2基因外显子10杂合重复c.1076dup p.(Leu359Phefs*6),诊断为LS。肿瘤分子特征提示与ls相关的OS发展。在第二个病例中,全基因组测序鉴定出一种杂合SNV c.1A > p ?在一个患有室管膜瘤的女孩的肿瘤和种系物质中发现PMS2外显子1。肿瘤分析显示ALT和低突变负荷(0.6),PMS2表达保留,MSI低。多重结扎依赖探针扩增未发现额外的PMS2变异,种系MSI检测未显示患者淋巴细胞gMSI比率增加。因此,我们最密切地排除了CMMRD,我们的数据并不表明室管膜瘤与儿童的LS有关。结论:我们的数据表明,LS癌症谱系可能包括儿童癌症。LS在儿童癌症中的重要性需要前瞻性数据收集。全面的肿瘤样本分子检查是必要的,以探索生殖系遗传变异的因果作用。
Beyond germline genetic testing - heterozygous pathogenic variants in PMS2 in two children with Osteosarcoma and Ependymoma.
Background: Lynch syndrome (LS) is not considered part of childhood cancer predisposition syndromes.
Case presentation: Analysis of a pediatric osteosarcoma (OS) displayed hypermutation (16.8), alternative lengthening of telomeres (ALT), loss of PMS2 expression in tumor tissue (retained in non-neoplastic cells), PMS2 loss of heterozygosity (LOH), and high-degree of microsatellite instability (MSI) tested by PCR. A heterozygous duplication c.1076dup p.(Leu359Phefs*6) in exon 10 of NM_000535.6:PMS2 was detected by SNV analysis in peripheral blood, confirming diagnosis of LS in the patient. The tumor molecular features suggest LS-associated development of OS. In a second case, whole-genome sequencing identified a heterozygous SNV c.1 A > T p.? in exon 1 of PMS2 in tumor and germline material of a girl with ependymoma. Tumor analysis displayed evidence for ALT and low mutational burden (0.6), PMS2 expression was retained, MSI was low. Multiplex ligation-dependent probe amplification identified no additional PMS2 variant and germline MSI testing did not reveal increased gMSI ratios in the patient´s lymphocytes. Thus, CMMRD was most closely excluded and our data do not suggest that ependymoma was related to LS in the child.
Conclusions: Our data suggest that the LS cancer spectrum may include childhood cancer. The importance of LS in pediatric cancers necessitates prospective data collection. Comprehensive molecular workup of tumor samples is necessary to explore the causal role of germline genetic variants.
期刊介绍:
Hereditary Cancer in Clinical Practice is an open access journal that publishes articles of interest for the cancer genetics community and serves as a discussion forum for the development appropriate healthcare strategies.
Cancer genetics encompasses a wide variety of disciplines and knowledge in the field is rapidly growing, especially as the amount of information linking genetic differences to inherited cancer predispositions continues expanding. With the increased knowledge of genetic variability and how this relates to cancer risk there is a growing demand not only to disseminate this information into clinical practice but also to enable competent debate concerning how such information is managed and what it implies for patient care.
Topics covered by the journal include but are not limited to:
Original research articles on any aspect of inherited predispositions to cancer.
Reviews of inherited cancer predispositions.
Application of molecular and cytogenetic analysis to clinical decision making.
Clinical aspects of the management of hereditary cancers.
Genetic counselling issues associated with cancer genetics.
The role of registries in improving health care of patients with an inherited predisposition to cancer.