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 amplificationBackground 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.show moreshow less

Download full text files

Export metadata

Statistics

Number of document requests

Additional Services

Share in Twitter Search Google Scholar
Metadaten
Author:Michaela KuhlenORCiDGND, Mariola Monika GolasORCiDGND, Tina Schaller, Nicole StadlerORCiD, Felicitas Maier, Olaf Witt, Michael C. FrühwaldORCiDGND
URN:urn:nbn:de:bvb:384-opus4-1055913
Frontdoor URLhttps://opus.bibliothek.uni-augsburg.de/opus4/105591
ISSN:1897-4287OPAC
Parent Title (English):Hereditary Cancer in Clinical Practice
Publisher:Springer Science and Business Media LLC
Place of publication:Berlin
Type:Article
Language:English
Year of first Publication:2023
Publishing Institution:Universität Augsburg
Release Date:2023/07/06
Tag:Genetics (clinical); Oncology
Volume:21
Issue:1
First Page:8
DOI:https://doi.org/10.1186/s13053-023-00254-4
Institutes:Medizinische Fakultät
Medizinische Fakultät / Universitätsklinikum
Medizinische Fakultät / Lehrstuhl für Innere Medizin mit Schwerpunkt Hämatologie und Onkologie
Medizinische Fakultät / Lehrstuhl für Kinder- und Jugendmedizin
Medizinische Fakultät / Lehrstuhl für Humangenetik
Nachhaltigkeitsziele
Nachhaltigkeitsziele / Ziel 3 - Gesundheit und Wohlergehen
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):CC-BY 4.0: Creative Commons: Namensnennung (mit Print on Demand)