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DOI: 10.1055/s-0034-1389905
Constitutional Mismatch Repair-deficiency and Whole-exome Sequencing as the Means of the Rapid Detection of the Causative MSH6 Defect
Erbliches Krebssyndrom und Gesamt-Exom-Sequenzierung als Mittel zur raschen Identifizierung des kausativen MSH6-DefektsPublikationsverlauf
Publikationsdatum:
28. November 2014 (online)
![](https://www.thieme-connect.de/media/klinpaed/20140607/lookinside/thumbnails/10.1055-s-0034-1389905-1.jpg)
Abstract
Background: Cases of children with more than one type of cancer either diagnosed simultaneously or successively, rarely occur in pediatric oncology. A second malignant neoplasm may be caused by mutagenic effects of the treatment of the primary malignancy and/or may point towards an underlying genetic cancer susceptibility syndrome. One example of such a syndrome is constitutional mismatch repair-deficiency, (CMMR-D) which carries an increased risk of various tumors including childhood hematologic malignancies and Lynch syndrome associated tumors. Timely diagnosis of CMMR-D is crucial, since this diagnosis has implications for the entire family.
Patient: We report the case of a 15-year-old girl who was born to consanguineous parents. At the age of 20 months she was diagnosed with a T-cell non-Hodgkin lymphoma. Treatment was given according to NHL-BFM 95. 12 years later, an invasive adenocarcinoma of the colon was surgically removed which relapsed shortly afterwards.
Methods: Whole-exome sequencing of germline DNA was employed to rapidly detect the underlying mutation in this suspected CMMR-D patient.
Results: After a short turnaround time of less than 3 weeks, the diagnosis of CMMR-D could be confirmed by the identification of a homozygous 29-bp deletion in MSH6 (exon 6), which was confirmed by independent methods.
Conclusions: We demonstrate that “bed-side” whole-exome sequencing is both feasible and cost-effective and may be the method of choice to rapidly uncover the genetical basis of (inherited) diseases.
Zusammenfassung
Hintergrund: Kinder mit 2 verschiedenen Malignomen, die entweder zeitgleich oder sukzessiv diagnostiziert werden, sind in der pädiatrischen Onkologie eine Rarität. Eine zweite Krebserkrankung kann entweder durch die Primärtherapie des Ersttumors verursacht worden sein oder kann auf ein zu Grunde liegendes erbliches Krebssyndrom hinweisen. Ein Beispiel hierfür ist die sogenannte constitutional mismatch repair-deficiency (CMMR-D), welche charakterisiert ist durch ein erhöhtes Tumorrisiko von u. a. malignen hämatolischen Erkrankungen und Lynch-Syndrom-assoziierten Tumoren. Eine zeitnahe Diagnosestellung ist hierbei entscheidend, da diese Diagnose Auswirkungen für die gesamte Familie mit sich bringt.
Patient: Vorgestellt wird der Fall eines 15 Jahre alten Mädchens konsanguiner Eltern. Im Alter von 20 Monaten wurde ein mediastinales T-Zell Non-Hodgkin-Lymphom diagnostiziert. 12 Jahre später wurde ein invasiv wachsendes Adenokarzinom des Kolons chirurgisch entfernt, welches kurze Zeit später rezidivierte.
Methoden: Um die zu Grunde liegende Mutation dieses putativen erblichen Krebssyndroms möglichst rasch zu identifizieren wurde eine Gesamt-Exom-Sequenzierung durchgeführt.
Resultate: Nur 3 Wochen nach Blutentnahme konnten wir die Diagnose CMMR-D durch den Nachweis einer homozygoten, 29 Basenpaare umfassenden Deletion im MSH6 Gen (Exon 6) stellen. Die Deletion konnte in unabhängigen Experimenten validiert werden.
Schlussfolgerungen: Patientennahe Gesamt-Exom-Sequenzierung ist sowohl praktikabel als auch kosteneffektiv. Sie ist die Methode der Wahl zur Charakterisierung des zu Grunde liegenden genetischen Defekts bei (Erb-) Krankheiten.
Key words
childhood cancer syndrome - constitutional mismatch repair syndrome - whole-exome sequencing - genetic testingSchlüsselwörter
erbliche Krebssyndrome - constitutional mismatch repair syndrome - Gesamt-Exom-Sequenzierung - genetische Testung-
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