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. 2020 Dec;41(Suppl 2):67-69.
doi: 10.1007/s00292-020-00870-0.

[Integrative molecular pathology of cancer]

[Article in German]
Thomas G P Grünewald  1   2   3
Affiliations

[Integrative molecular pathology of cancer]

[Article in German]
Thomas G P Grünewald. Pathologe. 2020 Dec.

Erratum in

Abstract
in English, German

The field of molecular pathology has revolutionized our understanding of relevant oncogenic alterations in cancer and yielded new diagnostic tools and therapeutic approaches for personalized oncology, especially for malignancies of adulthood. However, many pediatric tumors, such as Ewing sarcoma, are characterized by a remarkable paucity of recurrent driver mutations, which are usually not suitable as drug targets. Despite the relative homogeneity of the somatic mutational profiles, these tumors nevertheless exhibit a relatively strong clinical heterogeneity, indicating additional modulating factors. In this regard, a recent study could demonstrate that the mode of action of the EWSR1-FLI1 (Ewing sarcoma breakpoint region 1-Friend leukema integration 1) fusion oncoprotein, which is pathognomonic for Ewing sarcoma, is influenced by inherited genetic variants in regulatory DNA elements, which may ultimately affect the course of the disease and also enable new therapeutic options. Thus, these investigations demonstrate in the Ewing sarcoma model that the function of a driver mutation needs to be interpreted in its germline context, which should be taken into account in an integrative approach by the molecular pathology of the future.

Die molekulare Pathologie hat unser Verständnis hinsichtlich relevanter onkogener Veränderungen von malignen Tumoren revolutioniert und liefert neue diagnostische und therapeutische Ansätze für die personalisierte Onkologie, insbesondere bei Krebserkrankungen des Erwachsenenalters. Viele pädiatrische Tumoren wie das Ewing-Sarkom sind jedoch durch eine ausgesprochen geringe Anzahl an rekurrierenden Treibermutationen charakterisiert, die sich meist nicht als therapeutische Zielstrukturen eignen. Trotz der relativen Homogenität der somatischen Mutationsprofile zeigen diese Tumoren jedoch eine starke klinische Heterogenität, was auf zusätzliche modulierende Faktoren hinweist. In diesem Zusammenhang konnte kürzlich gezeigt werden, dass die Wirkungsweise des für Ewing-Sarkome pathognomonischen Fusionsonkoproteins EWSR1-FLI1 (Ewing sarcoma breakpoint region 1-Friend leukema integration 1) durch angeborene genetische Varianten in regulatorischen DNA-Elementen beeinflusst wird, was Auswirkungen auf den Krankheitsverlauf haben kann und auch neue therapeutische Optionen eröffnet. Diese Untersuchungen zeigen damit beispielhaft im Ewing-Sarkom, dass die Funktion einer Treibermutation auch im genetischen Keimbahnkontext betrachtet werden muss, der von der Molekularpathologie der Zukunft in einem integrativen Ansatz berücksichtigt werden sollte.

Keywords: Ewing sarcoma; Fusion oncogene; Germline variability; Molecular pathology; Somatic mutation.

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References

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