Targeted sequencing of FH-deficient uterine leiomyomas reveals biallelic inactivating somatic fumarase variants and allows characterization of missense variants

Popp B, Erber R, Kraus C, Vasileiou G, Hoyer J, Burghaus S, Hartmann A, Beckmann M, Reis A, Agaimy A (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Modern Pathology Nature Publishing Group: Open Access Hybrid Model Option B

Abstract

Uterine leiomyomas (ULs) constitute a considerable health burden in the general female population. The fumarate hydratase (FH) deficient subtype is found in up to 1.6% and can occur in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. We sequenced 13 FH deficient ULs from a previous immunohistochemical screen using a targeted panel and identified biallelic FH variants in all. In eight, we found an FH point mutation (two truncating, six missense) with evidence for loss of the second allele. Variant allele-frequencies in all cases with a point mutation pointed to somatic variants. Spatial clustering of the identified missense variants in the lyase domain indicated altered fumarase oligomerization with subsequent degradation as explanation for the observed FH deficiency. Biallelic FH deletions in five tumors confirm the importance of copy number loss as mutational mechanism. By curating all pathogenic FH variants and calculating their population frequency, we estimate a carrier frequency of up to 1/2,563. Comparing with the prevalence of FH deficient ULs, we conclude that most are sporadic and estimate 2.7–13.9% of females with an FH deficient UL to carry a germline FH variant. Further prospective tumor/normal sequencing studies are needed to develop a reliable screening strategy for HLRCC in women with ULs.

Authors with CRIS profile

Bernt Popp Lehrstuhl für Humangenetik Ramona Erber Institute of Pathology Juliane Hoyer Institute of Human Genetics Stefanie Burghaus Department of Obstetrics and Gynaecology Arndt Hartmann Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie Matthias Beckmann Lehrstuhl für Geburtshilfe und Frauenheilkunde André Wiesmann da Silva Reis Lehrstuhl für Humangenetik Abbas Agaimy Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie

How to cite

APA:

Popp, B., Erber, R., Kraus, C., Vasileiou, G., Hoyer, J., Burghaus, S.,... Agaimy, A. (2020). Targeted sequencing of FH-deficient uterine leiomyomas reveals biallelic inactivating somatic fumarase variants and allows characterization of missense variants. Modern Pathology. https://dx.doi.org/10.1038/s41379-020-0596-y

MLA:

Popp, Bernt, et al. "Targeted sequencing of FH-deficient uterine leiomyomas reveals biallelic inactivating somatic fumarase variants and allows characterization of missense variants." Modern Pathology (2020).

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