PT  - JOURNAL ARTICLE
AU  - Bernt Popp
AU  - Ramona Erber
AU  - Cornelia Kraus
AU  - Georgia Vasileiou
AU  - Juliane Hoyer
AU  - Stefanie Burghaus
AU  - Arndt Hartmann
AU  - Matthias W. Beckmann
AU  - André Reis
AU  - Abbas Agaimy
TI  - Panel Sequencing in Uterine Leiomyomas identifies Missense Mutations associated with immunohistochemical Fumarate Hydratase (FH)-Loss
AID  - 10.1101/663609
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 663609
4099  - http://biorxiv.org/content/early/2019/06/06/663609.short
4100  - http://biorxiv.org/content/early/2019/06/06/663609.full
AB  - 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% of cases. Identifying these individuals is important as a subset of cases is related to germline FH variants in the setting of the hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome which is associated with aggressive renal cell cancer.We sequenced 13 FH-deficient ULs using the TruSight Cancer Panel. In all 13 cases, we could identify biallelic FH variants. In eight cases, we found a FH point mutation (two truncating, six missense) with evidence for loss of the second allele. Variant allele-frequencies pointed to somatic variants in all cases with a point mutation. Spatial clustering of the identified missense variants in the lyase domain indicated their importance for proper fumarase oligomerization. In five tumors, we found a biallelic deletion of FH. Analysis of driver mutations of other genes revealed two truncating TP53 variants in one case. Copy number (CN) analysis found a large RB1 deletion in three tumors and enrichment for ALK CN gains.Following our recommendation, one individual presented for genetic consultation. A germline FH variant could not be identified. Clinical examination and family history raised the suspicion of tuberous sclerosis complex, which could subsequently be confirmed due to the splice variant c.2040A>G in TSC1. This case highlights that presence of FH deficiency does not exclude other concurrent genetic syndromes.By comparing the FH mutation carrier frequency in public databases and the prevalence of FH deficient ULs, we conclude that most of these are likely sporadic and estimate 3.5 - 14.3% 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.