Clinical, genetic and experimental studies of the Brooke-Spiegler (CYLD) skin tumor syndrome.

Brooke-Spiegler syndrome (BSS; a.k.a. tuban tumor syndrome) is an autosomal dominant inherited skin disorder caused by germline mutations in the CYLD tumor suppressor gene. BSS is characterized by multiple skin adnexal tumors, mainly cylindromas and spiradenomas on the head and neck. The tumors are often severely disfiguring and require repeated surgical interventions. Here, we describe a four-generation BSS-family with a novel germline c.1613_1614delGC CYLD mutation that introduces a premature STOP codon predicted to result in a truncated, inactivated CYLD protein. In addition, we present a pilot study describing establishment of the first patient-derived xenografts (PDXs) from cutaneous CYLD-defective cylindromas. Fresh tumor tissues from cylindromas were transplanted into immunocompromised mice to generate PDXs. One xenograft showed progressive tumor growth after 3 months whereas the others remained unchanged in size during the 6 months study period. Histopathological and immunohistochemical analyses of the PDXs revealed that they recapitulate the histological and molecular features of their respective primary tumors, including expression of NTRK3 and the oncogenic driver MYB. In summary, we present the first preclinical BSS-model that morphologically and genetically recapitulates human CYLD-defective cylindromas. This model will be useful for preclinical therapeutic drug testing and for further studies of the molecular pathogenesis of inherited cylindromas.