ALPK1 hotspot mutation as a driver of human spiradenoma and spiradenocarcinoma

• DOI: 10.1038/s41467-019-09979-0
• Publication Date: 2019-05-17T10:04:09Z
• Authors: Mamunur Rashid; Michiel van der H...; Thomas Mentzel; Francesca Butera; Ingrid Ferreira; Alena Pance; Arno Rütten; Bostjan Luzar; Zlatko Marusic; Nicolas de Saint ...; Jennifer S. Ko; Steven D. Billings; Sofia Chen; Marie Abi Daoud; James Hewinson; Sandra Louzada; Paul W. Harms; Guia Cerretelli; Carla Daniela Rob...; Rajiv M. Patel; Louise van der We...; Chris Bakal; Jason L. Hornick; Mark J. Arends; Thomas Brenn; David J. Adams
• Keywords: Male; Clinicopathology of Fibrous Tumors and Treatment Strategies; DNA Mutational Analysis; Adenoid Cystic -- genetics -- pathology; mutation ; spiradenoma ; spiradenocarcinoma; Gene; Whole Exome Sequencing; DNA Methyltransferase 3A; Cohort Studies; Somatic cell; Loss of Function Mutation; Cylindromatosis Gene; Germline mutation; 80 and over; Pathology; Missense mutation; Adenoid Cystic; DNA (Cytosine-5-)-Methyltransferases; Aged, 80 and over; 0303 health sciences; Q; Life Sciences; Middle Aged; Carcinoma, Adenoid Cystic; Deubiquitinating Enzyme CYLD; 3. Good health; Technologie de l'environnement, contrôle de la pollution; Malignant transformation; Hedgehog Signaling in Development and Cancer; Medicine; Female; Protein Kinases -- genetics; Adult; 572; Germline; Tumor Suppressor Protein p53 -- genetics; Science; Cylindroma; Mutation, Missense; 610; Dermatology; Cancer research; Article; Protein Domains -- genetics; 03 medical and health sciences; Protein Domains; Rheumatology; Deubiquitinating Enzyme CYLD -- genetics; Biochemistry, Genetics and Molecular Biology; Health Sciences; Adnexal Neoplasms; Genetics; Chimie; Humans; Cutaneous Adnexal Neoplasms and Related Syndromes; Sweat Glands -- pathology; Molecular Biology; Biology; Aged; Carcinoma, Adenoid Cystic -- genetics -- pathology; Physique; DNA (Cytosine-5-)-Methyltransferases -- genetics; Carcinoma; Astronomie; Sweat Gland Neoplasms -- genetics -- pathology; Sweat Glands; Sweat Gland Neoplasms; FOS: Biological sciences; Mutation; contrôle de la pollution; Technologie de l'environnement; Missense; Tumor Suppressor Protein p53; Protein Kinases

AbstractSpiradenoma and cylindroma are distinctive skin adnexal tumors with sweat gland differentiation and potential for malignant transformation and aggressive behaviour. We present the genomic analysis of 75 samples from 57 representative patients including 15 cylindromas, 17 spiradenomas, 2 cylindroma–spiradenoma hybrid tumors, and 24 low- and high-grade spiradenocarcinoma cases, together with morphologically benign precursor regions of these cancers. We reveal somatic or germline alterations of the CYLD gene in 15/15 cylindromas and 5/17 spiradenomas, yet only 2/24 spiradenocarcinomas. Notably, we find a recurrent missense mutation in the kinase domain of the ALPK1 gene in spiradenomas and spiradenocarcinomas, which is mutually exclusive from mutation of CYLD and can activate the NF-κB pathway in reporter assays. In addition, we show that high-grade spiradenocarcinomas carry loss-of-function TP53 mutations, while cylindromas may have disruptive mutations in DNMT3A. Thus, we reveal the genomic landscape of adnexal tumors and therapeutic targets.