ALPK1 hotspot mutation as a driver of human spiradenoma and spiradenocarcinoma.
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Date
2019-05-17Author
Rashid, M
van der Horst, M
Mentzel, T
Butera, F
Ferreira, I
Pance, A
Rütten, A
Luzar, B
Marusic, Z
de Saint Aubain, N
Ko, JS
Billings, SD
Chen, S
Abi Daoud, M
Hewinson, J
Louzada, S
Harms, PW
Cerretelli, G
Robles-Espinoza, CD
Patel, RM
van der Weyden, L
Bakal, C
Hornick, JL
Arends, MJ
Brenn, T
Adams, DJ
Type
Journal Article
Metadata
Show full item recordAbstract
Spiradenoma 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.
Collections
Subject
Sweat Glands
Humans
Carcinoma, Adenoid Cystic
Sweat Gland Neoplasms
Protein Kinases
Cohort Studies
DNA Mutational Analysis
Mutation, Missense
Adult
Aged
Aged, 80 and over
Middle Aged
Female
Male
Tumor Suppressor Protein p53
Protein Domains
Whole Exome Sequencing
Loss of Function Mutation
Deubiquitinating Enzyme CYLD
DNA (Cytosine-5-)-Methyltransferases
Research team
Dynamical Cell Systems
Language
eng
Date accepted
2019-04-08
License start date
2019-05-17
Citation
Nature communications, 2019, 10 (1), pp. 2213 - ?
Publisher
NATURE PUBLISHING GROUP