TY - JOUR
T1 - ALPK1 hotspot mutation as a driver of human spiradenoma and spiradenocarcinoma
AU - Rashid, Mamunur
AU - van der Horst, Michiel
AU - Mentzel, Thomas
AU - Butera, Francesca
AU - Ferreira, Ingrid
AU - Pance, Alena
AU - Rütten, Arno
AU - Luzar, Bostjan
AU - Marusic, Zlatko
AU - de Saint Aubain, Nicolas
AU - Ko, Jennifer S
AU - Billings, Steven D
AU - Chen, Sofia
AU - Abi Daoud, Marie
AU - Hewinson, James
AU - Louzada, Sandra
AU - Harms, Paul W
AU - Cerretelli, Guia
AU - Robles-Espinoza, Carla Daniela
AU - Patel, Rajiv M
AU - van der Weyden, Louise
AU - Bakal, Chris
AU - Hornick, Jason L
AU - Arends, Mark J
AU - Brenn, Thomas
AU - Adams, David J
PY - 2019/5/17
Y1 - 2019/5/17
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Carcinoma, Adenoid Cystic/genetics
KW - Cohort Studies
KW - DNA (Cytosine-5-)-Methyltransferases/genetics
KW - DNA Methyltransferase 3A
KW - DNA Mutational Analysis
KW - Deubiquitinating Enzyme CYLD/genetics
KW - Female
KW - Humans
KW - Loss of Function Mutation
KW - Male
KW - Middle Aged
KW - Mutation, Missense
KW - Protein Domains/genetics
KW - Protein Kinases/genetics
KW - Sweat Gland Neoplasms/genetics
KW - Sweat Glands/pathology
KW - Tumor Suppressor Protein p53/genetics
KW - Exome Sequencing
U2 - 10.1038/s41467-019-09979-0
DO - 10.1038/s41467-019-09979-0
M3 - Article
C2 - 31101826
SN - 2041-1723
VL - 10
SP - 2213
JO - Nature Communications
JF - Nature Communications
IS - 1
ER -