ALPK1 hotspot mutation as a driver of human spiradenoma and spiradenocarcinoma

Mamunur Rashid, Michiel van der Horst, Thomas Mentzel, Francesca Butera, Ingrid Ferreira, Alena Pance, Arno Rütten, Bostjan Luzar, Zlatko Marusic, Nicolas de Saint Aubain, Jennifer S. Ko, Steven D. Billings, Sofia Chen, Marie Abi Daoud, James Hewinson, Sandra Louzada, Paul W. Harms, Guia Cerretelli, Carla Daniela Robles-Espinoza, Rajiv M. Patel, Louise van der Weyden, Chris Bakal, Jason L. Hornick, Mark J. Arends, Thomas Brenn and David J. Adams ()
Additional contact information
Mamunur Rashid: Wellcome Trust Sanger Institute
Michiel van der Horst: Maasstad Hospital
Thomas Mentzel: Dermatopathologie Friedrichshafen
Francesca Butera: Division of Cancer Biology. Institute of Cancer Research
Ingrid Ferreira: Wellcome Trust Sanger Institute
Alena Pance: Wellcome Trust Sanger Institute
Arno Rütten: Dermatopathologie Friedrichshafen
Bostjan Luzar: Medical Faculty University of Ljubljana
Zlatko Marusic: University Hospital Center Zagreb
Nicolas de Saint Aubain: Institut Jules Bordet
Jennifer S. Ko: Cleveland Clinic
Steven D. Billings: Cleveland Clinic
Sofia Chen: Wellcome Trust Sanger Institute
Marie Abi Daoud: University of Calgary
James Hewinson: Wellcome Trust Sanger Institute
Sandra Louzada: Wellcome Trust Sanger Institute
Paul W. Harms: University of Michigan Medical School
Guia Cerretelli: The University of Edinburgh, Institute of Genetics & Molecular Medicine
Carla Daniela Robles-Espinoza: Wellcome Trust Sanger Institute
Rajiv M. Patel: University of Michigan Medical School
Louise van der Weyden: Wellcome Trust Sanger Institute
Chris Bakal: Division of Cancer Biology. Institute of Cancer Research
Jason L. Hornick: Harvard Medical School
Mark J. Arends: The University of Edinburgh, Institute of Genetics & Molecular Medicine
Thomas Brenn: University of Calgary
David J. Adams: Wellcome Trust Sanger Institute

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-09979-0

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