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ALPK1 hotspot mutation as a driver of human spiradenoma and spiradenocarcinoma

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  • Mamunur Rashid
  • Michiel P J van der Horst
  • Thomas Mentzel
  • Francesca Butera
  • Ingrid Ferreira
  • Alena Pance
  • Arno Ruetten
  • Boštjan Luzar
  • Zlatko Marusic
  • Nicolas Aubain
  • Jennifer Ko
  • Steve Billings
  • Sofia Chen
  • Marie Abi-Daoud
  • James Hewinson
  • Sandra Louzada
  • Paul W. Harms
  • Guia Cerretelli
  • Carla Daniela Robles-Espinoza
  • Rajiv Patel
  • Louise van der Weyden
  • Chris Bakal
  • Jason L Hornick
  • David Adams

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Original languageEnglish
Pages (from-to)2213
JournalNature Communications
Issue number1
Publication statusPublished - 17 May 2019


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 (22 tumors, 18 patients) 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 genetic landscape of adnexal tumors and therapeutic targets.

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