Author/Editor		Rashid, Mamunur; Horst, Michiel P J; Mentzel, Thomas; Butera, Francesca; Ferreira, Ingrid; Pance, Alena; Rütten, Arno; Luzar, Boštjan; Marušić, Zlatko; de Saint Aubain, Nicolas
Title		ALPK1 hotspot mutation as a driver of human spiradenoma and spiradenocarcinoma
Type		članek
Vol. and No.		Letnik 10, št. 1
Publication year		2019
Volume		str. 1-10
ISSN		2041-1723 - Nature communications
Language		eng
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-%B 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.
Keywords		adneksalni tumorji genomska analiza spiradenokarcinomi adnexal tumors genomic analysis spiradenocarcinomas