Dataset Information

ALPK1 hotspot mutation as a driver of human spiradenoma and spiradenocarcinoma.

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.

SUBMITTER: Rashid M

PROVIDER: S-EPMC6525246 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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ALPK1 hotspot mutation as a driver of human spiradenoma and spiradenocarcinoma.

Rashid Mamunur M van der Horst Michiel M Mentzel Thomas T Butera Francesca F Ferreira Ingrid I Pance Alena A Rütten Arno A Luzar Bostjan B Marusic Zlatko Z de Saint Aubain Nicolas N Ko Jennifer S JS Billings Steven D SD Chen Sofia S Abi Daoud Marie M Hewinson James J Louzada Sandra S Harms Paul W PW Cerretelli Guia G Robles-Espinoza Carla Daniela CD Patel Rajiv M RM van der Weyden Louise L Bakal Chris C Hornick Jason L JL Arends Mark J MJ Brenn Thomas T Adams David J DJ

Nature communications 20190517 1

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 ...[more]

PMID: 31101826

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Project description:The impact of somatic missense mutation on cancer etiology and progression is often difficult to interpret. One common approach for assessing the contribution of missense mutations in carcinogenesis is to identify genes mutated with statistically nonrandom frequencies. Even given the large number of sequenced cancer samples currently available, this approach remains underpowered to detect drivers, particularly in less studied cancer types. Alternative statistical and bioinformatic approaches are needed. One approach to increase power is to focus on localized regions of increased missense mutation density or hotspot regions, rather than a whole gene or protein domain. Detecting missense mutation hotspot regions in three-dimensional (3D) protein structure may also be beneficial because linear sequence alone does not fully describe the biologically relevant organization of codons. Here, we present a novel and statistically rigorous algorithm for detecting missense mutation hotspot regions in 3D protein structures. We analyzed approximately 3 × 10(5) mutations from The Cancer Genome Atlas (TCGA) and identified 216 tumor-type-specific hotspot regions. In addition to experimentally determined protein structures, we considered high-quality structural models, which increase genomic coverage from approximately 5,000 to more than 15,000 genes. We provide new evidence that 3D mutation analysis has unique advantages. It enables discovery of hotspot regions in many more genes than previously shown and increases sensitivity to hotspot regions in tumor suppressor genes (TSG). Although hotspot regions have long been known to exist in both TSGs and oncogenes, we provide the first report that they have different characteristic properties in the two types of driver genes. We show how cancer researchers can use our results to link 3D protein structure and the biologic functions of missense mutations in cancer, and to generate testable hypotheses about driver mechanisms. Our results are included in a new interactive website for visualizing protein structures with TCGA mutations and associated hotspot regions. Users can submit new sequence data, facilitating the visualization of mutations in a biologically relevant context. Cancer Res; 76(13); 3719-31. ©2016 AACR.

Dataset Information

ALPK1 hotspot mutation as a driver of human spiradenoma and spiradenocarcinoma.

Publications

ALPK1 hotspot mutation as a driver of human spiradenoma and spiradenocarcinoma.

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