Comprehensive mutational profiling identifies new driver events in cutaneous leiomyosarcoma Article Swipe
Louise van der Weyden
,
Martin Del Castillo Velasco‐Herrera
,
Saamin Cheema
,
Kim Ping Wong
,
Jacqueline Marcia Boccacino
,
Victoria Offord
,
Alastair Droop
,
David R A Jones
,
Ian Vermes
,
Elizabeth Anderson
,
Claire Hardy
,
Nicolas de Saint Aubain
,
Peter M. Ferguson
,
Emily L. Clarke
,
William Merchant
,
Carolin Mogler
,
Derek Frew
,
Paul W. Harms
,
Carlos Monteagudo
,
Steven D. Billings
,
Mark J. Arends
,
Ingrid Ferreira
,
Thomas Brenn
,
David J. Adams
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1093/bjd/ljae386
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1093/bjd/ljae386
Background Cutaneous leiomyosarcoma (cLMS) is a rare soft-tissue neoplasm, showing smooth muscle differentiation, that arises from the mesenchymal cells of the dermis. To date, genetic investigation of these tumours has involved studies with small sample sizes and limited analyses that identified recurrent somatic mutations in RB1 and TP53, copy number gain of MYOCD and IGF1R, and copy number loss of PTEN. Objectives To better understand the molecular pathogenesis of cLMS, we comprehensively explored the mutational landscape of these rare tumours to identify candidate driver events. Methods In this retrospective, multi-institutional study, we performed whole-exome sequencing and RNA sequencing in 38 cases of cLMS. Results TP53 and RB1 were identified as significantly mutated and thus represent validated driver genes of cLMS. COSMIC mutational signatures SBS7a/b and DBS1 were recurrent; thus, ultraviolet light exposure may be an aetiological factor driving cLMS. Analysis of significantly recurrent somatic copy number alterations, which represent candidate driver events, found focal (< 10 Mb) deletions encompassing TP53 and KDM6B, and amplifications encompassing ZMYM2, MYOCD, MAP2K4 and NCOR1. A larger (24 Mb) recurrent deletion encompassing CYLD was also identified as significant. Significantly recurrent broad copy number alterations, involving at least half of a chromosome arm, included deletions of 6p/q, 10p/q, 11q, 12q, 13q and 16p/q, and amplification of 15q. Notably PTEN is located on 10q, RB1 on 13q and IGFR1 on 15q. Fusion gene analysis identified recurrent CRTC1/CRTC3::MAML2 fusions, as well as many novel fusions in individual samples. Conclusions Our analysis of the largest number of cases of cLMS to date highlights the importance of large cohort sizes and exploration beyond small targeted gene panels when performing molecular analyses, as it allowed a comprehensive exploration of the mutational landscape of these tumours and identification of novel candidate driver events. It also uniquely afforded the opportunity to compare the molecular phenotype of cLMS with LMS of other tissue types, such as uterine and soft-tissue LMS. Given that molecular profiling has resulted in the development of novel targeted treatment approaches for uterine and soft-tissue LMS, our study now allows the same opportunities to become available for patients with cLMS.
Related Topics
Concepts
Copy number analysis
Biology
Copy-number variation
PTEN
Gene duplication
Comparative genomic hybridization
Exome sequencing
Chromosomal translocation
Genetics
Chromosome
Cancer research
Gene
Mutation
Genome
PI3K/AKT/mTOR pathway
Apoptosis
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1093/bjd/ljae386
- OA Status
- green
- Cited By
- 5
- References
- 63
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4403329069
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4403329069Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1093/bjd/ljae386Digital Object Identifier
- Title
-
Comprehensive mutational profiling identifies new driver events in cutaneous leiomyosarcomaWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2024Year of publication
- Publication date
-
2024-10-11Full publication date if available
- Authors
-
Louise van der Weyden, Martin Del Castillo Velasco‐Herrera, Saamin Cheema, Kim Ping Wong, Jacqueline Marcia Boccacino, Victoria Offord, Alastair Droop, David R A Jones, Ian Vermes, Elizabeth Anderson, Claire Hardy, Nicolas de Saint Aubain, Peter M. Ferguson, Emily L. Clarke, William Merchant, Carolin Mogler, Derek Frew, Paul W. Harms, Carlos Monteagudo, Steven D. Billings, Mark J. Arends, Ingrid Ferreira, Thomas Brenn, David J. AdamsList of authors in order
- Landing page
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https://doi.org/10.1093/bjd/ljae386Publisher landing page
- Open access
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YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
- OA URL
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https://pmc.ncbi.nlm.nih.gov/articles/PMC11758588/Direct OA link when available
- Concepts
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Copy number analysis, Biology, Copy-number variation, PTEN, Gene duplication, Comparative genomic hybridization, Exome sequencing, Chromosomal translocation, Genetics, Chromosome, Cancer research, Gene, Mutation, Genome, PI3K/AKT/mTOR pathway, ApoptosisTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
5Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 5Per-year citation counts (last 5 years)
- References (count)
-
63Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.15q. | 211, 224 |
| abstract_inverted_index.CYLD | 178 |
| abstract_inverted_index.DBS1 | 126 |
| abstract_inverted_index.LMS, | 335 |
| abstract_inverted_index.LMS. | 316 |
| abstract_inverted_index.PTEN | 213 |
| abstract_inverted_index.TP53 | 105, 160 |
| abstract_inverted_index.also | 180, 293 |
| abstract_inverted_index.arm, | 197 |
| abstract_inverted_index.cLMS | 251, 304 |
| abstract_inverted_index.copy | 49, 57, 145, 187 |
| abstract_inverted_index.date | 253 |
| abstract_inverted_index.from | 16 |
| abstract_inverted_index.gain | 51 |
| abstract_inverted_index.gene | 226, 266 |
| abstract_inverted_index.half | 193 |
| abstract_inverted_index.loss | 59 |
| abstract_inverted_index.many | 235 |
| abstract_inverted_index.rare | 7, 79 |
| abstract_inverted_index.same | 341 |
| abstract_inverted_index.such | 311 |
| abstract_inverted_index.that | 14, 40, 318 |
| abstract_inverted_index.this | 88 |
| abstract_inverted_index.thus | 114 |
| abstract_inverted_index.well | 233 |
| abstract_inverted_index.were | 108, 127 |
| abstract_inverted_index.when | 268 |
| abstract_inverted_index.with | 33, 305, 348 |
| abstract_inverted_index.6p/q, | 201 |
| abstract_inverted_index.Given | 317 |
| abstract_inverted_index.IGFR1 | 222 |
| abstract_inverted_index.MYOCD | 53 |
| abstract_inverted_index.PTEN. | 61 |
| abstract_inverted_index.TP53, | 48 |
| abstract_inverted_index.broad | 186 |
| abstract_inverted_index.cLMS, | 70 |
| abstract_inverted_index.cLMS. | 103, 120, 139, 349 |
| abstract_inverted_index.cases | 101, 249 |
| abstract_inverted_index.cells | 19 |
| abstract_inverted_index.date, | 24 |
| abstract_inverted_index.focal | 154 |
| abstract_inverted_index.found | 153 |
| abstract_inverted_index.genes | 118 |
| abstract_inverted_index.large | 258 |
| abstract_inverted_index.least | 192 |
| abstract_inverted_index.light | 131 |
| abstract_inverted_index.novel | 236, 288, 327 |
| abstract_inverted_index.other | 308 |
| abstract_inverted_index.sizes | 36, 260 |
| abstract_inverted_index.small | 34, 264 |
| abstract_inverted_index.study | 337 |
| abstract_inverted_index.these | 28, 78, 283 |
| abstract_inverted_index.thus, | 129 |
| abstract_inverted_index.which | 148 |
| abstract_inverted_index.(cLMS) | 4 |
| abstract_inverted_index.10p/q, | 202 |
| abstract_inverted_index.16p/q, | 207 |
| abstract_inverted_index.COSMIC | 121 |
| abstract_inverted_index.Fusion | 225 |
| abstract_inverted_index.IGF1R, | 55 |
| abstract_inverted_index.KDM6B, | 162 |
| abstract_inverted_index.MAP2K4 | 168 |
| abstract_inverted_index.MYOCD, | 167 |
| abstract_inverted_index.NCOR1. | 170 |
| abstract_inverted_index.ZMYM2, | 166 |
| abstract_inverted_index.allows | 339 |
| abstract_inverted_index.arises | 15 |
| abstract_inverted_index.become | 344 |
| abstract_inverted_index.better | 64 |
| abstract_inverted_index.beyond | 263 |
| abstract_inverted_index.cohort | 259 |
| abstract_inverted_index.driver | 84, 117, 151, 290 |
| abstract_inverted_index.factor | 137 |
| abstract_inverted_index.larger | 172 |
| abstract_inverted_index.muscle | 12 |
| abstract_inverted_index.number | 50, 58, 146, 188, 247 |
| abstract_inverted_index.panels | 267 |
| abstract_inverted_index.sample | 35 |
| abstract_inverted_index.smooth | 11 |
| abstract_inverted_index.study, | 91 |
| abstract_inverted_index.tissue | 309 |
| abstract_inverted_index.types, | 310 |
| abstract_inverted_index.Methods | 86 |
| abstract_inverted_index.Notably | 212 |
| abstract_inverted_index.Results | 104 |
| abstract_inverted_index.SBS7a/b | 124 |
| abstract_inverted_index.allowed | 274 |
| abstract_inverted_index.compare | 299 |
| abstract_inverted_index.dermis. | 22 |
| abstract_inverted_index.driving | 138 |
| abstract_inverted_index.events, | 152 |
| abstract_inverted_index.events. | 85, 291 |
| abstract_inverted_index.fusions | 237 |
| abstract_inverted_index.genetic | 25 |
| abstract_inverted_index.largest | 246 |
| abstract_inverted_index.limited | 38 |
| abstract_inverted_index.located | 215 |
| abstract_inverted_index.mutated | 112 |
| abstract_inverted_index.showing | 10 |
| abstract_inverted_index.somatic | 43, 144 |
| abstract_inverted_index.studies | 32 |
| abstract_inverted_index.tumours | 29, 80, 284 |
| abstract_inverted_index.uterine | 313, 332 |
| abstract_inverted_index.Abstract | 0 |
| abstract_inverted_index.Analysis | 140 |
| abstract_inverted_index.afforded | 295 |
| abstract_inverted_index.analyses | 39 |
| abstract_inverted_index.analysis | 227, 243 |
| abstract_inverted_index.deletion | 176 |
| abstract_inverted_index.explored | 73 |
| abstract_inverted_index.exposure | 132 |
| abstract_inverted_index.fusions, | 231 |
| abstract_inverted_index.identify | 82 |
| abstract_inverted_index.included | 198 |
| abstract_inverted_index.involved | 31 |
| abstract_inverted_index.patients | 347 |
| abstract_inverted_index.resulted | 322 |
| abstract_inverted_index.samples. | 240 |
| abstract_inverted_index.targeted | 265, 328 |
| abstract_inverted_index.uniquely | 294 |
| abstract_inverted_index.(&lt; | 155 |
| abstract_inverted_index.Cutaneous | 2 |
| abstract_inverted_index.analyses, | 271 |
| abstract_inverted_index.available | 345 |
| abstract_inverted_index.candidate | 83, 150, 289 |
| abstract_inverted_index.deletions | 158, 199 |
| abstract_inverted_index.involving | 190 |
| abstract_inverted_index.landscape | 76, 281 |
| abstract_inverted_index.molecular | 67, 270, 301, 319 |
| abstract_inverted_index.mutations | 44 |
| abstract_inverted_index.neoplasm, | 9 |
| abstract_inverted_index.performed | 93 |
| abstract_inverted_index.phenotype | 302 |
| abstract_inverted_index.profiling | 320 |
| abstract_inverted_index.recurrent | 42, 143, 175, 185, 229 |
| abstract_inverted_index.represent | 115, 149 |
| abstract_inverted_index.treatment | 329 |
| abstract_inverted_index.validated | 116 |
| abstract_inverted_index.Background | 1 |
| abstract_inverted_index.Objectives | 62 |
| abstract_inverted_index.approaches | 330 |
| abstract_inverted_index.chromosome | 196 |
| abstract_inverted_index.highlights | 254 |
| abstract_inverted_index.identified | 41, 109, 181, 228 |
| abstract_inverted_index.importance | 256 |
| abstract_inverted_index.individual | 239 |
| abstract_inverted_index.mutational | 75, 122, 280 |
| abstract_inverted_index.performing | 269 |
| abstract_inverted_index.recurrent; | 128 |
| abstract_inverted_index.sequencing | 95, 98 |
| abstract_inverted_index.signatures | 123 |
| abstract_inverted_index.understand | 65 |
| abstract_inverted_index.Conclusions | 241 |
| abstract_inverted_index.development | 325 |
| abstract_inverted_index.exploration | 262, 277 |
| abstract_inverted_index.mesenchymal | 18 |
| abstract_inverted_index.opportunity | 297 |
| abstract_inverted_index.soft-tissue | 8, 315, 334 |
| abstract_inverted_index.ultraviolet | 130 |
| abstract_inverted_index.whole-exome | 94 |
| abstract_inverted_index.aetiological | 136 |
| abstract_inverted_index.alterations, | 147, 189 |
| abstract_inverted_index.encompassing | 159, 165, 177 |
| abstract_inverted_index.pathogenesis | 68 |
| abstract_inverted_index.significant. | 183 |
| abstract_inverted_index.Significantly | 184 |
| abstract_inverted_index.amplification | 209 |
| abstract_inverted_index.comprehensive | 276 |
| abstract_inverted_index.investigation | 26 |
| abstract_inverted_index.opportunities | 342 |
| abstract_inverted_index.significantly | 111, 142 |
| abstract_inverted_index.amplifications | 164 |
| abstract_inverted_index.identification | 286 |
| abstract_inverted_index.leiomyosarcoma | 3 |
| abstract_inverted_index.retrospective, | 89 |
| abstract_inverted_index.comprehensively | 72 |
| abstract_inverted_index.differentiation, | 13 |
| abstract_inverted_index.CRTC1/CRTC3::MAML2 | 230 |
| abstract_inverted_index.multi-institutional | 90 |
| cited_by_percentile_year.max | 98 |
| cited_by_percentile_year.min | 97 |
| countries_distinct_count | 6 |
| institutions_distinct_count | 24 |
| citation_normalized_percentile.value | 0.91197356 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | True |