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Inherited mutations affecting the SRCAP complex are central in moderate-penetrance predisposition to uterine leiomyomas

Uterine leiomyomas (ULs) are benign smooth muscle tumors that are common in premenopausal women. Somatic alterations in MED12, HMGA2, FH, genes encoding subunits of the SRCAP complex, and genes involved in Cullin 3-RING E3 ligase neddylation are mutually exclusive UL drivers. Established predisposit...

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Autores principales: Välimäki, Niko, Jokinen, Vilja, Cajuso, Tatiana, Kuisma, Heli, Taira, Aurora, Dagnaud, Olivia, Ilves, Sini, Kaukomaa, Jaana, Pasanen, Annukka, Palin, Kimmo, Heikinheimo, Oskari, Bützow, Ralf, Aaltonen, Lauri A., Karhu, Auli
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10027472/
https://www.ncbi.nlm.nih.gov/pubmed/36773604
http://dx.doi.org/10.1016/j.ajhg.2023.01.009
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author Välimäki, Niko
Jokinen, Vilja
Cajuso, Tatiana
Kuisma, Heli
Taira, Aurora
Dagnaud, Olivia
Ilves, Sini
Kaukomaa, Jaana
Pasanen, Annukka
Palin, Kimmo
Heikinheimo, Oskari
Bützow, Ralf
Aaltonen, Lauri A.
Karhu, Auli
author_facet Välimäki, Niko
Jokinen, Vilja
Cajuso, Tatiana
Kuisma, Heli
Taira, Aurora
Dagnaud, Olivia
Ilves, Sini
Kaukomaa, Jaana
Pasanen, Annukka
Palin, Kimmo
Heikinheimo, Oskari
Bützow, Ralf
Aaltonen, Lauri A.
Karhu, Auli
author_sort Välimäki, Niko
collection PubMed
description Uterine leiomyomas (ULs) are benign smooth muscle tumors that are common in premenopausal women. Somatic alterations in MED12, HMGA2, FH, genes encoding subunits of the SRCAP complex, and genes involved in Cullin 3-RING E3 ligase neddylation are mutually exclusive UL drivers. Established predisposition genes explain only partially the estimated heritability of leiomyomas. Here, we examined loss-of-function variants across 18,899 genes in a cohort of 233,614 White European women, revealing variants in four genes encoding SRCAP complex subunits (YEATS4, ZNHIT1, DMAP1, and ACTL6A) with a significant association to ULs, and YEATS4 and ZNHIT1 strikingly rank first and second, respectively. Positive mutation status was also associated with younger age at diagnosis and hysterectomy. Moderate-penetrance UL risk was largely attributed to rare non-synonymous mutations affecting the SRCAP complex. To examine this disease phenotype more closely, we set out to identify inherited mutations affecting the SRCAP complex in our in-house sample collection of Finnish individuals with ULs (n = 860). We detected one individual with an ACTL6A splice-site mutation, two individuals with a YEATS4 missense mutation, and four individuals with DMAP1 mutations: one splice-site, one nonsense, and two missense variants. These individuals had large and/or multiple ULs, were often diagnosed at an early age, and many had family history of ULs. When a somatic second hit was found, ACTL6A and DMAP1 were silenced in tumors by somatic mutation and YEATS4 by promoter hypermethylation. Decreased H2A.Z staining was observed in the tumors, providing further evidence for the pathogenic nature of the germline mutations. Our results establish inactivation of genes encoding SRCAP complex subunits as a central contributor to moderate-penetrance UL predisposition.
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spelling pubmed-100274722023-03-21 Inherited mutations affecting the SRCAP complex are central in moderate-penetrance predisposition to uterine leiomyomas Välimäki, Niko Jokinen, Vilja Cajuso, Tatiana Kuisma, Heli Taira, Aurora Dagnaud, Olivia Ilves, Sini Kaukomaa, Jaana Pasanen, Annukka Palin, Kimmo Heikinheimo, Oskari Bützow, Ralf Aaltonen, Lauri A. Karhu, Auli Am J Hum Genet Article Uterine leiomyomas (ULs) are benign smooth muscle tumors that are common in premenopausal women. Somatic alterations in MED12, HMGA2, FH, genes encoding subunits of the SRCAP complex, and genes involved in Cullin 3-RING E3 ligase neddylation are mutually exclusive UL drivers. Established predisposition genes explain only partially the estimated heritability of leiomyomas. Here, we examined loss-of-function variants across 18,899 genes in a cohort of 233,614 White European women, revealing variants in four genes encoding SRCAP complex subunits (YEATS4, ZNHIT1, DMAP1, and ACTL6A) with a significant association to ULs, and YEATS4 and ZNHIT1 strikingly rank first and second, respectively. Positive mutation status was also associated with younger age at diagnosis and hysterectomy. Moderate-penetrance UL risk was largely attributed to rare non-synonymous mutations affecting the SRCAP complex. To examine this disease phenotype more closely, we set out to identify inherited mutations affecting the SRCAP complex in our in-house sample collection of Finnish individuals with ULs (n = 860). We detected one individual with an ACTL6A splice-site mutation, two individuals with a YEATS4 missense mutation, and four individuals with DMAP1 mutations: one splice-site, one nonsense, and two missense variants. These individuals had large and/or multiple ULs, were often diagnosed at an early age, and many had family history of ULs. When a somatic second hit was found, ACTL6A and DMAP1 were silenced in tumors by somatic mutation and YEATS4 by promoter hypermethylation. Decreased H2A.Z staining was observed in the tumors, providing further evidence for the pathogenic nature of the germline mutations. Our results establish inactivation of genes encoding SRCAP complex subunits as a central contributor to moderate-penetrance UL predisposition. Elsevier 2023-03-02 2023-02-10 /pmc/articles/PMC10027472/ /pubmed/36773604 http://dx.doi.org/10.1016/j.ajhg.2023.01.009 Text en © 2023 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Välimäki, Niko
Jokinen, Vilja
Cajuso, Tatiana
Kuisma, Heli
Taira, Aurora
Dagnaud, Olivia
Ilves, Sini
Kaukomaa, Jaana
Pasanen, Annukka
Palin, Kimmo
Heikinheimo, Oskari
Bützow, Ralf
Aaltonen, Lauri A.
Karhu, Auli
Inherited mutations affecting the SRCAP complex are central in moderate-penetrance predisposition to uterine leiomyomas
title Inherited mutations affecting the SRCAP complex are central in moderate-penetrance predisposition to uterine leiomyomas
title_full Inherited mutations affecting the SRCAP complex are central in moderate-penetrance predisposition to uterine leiomyomas
title_fullStr Inherited mutations affecting the SRCAP complex are central in moderate-penetrance predisposition to uterine leiomyomas
title_full_unstemmed Inherited mutations affecting the SRCAP complex are central in moderate-penetrance predisposition to uterine leiomyomas
title_short Inherited mutations affecting the SRCAP complex are central in moderate-penetrance predisposition to uterine leiomyomas
title_sort inherited mutations affecting the srcap complex are central in moderate-penetrance predisposition to uterine leiomyomas
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10027472/
https://www.ncbi.nlm.nih.gov/pubmed/36773604
http://dx.doi.org/10.1016/j.ajhg.2023.01.009
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