Multi-omic analysis reveals significantly mutated genes and DDX3X as a sex-specific tumor suppressor in cutaneous melanoma.
Journal
Nature cancer
ISSN: 2662-1347
Titre abrégé: Nat Cancer
Pays: England
ID NLM: 101761119
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
30
05
2019
accepted:
15
05
2020
entrez:
5
2
2022
pubmed:
1
6
2020
medline:
1
6
2020
Statut:
ppublish
Résumé
The high background tumor mutation burden in cutaneous melanoma limits the ability to identify significantly mutated genes (SMGs) that drive this cancer. To address this, we performed a mutation significance study of over 1,000 melanoma exomes, combined with a multi-omic analysis of 470 cases from The Cancer Genome Atlas. We discovered several SMGs with co-occurring loss-of-heterozygosity and loss-of-function mutations, including PBRM1, PLXNC1 and PRKAR1A, which encodes a protein kinase A holoenzyme subunit. Deconvolution of bulk tumor transcriptomes into cancer, immune and stromal components revealed a melanoma-intrinsic oxidative phosphorylation signature associated with protein kinase A pathway alterations. We also identified SMGs on the X chromosome, including the RNA helicase DDX3X, whose loss-of-function mutations were exclusively observed in males. Finally, we found that tumor mutation burden and immune infiltration contain complementary information on survival of patients with melanoma. In summary, our multi-omic analysis provides insights into melanoma etiology and supports contribution of specific mutations to the sex bias observed in this cancer.
Identifiants
pubmed: 35121978
doi: 10.1038/s43018-020-0077-8
pii: 10.1038/s43018-020-0077-8
pmc: PMC8832745
mid: NIHMS1756655
doi:
Substances chimiques
Biomarkers, Tumor
0
Cyclic AMP-Dependent Protein Kinases
EC 2.7.11.11
DDX3X protein, human
EC 3.6.1.-
DEAD-box RNA Helicases
EC 3.6.4.13
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
635-652Subventions
Organisme : NCI NIH HHS
ID : R21 CA224391
Pays : United States
Organisme : The V Foundation for Cancer Research
ID : V2016-023
Pays : United States
Organisme : CIHR
ID : PJT-152975
Pays : Canada
Informations de copyright
© 2020. The Author(s), under exclusive licence to Springer Nature America, Inc.
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