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Gene alterations in epigenetic modifiers and JAK-STAT signaling are frequent in breast implant-associated ALCL
- Source :
- Blood, Blood, American Society of Hematology, 2019, ⟨10.1182/blood.2019001904⟩, Blood, 2019, 135 (5), pp.360-370. ⟨10.1182/blood.2019001904⟩, Blood, Vol. 135, no. 5, p. 360-370 (2020), Blood, American Society of Hematology, 2019, 135 (5), pp.360-370. ⟨10.1182/blood.2019001904⟩
- Publication Year :
- 2019
- Publisher :
- HAL CCSD, 2019.
-
Abstract
- The oncogenic events involved in breast implant-associated anaplastic large cell lymphoma (BI-ALCL) remain elusive. To clarify this point, we have characterized the genomic landscape of 34 BI-ALCLs (15 tumor and 19 in situ subtypes) collected from 54 BI-ALCL patients diagnosed through the French Lymphopath network. Whole-exome sequencing (n = 22, with paired tumor/germline DNA) and/or targeted deep sequencing (n = 24) showed recurrent mutations of epigenetic modifiers in 74% of cases, involving notably KMT2C (26%), KMT2D (9%), CHD2 (15%), and CREBBP (15%). KMT2D and KMT2C mutations correlated with a loss of H3K4 mono- and trimethylation by immunohistochemistry. Twenty cases (59%) showed mutations in ≥1 member of the JAK/STAT pathway, including STAT3 (38%), JAK1 (18%), and STAT5B (3%), and in negative regulators, including SOCS3 (6%), SOCS1 (3%), and PTPN1 (3%). These mutations were more frequent in tumor-type samples than in situ samples (P = .038). All BI-ALCLs expressed pSTAT3, regardless of the mutational status of genes in the JAK/STAT pathway. Mutations in the EOMES gene (12%) involved in lymphocyte development, PI3K-AKT/mTOR (6%), and loss-of-function mutations in TP53 (12%) were also identified. Copy-number aberration (CNA) analysis identified recurrent alterations, including gains on chromosomes 2, 9p, 12p, and 21 and losses on 4q, 8p, 15, 16, and 20. Regions of CNA encompassed genes involved in the JAK/STAT pathway and epigenetic regulators. Our results show that the BI-ALCL genomic landscape is characterized by not only JAK/STAT activating mutations but also loss-of-function alterations of epigenetic modifiers.
- Subjects :
- Adult
0301 basic medicine
DNA Copy Number Variations
Breast Implants
[SDV]Life Sciences [q-bio]
Immunology
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
Biology
medicine.disease_cause
Biochemistry
Germline
Epigenesis, Genetic
03 medical and health sciences
0302 clinical medicine
medicine
Humans
Epigenetics
SOCS3
STAT3
[SDV.BC] Life Sciences [q-bio]/Cellular Biology
Anaplastic large-cell lymphoma
PI3K/AKT/mTOR pathway
ComputingMilieux_MISCELLANEOUS
Aged
Janus Kinases
Aged, 80 and over
Mutation
Lymphoid Neoplasia
Genome, Human
JAK-STAT signaling pathway
Cell Biology
Hematology
Middle Aged
medicine.disease
[SDV] Life Sciences [q-bio]
STAT Transcription Factors
030104 developmental biology
Cancer research
biology.protein
Lymphoma, Large-Cell, Anaplastic
[SDV.IMM]Life Sciences [q-bio]/Immunology
Female
Signal Transduction
030215 immunology
Subjects
Details
- Language :
- English
- ISSN :
- 00064971 and 15280020
- Database :
- OpenAIRE
- Journal :
- Blood, Blood, American Society of Hematology, 2019, ⟨10.1182/blood.2019001904⟩, Blood, 2019, 135 (5), pp.360-370. ⟨10.1182/blood.2019001904⟩, Blood, Vol. 135, no. 5, p. 360-370 (2020), Blood, American Society of Hematology, 2019, 135 (5), pp.360-370. ⟨10.1182/blood.2019001904⟩
- Accession number :
- edsair.doi.dedup.....1bf1272495739fb81180f489c97e40f3