Prevalence of Cytoplasmic Actin Mutations in Diffuse Large B-Cell Lymphoma and Multiple Myeloma: A Functional Assessment Based on Actin Three-Dimensional Structures
Abstract
:1. Introduction
2. Results
2.1. Actin Genes Display Amplifications, Deletions And Mutations Across Several Cancers.
2.2. Cytoplasmic Actin Genes Display Mutations Across Cancer Types In A Non-Random Manner
2.3. Within Hematological Cancers, Mutations in ACTB and ACTG1 are Associated with Lymphoid Cancers and not With Myeloid Cancers
2.4. For DLBCL ACTB Mutations Occur More Frequently Than ACTG1 Mutations, Whereas for Multiple Myeloma This Is the Opposite
2.5. The Mutation Frequency of ACTB is Similar to that of RHOA, a Proposed Driver in DLBCL
2.6. The ACTB and ACTG1 Mutations in DLBCL and Multiple Myeloma are not Randomly Distributed Across the Protein’s Primary And Tertiary Sequences
3. Discussion
3.1. Structural Interpretation of the Mutational Profile and Possible Impact on Functional Properties of Actin
3.2. A Comparison with ACTB and ACTG1 Mutations in Developmental Diseases
3.3. ACTB and ACTG1 Mutations: More Than Passenger Mutations in DLBCL and Multiple Myeloma?
4. Materials and Methods
4.1. Queries in cBioPortal
4.2. Handling of Query Results from cBioPortal
4.3. D Structures
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ACTB-AST | ACTB-associated thrombocytopenia |
B-ALL | B-cell acute lymphoblastic leukemia |
BWCFF | Baraitser-Winter Cerebrofrontofacial Syndrome |
CNA | Copy number alteration |
DLBCL | Diffuse large B-cell lymphoma |
F-actin | Filamentous actin |
PDB | Protein Data Bank |
SD | Subdomain |
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CNA + Mut | CNA | Mut | |
---|---|---|---|
Number of patients profiled (100%) | 29,522 | 18,166 | 24,471 |
ACTB | 2.2 | 2 | 1.2 |
ACTG1 | 2 | 2.4 | 0.7 |
ACTA2 | 1.4 | 1.6 | 0.5 |
ACTG2 | 0.8 | 0.5 | 0.7 |
ACTA1 | 4 | 5 | 0.7 |
ACTC1 | 1.3 | 0.8 | 0.9 |
Study | ACTB + ACTG1 | ACTB | ACTG1 | cBioPortal Division | |||
---|---|---|---|---|---|---|---|
% | Rank | % | Rank | % | Rank | ||
BCC (UNIGE 2016) | 22.22 | 1 | 15.08 | 1 | 7.94 | 2 | Basal cell carcinoma |
DLBCL (TCGA PanCan) | 17.07 | 2 | 9.76 | 4 | 9.76 | 1 | Diffuse Large B-Cell Lymphoma |
DLBCLNOS (DFCI) | 13.33 | 3 | 10.37 | 2 | 2.22 | 15 | Diffuse Large B-Cell Lymphoma |
cSCC (MD ANDERSON 2014) | 10.26 | 4 | 5.13 | 8 | 7.69 | 3 | Cutaneous Squamous Cell Carcinoma |
Acyc (MGH 2016) | 10.00 | 5 | 10.00 | 3 | 0.00 | NR | Adenoid Cystic Carcinoma (small dataset) |
Bladder (BGI 2013) | 9.09 | 6 | 7.07 | 5 | 2.02 | 16 | Bladder Urothelial Carcinoma |
BLCA (Cornell 2016) | 8.33 | 7 | 2.78 | 20 | 5.56 | 4 | Urothelial Carcinoma |
COAD (CPTAC-2 2019) | 5.66 | 12 | 1.89 | 32 | 3.77 | 5 | Colon Cancer |
All Studies | L + M | M | L | DLBCL (Absolute Counts) | |
---|---|---|---|---|---|
Number of patients profiled (100%) | 29,473 | 4,179 | 1,134 | 3045 | 1250 |
ACTB | 1.2 | 1 | 0 | 1.3 | 2.7 (34) |
ACTG1 | 0.7 | 0.4 | 0 | 0.6 | 0.6 (8) |
RHOA | 0.9 | 0.9 | 0 | 1.3 | 3.1 (39) |
RHOB | 0.4 | 0 | 0 | 0 | 0.1 (1) |
RHOC | 0.2 | 0 | 0 | 0.1 | 0.1 (1) |
RAC1 | 0.6 | 0.1 | 0 | 0.1 | 0.1 (1) |
RAC2 | 0.4 | 0.2 | 0.2 | 0.2 | 0.3 (4) |
RAC3 | 0.2 | 0.1 | 0.2 | 0 | 0.1 (1) |
CDC42 | 0.3 | 0.1 | 0.1 | 0.1 | 0.2 (2) |
Actin Region or Subdomain (SD) Involved | Mutation in ACTB | Mutation in ACTG1 | |
---|---|---|---|
Polymer contact | SD2:D-loop (40–50) | M44T, M44I, G46D, M47L | - |
Other SD2 contacts with SD3 | K61N | I64N, R62G | |
SD3: W-loop (165–172) | - | - | |
Other SD3 contacts with SD2 | T148A | - | |
Pro-rich loop (108–112) | - | L110V, P112S | |
SD4 H-plug (263–273) | - | - | |
SD2 H-plug contact | - | R39I | |
SD1–3: Hinge Helix (137–145) | - | - | |
SD3-1: Hinge Loop (P335-S337) | Y337S | - | |
ATP-binding, phosphate release | P-loop1 (13–16) | G13A, G15D | - |
P-loop2 (156–159) | G156S | - | |
SD3-1: Hinge Loop with K336 contacting the adenosine base | Y337S | - | |
Sensor loop (71–77) | - | - |
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Witjes, L.; Van Troys, M.; Verhasselt, B.; Ampe, C. Prevalence of Cytoplasmic Actin Mutations in Diffuse Large B-Cell Lymphoma and Multiple Myeloma: A Functional Assessment Based on Actin Three-Dimensional Structures. Int. J. Mol. Sci. 2020, 21, 3093. https://doi.org/10.3390/ijms21093093
Witjes L, Van Troys M, Verhasselt B, Ampe C. Prevalence of Cytoplasmic Actin Mutations in Diffuse Large B-Cell Lymphoma and Multiple Myeloma: A Functional Assessment Based on Actin Three-Dimensional Structures. International Journal of Molecular Sciences. 2020; 21(9):3093. https://doi.org/10.3390/ijms21093093
Chicago/Turabian StyleWitjes, Laura, Marleen Van Troys, Bruno Verhasselt, and Christophe Ampe. 2020. "Prevalence of Cytoplasmic Actin Mutations in Diffuse Large B-Cell Lymphoma and Multiple Myeloma: A Functional Assessment Based on Actin Three-Dimensional Structures" International Journal of Molecular Sciences 21, no. 9: 3093. https://doi.org/10.3390/ijms21093093