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| Content Provider | Springer Nature : BioMed Central |
|---|---|
| Author | Spinella, Jean-François Cassart, Pauline Garnier, Nicolas Rousseau, Philippe Drullion, Claire Richer, Chantal Ouimet, Manon Saillour, Virginie Healy, Jasmine Autexier, Chantal Sinnett, Daniel |
| Abstract | Background The identification of oncogenic driver mutations has largely relied on the assumption that genes that exhibit more mutations than expected by chance are more likely to play an active role in tumorigenesis. Major cancer sequencing initiatives have therefore focused on recurrent mutations that are more likely to be drivers. However, in specific genetic contexts, low frequency mutations may also be capable of participating in oncogenic processes. Reliable strategies for identifying these rare or even patient-specific (private) mutations are needed in order to elucidate more personalized approaches to cancer diagnosis and treatment. Methods Here we performed whole-exome sequencing on three cases of childhood pre-B acute lymphoblastic leukemia (cALL), representing three cytogenetically-defined subgroups (high hyperdiploid, t(12;21) translocation, and cytogenetically normal). We applied a data reduction strategy to identify both common and rare/private somatic events with high functional potential. Top-ranked candidate mutations were subsequently validated at high sequencing depth on an independent platform and in vitro expression assays were performed to evaluate the impact of identified mutations on cell growth and survival. Results We identified 6 putatively damaging non-synonymous somatic mutations among the three cALL patients. Three of these mutations were well-characterized common cALL mutations involved in constitutive activation of the mitogen-activated protein kinase pathway (FLT3 p.D835Y, NRAS p.G13D, BRAF p.G466A). The remaining three patient-specific mutations (ACD p.G223V, DOT1L p.V114F, HCFC1 p.Y103H) were novel mutations previously undescribed in public cancer databases. Cytotoxicity assays demonstrated a protective effect of the ACD p.G223V mutation against apoptosis in leukemia cells. ACD plays a key role in protecting telomeres and recruiting telomerase. Using a telomere restriction fragment assay, we also showed that this novel mutation in ACD leads to increased telomere length in leukemia cells. Conclusion This study identified ACD as a novel gene involved in cALL and points to a functional role for ACD in enhancing leukemia cell survival. These results highlight the importance of rare/private somatic mutations in understanding cALL etiology, even within well-characterized molecular subgroups. |
| Related Links | https://bmccancer.biomedcentral.com/counter/pdf/10.1186/s12885-015-1639-5.pdf |
| Ending Page | 8 |
| Page Count | 8 |
| Starting Page | 1 |
| File Format | HTM / HTML |
| ISSN | 14712407 |
| DOI | 10.1186/s12885-015-1639-5 |
| Journal | BMC Cancer |
| Issue Number | 1 |
| Volume Number | 15 |
| Language | English |
| Publisher | BioMed Central |
| Publisher Date | 2015-09-07 |
| Access Restriction | Open |
| Subject Keyword | Cancer Research Oncology Surgical Oncology Health Promotion and Disease Prevention Biomedicine Medicine Public Health Chronic Lymphocytic Leukemia Somatic Mutation Bone Marrow Sample Variant Allele Frequency Telomere Dysfunction Medicine/Public Health |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cancer Research Oncology Genetics |
| Journal Impact Factor | 3.4/2023 |
| 5-Year Journal Impact Factor | 3.8/2023 |
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