KMT2E-ASNS: a novel relapse-specific fusion gene in early T-cell precursor acute lymphoblastic leukemia

Khater, Fida; Lajoie, Mathieu; Langlois, Sylvie; Healy, Jasmine; Cellot, Sonia; Richer, Chantal; Beaulieu, Patrick; St-Onge, Pascal; Saillour, Virginie; Minden, Mark D.; Marzouki, Monia; Krajinović, Maja; Bittencourt, Henrique; Sinnett, Daniel

doi:10.1182/blood-2016-10-744219

Cited by 5 publications

(9 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The TRICEPS study analysis revealed, among others, the presence of the KMT2E (55904)- ASNS (440) fusion in conjunction with a cryptic t(10;11)(p13;q21) that was missed by conventional cytogenetics within the tumoral material in both patient 22 and patient 2. 14 , 16 These findings would have changed the stratification from the diagnosis, and patients would have been treated on a higher-risk arm (very high risk).…”

Section: Resultsmentioning

confidence: 99%

“…In addition, we identified alterations, including novel alterations of previously unknown significance that have now been further characterized. 14 , 16 …”

Section: Discussionmentioning

confidence: 99%

“… 7 , 8 , 9 , 10 , 11 , 12 In-depth molecular profiling of individual tumors has allowed the identification of potentially actionable mutations that could lead to therapeutic interventions and new drug targets. 11 , 13 , 14 , 15 , 16 Several initiatives have begun to integrate cancer genomic–based information into the care of patients with childhood cancer. These initiatives have demonstrated the feasibility of such strategies at a single site or across multiple sites.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Molecular Profiling of Hard-to-Treat Childhood and Adolescent Cancers

et al. 2019

Self Cite

View full text Add to dashboard Cite

IMPORTANCE Little progress in pediatric cancer treatment has been noted in the past decade, urging the development of novel therapeutic strategies for adolescents and children with hard-totreat cancers. Use of comprehensive molecular profiling in the clinical management of children and adolescents with cancer appears a suitable approach to improve patient care and outcomes, particularly for hard-to-treat cases. OBJECTIVE To assess the feasibility of identifying potentially actionable mutations using nextgeneration sequencing-based assays in a clinically relevant time frame. DESIGN, SETTING, AND PARTICIPANTS This diagnostic study reports the results of the TRICEPS study, a prospective genome sequencing study conducted in Québec, Canada. Participants, aged 18 years or younger at diagnosis, with refractory or relapsed childhood and adolescent cancers were enrolled from April 2014 through January 2018. Whole-exome sequencing (WES) of matched tumor normal samples and RNA sequencing of tumor were performed to identify single-nucleotide variants, fusion transcripts, differential gene expression, and copy number alterations. Results reviewed by a team of experts were further annotated, synthesized into a report, and subsequently discussed in a multidisciplinary molecular tumor board. MAIN OUTCOMES AND MEASURES Molecular profiling of pediatric patients with hard-to-treat cancer, identification of actionable and targetable alteration needed for the management of these patients, and proposition of targeted and personalized novel therapeutic strategies. RESULTS A total of 84 patients with hard-to-treat cancers were included in the analysis. These patients had a mean (range) age of 10.1 (1-21) years and a similar proportion of male (45 [54%]) and female (39 [46%]). Sixty-two patients (74%) had suitable tissues for multimodal molecular profiling (WES and RNA sequencing). The process from DNA or RNA isolation to genomic sequencing and data analysis steps took a median (range) of 24 (4-41) days. Potentially actionable alterations were identified in 54 of 62 patients (87%). Actions were taken in 22 of 54 patients (41%), and 18 (33%) either were on a second or third line of treatment, were in remission, or had stable disease and thus no actions were taken. CONCLUSIONS AND RELEVANCE Incorporating genomic sequencing into the management of hard-to-treat childhood and adolescent cancers appeared feasible; molecular profiling may enable the identification of potentially actionable alterations with clinical implications for most patients, (continued) Key Points Question Can genome sequencing facilitate the molecular profiling of the patient's tumor to identify actionable and targetable alterations? Findings In this diagnostic study of 62 consecutive pediatric patients with hard-to-treat cancer who were enrolled in the TRICEPS study, incorporating multimodal genomic sequencing, including RNA sequencing, into the management of refractory or relapsed childhood and adolescent cancers identified potentially actionable alterations in 54 (87%)...

show abstract

Section: Resultsmentioning

confidence: 99%

“…In addition, we identified alterations, including novel alterations of previously unknown significance that have now been further characterized. 14 , 16 …”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Molecular Profiling of Hard-to-Treat Childhood and Adolescent Cancers

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…18 A recent publication reported a cryptic inversion [inv(7)(q22.3q21.3)] in patients with relapsed ETP-ALL that led to enhanced levels of asparagine synthetase (ASNS). 32 Increased levels of ASNS may play a role in conferring resistance to asparaginase. 33 The importance of this finding is hampered by the limited number of reported patients and the conflicting reports regarding the ASNS role in chemo-resistance.…”

Section: Outcomes Of Conventional Chemotherapy Are Suboptimal In Adulmentioning

confidence: 99%

Early precursor T-cell acute lymphoblastic leukemia: current paradigms and evolving concepts

Puglianini

Papadantonakis

2020

Therapeutic Advances in Hematology

View full text Add to dashboard Cite

show abstract

“…In this line, recently, it has been demonstrated that KMT2E-ASNS fusion transcript contributes to acquired chemotherapy resistance and relapse in ETP-ALL through ASNS over-expression [90].…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

Review of pharmacogenetics studies of L-asparaginase hypersensitivity in acute lymphoblastic leukemia points to variants in the GRIA1 gene

Lopez-Santillan

Iparraguirre

Martín-Guerrero

et al. 2017

Drug Metabolism and Personalized Therapy

View full text Add to dashboard Cite

Acute lymphoblastic leukemia (ALL) is a major pediatric cancer in developed countries. Although treatment outcome has improved owing to advances in chemotherapy, there is still a group of patients who experience severe adverse events. L-Asparaginase is an effective antineoplastic agent used in chemotherapy of ALL. Despite its indisputable indication, hypersensitivity reactions are common. In those cases, discontinuation of treatment is usually needed and anti-asparaginase antibody production may also attenuate asparaginase activity, compromising its antileukemic effect. Till now, six pharmacogenetic studies have been performed in order to elucidate possible genetic predisposition for inter-individual differences in asparaginase hypersensitivity. In this review we have summarized the results of those studies which describe the involvement of four different genes, being polymorphisms in the glutamate receptor, ionotropic, AMPA 1 (GRIA1) the most frequently associated with asparaginase hypersensitivity. We also point to new approaches focusing on epigenetics that could be interesting for consideration in the near future.

show abstract

KMT2E-ASNS: a novel relapse-specific fusion gene in early T-cell precursor acute lymphoblastic leukemia

Cited by 5 publications

References 27 publications

Molecular Profiling of Hard-to-Treat Childhood and Adolescent Cancers

Molecular Profiling of Hard-to-Treat Childhood and Adolescent Cancers

Early precursor T-cell acute lymphoblastic leukemia: current paradigms and evolving concepts

Review of pharmacogenetics studies of L-asparaginase hypersensitivity in acute lymphoblastic leukemia points to variants in the GRIA1 gene

Contact Info

Product

Resources

About