Relevance of Fusion Genes in Pediatric Cancers: Toward Precision Medicine

Dupain, Célia; Harttrampf, Anne C.; Urbinati, Giorgia; Geoerger, Birgit; Massaad-Massade, Liliane

doi:10.1016/j.omtn.2017.01.005

Cited by 56 publications

(60 citation statements)

References 139 publications

(106 reference statements)

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“…This is the largest molecular study involving sporadic pediatric PTC (up to 18 years old) ( to tumors without fusions. 49,50 Notably, AGK-BRAF fusion was significantly associated with the presence of distant metastasis, with the lung being the only metastatic site outside of the neck in this set of PTC samples.…”

Section: Discussionmentioning

confidence: 78%

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AGK‐BRAF is associated with distant metastasis and younger age in pediatric papillary thyroid carcinoma

Sisdelli

Cordioli

Vaisman

et al. 2019

Pediatric Blood & Cancer

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Background The incidence of thyroid carcinoma has increased in most populations, including pediatric patients. The increase is almost exclusively due to an increase in the incidence of papillary thyroid carcinoma (PTC). Genetic alterations leading to mitogen‐activated protein kinase (MAPK) pathway activation are highly prevalent in PTC, with BRAF V600E mutation being the most common event in adult PTC. Although a lower prevalence of BRAF V600E had been reported among pediatric patients, a higher prevalence of BRAF fusion has been identified in both radiation‐exposed and sporadic pediatric PTC. However, little is known about the prognostic implications of BRAF fusions in pediatric PTC. Procedure In this study, we investigated the prevalence of BRAF alterations (AGK‐BRAF fusion and BRAF V600E mutation) in a large set of predominantly sporadic pediatric PTC cases and correlate with clinicopathological features. Somatic AGK‐BRAF fusion was investigated by RT‐PCR and confirmed by FISH break‐apart. The BRAF V600E mutation was screened using Sanger sequencing. Results AGK‐BRAF fusion, found in 19% of pediatric PTC patients, was associated with distant metastasis and younger age. Conversely, the BRAF V600E, found in 15% of pediatric PTC patients, was correlated with older age and larger tumor size. Conclusion Collectively, our results advance knowledge concerning genetic bases of pediatric thyroid carcinoma, with potential implications for diagnosis, prognosis, and therapeutic approaches.

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Section: Discussionmentioning

confidence: 78%

“…These data are in agreement with the literature. It has been suggested that pediatric cancers usually harbor fewer mutations than adult cancers and that tumors with fusions have a much lower mutational burden compared to tumors without fusions …”

Section: Discussionmentioning

confidence: 99%

AGK‐BRAF is associated with distant metastasis and younger age in pediatric papillary thyroid carcinoma

Sisdelli

Cordioli

Vaisman

et al. 2019

Pediatric Blood & Cancer

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“…The detection of DNAJB1-PRKCA gene fusion in fibrolamellar hepatocellular carcinoma (FLHCC) serves as illustrative example for both the powerful detection at unprecedented resolution by RNA sequencing (RNA-seq) and its successful diagnostic use in extremely rare tumors. 6 Therefore, the discovery of additional actionable fusion transcripts in cancers is attracting more attention.…”

Section: Introductionmentioning

confidence: 99%

“…It is well-known that pediatric cancers differ from those of adults, as many arise from embryonal rather than epithelial cells 13 and as they particularly harbor low mutation rates, mostly due to the lower implication of exogenous toxic effects. 6 The exploration of the fusion landscape in these pathologies could, therefore, help to unravel the particularity of these malignancies and provide new therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

Discovery of New Fusion Transcripts in a Cohort of Pediatric Solid Cancers at Relapse and Relevance for Personalized Medicine

et al. 2019

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We hypothetized that pediatric cancers would more likely harbor fusion transcripts. To dissect the complexity of the fusions landscape in recurrent solid pediatric cancers, we conducted a study on 48 patients with different relapsing or resistant malignancies. By analyzing RNA sequencing data with a new in-house pipeline for fusions detection named Chim-Comp, followed by verification by real-time PCR, we identified and classified the most confident fusion transcripts (FTs) according to their potential biological function and druggability. The majority of FTs were predicted to affect key cancer pathways and described to be involved in oncogenesis. Contrary to previous descriptions, we found no significant correlation between the number of fusions and mutations, emphasizing the particularity to study pre-treated pediatric patients. A considerable proportion of FTs containing tumor suppressor genes was detected, reflecting their importance in pediatric cancers. FTs containing non-receptor tyrosine kinases occurred at low incidence and predominantly in brain tumors. Remarkably, more than 30% of patients presented a potentially druggable high-confidence fusion. In conclusion, we detected new oncogenic FTs in relapsing pediatric cancer patients by establishing a robust pipeline that can be applied to other malignancies, to detect and prioritize experimental validation studies leading to the development of new therapeutic options.

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“…They occur when two genes become fused together due to chromosomal rearrangements and can result in inactivation of tumour suppressor genes and activation of proto-oncogenes. MYC is a proto-oncogene that exerts its effect by controlling multiple splicing factors 14. Cancers that overexpress MYC can be targeted by specific splice-modifying agents 15.…”

Section: How Is Transcriptomics Clinically Relevant?mentioning

confidence: 99%