Mutations in the BRAF and N-ras genes in childhood acute lymphoblastic leukaemia

Gustafsson, Britt; Angelini, Sabrina; Sander, Birgitta; Christensson, Birger; Hemminki, Kari; Kumar, Rajiv

doi:10.1038/sj.leu.2403589

Cited by 44 publications

(39 citation statements)

References 9 publications

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“…The only previous study investigating PTPN11 mutations in pediatric ALL found no age-or gender-related differences between those with or without mutations (Tartaglia et al, 2004). The prognostic importance, if any, of FLT3, NRAS, KRAS, and PTPN11 mutations remains virtually unknown in childhood ALL, except for two studies which reported no impact of RAS mutations on overall survival or event-free survival Gustafsson et al, 2005). We did not detect any difference in the frequency of relapses between cases with or without mutation.…”

Section: Discussionmentioning

confidence: 94%

Mutations of FLT3, NRAS, KRAS, and PTPN11 are frequent and possibly mutually exclusive in high hyperdiploid childhood acute lymphoblastic leukemia

Paulsson

Horvat

Strömbeck

et al. 2007

Genes Chromosomes & Cancer

102

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Although it has been suggested that mutations of the FLT3, NRAS, KRAS, and PTPN11 genes are particularly frequent in high hyperdiploid (>50 chromosomes) pediatric acute lymphoblastic leukemias (ALLs), this has as yet not been confirmed in a large patient cohort. Furthermore, it is unknown whether mutations of these genes coexist in hyperdiploid cases. We performed mutation analyses of FLT3, NRAS, KRAS, and PTPN11 in a consecutive series of 78 high hyperdiploid ALLs. Twenty-six (33%) of the cases harbored a mutation, comprising six activating point mutations and one internal tandem duplication of FLT3 (7/78 cases; 9.0%), eight codon 12, 13, or 61 NRAS mutations (8/78 cases; 10%), five codon 12 or 13 KRAS mutations (5/78 cases, 6.4%), and seven exon 3 or 13 PTPN11 mutations (7/78 cases; 9.0%). No association was seen between the presence of a mutation in FLT3, NRAS, KRAS, or PTPN11 and gender, age, white blood cell count, or relapse, suggesting that they do not confer a negative prognostic impact. Only one case harbored mutations in two different genes, suggesting that mutations of these four genes are generally mutually exclusive. In total, one third of the cases harbored a FLT3, NRAS, KRAS, or PTPN11 mutation, identifying the RTK-RAS signaling pathway as a potential target for novel therapies of high hyperdiploid pediatric ALLs. V V C 2007 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 94%

Mutations of FLT3, NRAS, KRAS, and PTPN11 are frequent and possibly mutually exclusive in high hyperdiploid childhood acute lymphoblastic leukemia

Paulsson

Horvat

Strömbeck

et al. 2007

Genes Chromosomes & Cancer

102

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“…This is a rare BRAF point mutation that has been previously reported 24 and described in malignant melanoma and childhood acute lymphoblastic leukemia. 25,26 However, to our knowledge, it has never been reported in thyroid tissue. Follow-up on this case showed Hashimoto's thyroiditis with no evidence of malignancy.…”

Section: Discussionmentioning

confidence: 87%

Assessment of cellularity, genomic DNA yields, and technical platforms for BRAF mutational testing in thyroid fine‐needle aspirate samples

Dyhdalo

MacNamara

Brainard

et al. 2013

Cancer Cytopathology

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BACKGROUND: BRAF mutation V600E (substitution Val600Glu) is a molecular signature for papillary thyroid carcinoma (PTC). Testing for BRAF mutation is clinically useful in providing prognostic prediction and facilitating accurate diagnosis of PTC in thyroid fine-needle aspirate (FNA) samples. METHODS: This study assessed the correlation of cellularity with DNA yield and compared 2 technical platforms with different sensitivities in detection of BRAF mutation in cytologic specimens. Cellularity was evaluated based on groups of 101 cells on a ThinPrep slide: 11 (1-5 groups), 21 (6-10 groups), 31 (11-20 groups), and 41 (> 20 groups). Genomic DNA was extracted from residual materials of thyroid FNAs after cytologic diagnosis. RESULTS: Approximately 49% of thyroid FNA samples had low cellularity (1-21). DNA yield is proportionate with increased cellularity and increased nearly 4-fold from 11 to 41 cellularity in cytologic samples. When applied to BRAF mutational assay, using a cutoff of 6 groups of follicular cells with 101 cells per group, 96.7% of cases yielded enough DNA for at least one testing for BRAF mutation. Five specimens (11.6%) with lower cellularity did not yield sufficient DNA for duplicate testing. Comparison of Sanger sequencing to allele-specific polymerase chain reaction methods shows the latter confers better sensitivity in detection of BRAF mutation, especially in limited cytologic specimens with a lower percentage of malignant cells. CONCLUSIONS: This study demonstrates that by using 6 groups of 101 follicular cells as a cutoff, nearly 97% of thyroid FNA samples contain enough DNA for BRAF mutational assay. Careful selection of a molecular testing system with high sensitivity facilitates the successful conduction of molecular testing in limited cytologic specimens.

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“…Hou et al 2 recently demonstrated that the L597Q mutation is a functional oncogene, at least in an in vitro experimental system. In the study by Gustafsson et al, 1 and as expected based on previous studies, 3,4 the BRAF and NRAS mutations were generally mutually exclusive. The high frequency of BRAF mutations was unexpected since such mutations otherwise have been demonstrated to be very rare in hematologic malignancies.…”

mentioning

confidence: 75%

“…Thus it may be useful to harvest hematopoietic precursors at the nadir of leukemia cells in the body in patients, whose probability of remaining in remission is arguably lower than that of patients with a durable response to initial treatment with imatinib. We read with interest the study by Gustafsson et al 1 regarding BRAF mutations in childhood acute lymphoblastic leukemia (ALL). They investigated exons 11 and 15 of BRAF and exons 1 and 2 of NRAS in 29 cases (25 pre-B ALL, 3 T-cell ALL and 1 undifferentiated ALL), and identified six (21%) BRAF mutations and seven (24%) NRAS mutations.…”

mentioning

confidence: 95%

BRAF mutations are very rare in B- and T-cell pediatric acute lymphoblastic leukemias

et al. 2008

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Mutations in the BRAF and N-ras genes in childhood acute lymphoblastic leukaemia

Cited by 44 publications

References 9 publications

Mutations of FLT3, NRAS, KRAS, and PTPN11 are frequent and possibly mutually exclusive in high hyperdiploid childhood acute lymphoblastic leukemia

Mutations of FLT3, NRAS, KRAS, and PTPN11 are frequent and possibly mutually exclusive in high hyperdiploid childhood acute lymphoblastic leukemia

Assessment of cellularity, genomic DNA yields, and technical platforms for BRAF mutational testing in thyroid fine‐needle aspirate samples

BRAF mutations are very rare in B- and T-cell pediatric acute lymphoblastic leukemias

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