Characteristics of RAS pathway mutations in juvenile myelomonocytic leukaemia: a single‐institution study from Korea

Abstract

Juvenile myelomonocytic leukaemia (JMML), a rare clonal haematopoietic disorder of childhood, is characterised as a myelodysplastic/myeloproliferative neoplasm. Despite ground-breaking genetic discoveries, JMML remains difficult to diagnose given its diverse clinical features and disease course. A total of 24 patients with JMML were diagnosed and treated at a single institution, and their genetic profiles and association with clinical and laboratory characteristics were analysed. In all, 22 of the patients received allogeneic haematopoietic stem cell transplantation after myeloablative conditioning, mostly from a haploidentical family donor. RAS pathway mutations were identified in 88% of patients: PTPN11 [nine (38%)], NRAS [nine (38%)], KRAS [two (8%)], NF1 [five (21%)] and CBL [one (4%)]. Secondary mutations were found in 25% of patients: SETBP1, JAK3, ASXL1, GATA2, KIT, KDM6A, and BCOR. Six patients showed cytogenetic abnormalities, including three with monosomy 7. The estimated 5-year event-free survival (EFS) and overall survival (AE standard error) of the entire cohort were 58Á9 (10Á9)% and 73Á5 (10Á8)% respectively. NRAS (+) patients had a higher 5-year EFS than NRAS (À) patients [72Á9 (16Á5)% vs. 52Á5 (13Á1)%, P = 0Á127]. NRAS (+) patients had a better 5-year EFS than PTPN11 (+) patients [41Á7 (17Á3)%, P = 0Á071]. Our study revealed the genetic characteristics of Korean JMML patients with RAS pathway and secondary mutations.

The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms

“…Myeloid neoplasms in RASopathies involve MAPK hyperactivation, leading to myeloid cell proliferation [ 110 ]. Genomic analysis of NF1 , NRAS , KRAS , PTPN11 , and CBL from myeloid neoplasms of patients suspected of having a RASopathy is important and aids in the diagnosis of JMML in the majority of cases [ 111 , 112 ]. Diagnostic criteria include pathogenic variants in genes associated with the RAS pathway and/or classic phenotype suggestive of a RASopathy [ 113 ].…”

The impact of SETBP1 mutations in neurological diseases and cancer

“…T A B L E 1 SETBP1 mutation and diseases. -Hidalgo et al, 2017;Carvalho et al, 2015) p.D868A ND SGS (Hoischen et al, 2010) p.D868N PS SGS, aCML, sAML, RAEB, CMML1, CMML2, CNL, JMML, PT, MDS (Carvalho et al, 2015;Cui et al, 2014;Elliott et al, 2015;Gao et al, 2020;Hirao et al, 2022;Hoischen et al, 2010;Kwon et al, 2022;Li et al, 2019;Makishima et al, 2013;Montalban-Bravo et al, 2021;Mori et al, 2022;Piazza et al, 2013;Polprasert et al, 2022;Volk et al, 2015;Wakamatsu et al, 2021;Yin et al, 2019) p.D868Y ND CMML2 (Makishima et al, 2013) p.S869C ND SGS (Landim et al, 2015) p.S869G ND aCML (Piazza et al, 2013) p (Acuna-Hidalgo et al, 2017;Elliott et al, 2015;Hoischen et al, 2010;Mori et al, 2022) p.G870N ND CNL (Cui et al, 2014) p.G870S PS SGS, aCML, CMML, CNL, sAML, JMML PMF, PNH, MDS (Fontana et al, 2020;Herenger et al, 2015;Hirao et al, 2022;Hoischen et al, 2010;Kim et al, 2021;Ko et al, 2013;Kwon et al, 2022;Leone et al, 2020;Makishima et al, 2013;Montalban-Bravo et al, 2021;Park et al, 2021;Piazza et al, 2013;…”

Advances and challenges in gene therapy strategies for pediatric cancer: a comprehensive update

“…The relative rarity of mutations may reflect the shorter time frame for accumulation of genetic defects early in life ( Ruan et al, 2020 ). Nevertheless, certain consistent mutational hotspots are observed, such as activating mutations in the RAS-MAPK pathway in juvenile myelomonocytic leukemia ( Kim et al, 2021 ). Table 1 shows the different types of pediatric cancers and their associated genetic alterations.…”