Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia

Abstract

Juvenile myelomonocytic leukemia (JMML) is an intractable pediatric leukemia with poor prognosis whose molecular pathogenesis is poorly understood, except for somatic or germline mutations of RAS pathway genes, including PTPN11, NF1, NRAS, KRAS and CBL, in the majority of cases. To obtain a complete registry of gene mutations in JMML, whole-exome sequencing was performed for paired tumor-normal DNA from 13 individuals with JMML (cases), which was followed by deep sequencing of 8 target genes in 92 tumor samples. JMML was characterized by a paucity of gene mutations (0.85 non-silent mutations per sample) with somatic or germline RAS pathway involvement in 82 cases (89%). The SETBP1 and JAK3 genes were among common targets for secondary mutations. Mutations in the latter were often subclonal and may be involved in the progression rather than the initiation of leukemia, and these mutations associated with poor clinical outcome. Our findings provide new insights into the pathogenesis and progression of JMML.

RASA4undergoes DNA hypermethylation in resistant juvenile myelomonocytic leukemia

“…A recent exome-wide sequencing study identified mutations in SETBP1 and JAK3 as genetic lesions in JMML with probable prognostic impact, but information on these mutations was unavailable in our cohort, precluding a comparison with RASA4 methylation. 20 We also determined whether there were differences between cytogenetic subgroups of JMML. The overall association between RASA4 methylation tertiles and karyotype did not reach statistical significance (Table 1), but it was still noteworthy that there were only 6 cases with < 5% RASA4 methylation among 25 cases with monosomy 7.…”

Ras-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia

“…These new mutations also result in activation of intracellular signaling pathways including RAS and JAK/STAT signaling. RAS pathway mutations generally occur in a mutually exclusive manner in JMML and co-occurrence has only been described in some cases [10][11][12] . Together, the emerging picture of genetic alterations suggests underlying signaling defects involving the RAS pathway in almost all cases of JMML.…”

“…Moreover, some patients with Noonan syndrome develop a self-limiting MPD, which is hematologically indistinguishable from JMML 9 . Recently, less frequent recurrent mutations in JAK3, RAC, and RRAS have been identified [10][11][12] . These new mutations also result in activation of intracellular signaling pathways including RAS and JAK/STAT signaling.…”

Une approche réductionniste du cancer

“…Si l'on considère les séquences codantes du génome, une tumeur peut être la conséquence de l'altération d'un seul gène, comme on l'observe dans certaines tumeurs pédiatriques. Dans la leucémie myélomo-nocytaire chronique juvénile par exemple, il n'existe le plus souvent qu'une seule mutation induisant l'activation constitutive d'une voie de signalisation, en l'occurrence la voie Ras [4]. À l'opposé, dans les tumeurs induites par une exposition chronique à des agents mutagènes (mélanomes dus aux ultra-violets, cancers du poumon dus au tabac), on détecte plusieurs centaines de mutations géniques par cellule tumorale [5,6].…”