Untitled

Abstract

A point mutation of the N-ras gene is one of the known genetic alterations identified in patients with acute lymphoblastic leukemia (ALL), but its clinical importance is still controversial. Using polymerase chain reactions, we examined codons 12, 13 and 61 of this gene in 125 Japanese childhood ALL patients (64 common-ALL, 22 pre-B-ALL, 33 T-ALL, 2 B-ALL, 3 undifferentiated ALL, and 1 unclassified ALL) including 9 relapsed patients. An N-ras point mutation was observed in 14 (11%) patients (9 common-ALL, 3 T-ALL, and 2 undifferentiated ALL; 13 patients at diagnosis and 1 at relapse). The patients with undifferentiated ALL harbored an N-ras mutation at a significantly higher rate. However, no correlation was found between the presence of an N-ras mutation and sex, age, or white blood count. There was no significant difference in the event-free survival rate between 13 fresh patients with an N-ras mutation and 103 patients with a wild-type configuration. The N-ras mutation was present in about 10% of childhood ALL cases but it did not have a prognostic impact. The sequence analyses revealed that the majority of the patients (13/14) had an N-ras mutation of a G to A transition. This finding was consistent with previous reports on N-ras mutations in acute leukemias in which the incidence of a G to A mutation was significantly higher in ALL than in myeloid malignancies.

The genetic basis of early T-cell precursor acute lymphoblastic leukaemia

“…In addition to genes known to be mutated in T-ALL, including NRAS 10,11 ( N = 3 out of 12 WGS cases) JAK1 (ref. 12, N = 2), NOTCH1 (ref.…”

Ras/Raf/MEK/ERK Pathway Activation in Childhood Acute Lymphoblastic Leukemia and Its Therapeutic Targeting

“…While early studies focused solely on mutations in NRAS and KRAS , more comprehensive screens with inclusion of additional genes impacting on the pathway, including PTPN11, FLT3 , and CBL , report mutations in up to 35% of newly diagnosed ALL, with a predominance in B lineage ALL (9–11, 13, 14, 16, 18–20, 32, 72–74). Table 1 summarizes the largest studies to date and Figure 3 shows the frequencies of mutated genes identified in a UK diagnostic cohort (15, 48).…”

“…While one early study demonstrated a significantly higher rate of hematological relapse and a trend toward reduced complete remission rates amongst cases harboring NRAS mutations, the association between RAS mutation and adverse outcome has not been replicated in more recent studies, raising the possibility that contemporary chemotherapeutic regimens have negated the effect (9, 12, 18, 74). In the largest investigation of the prognostic significance of NRAS and KRAS mutation that included 870 patients enrolled on an US study, mutation status had no discernable effect on event free survival, disease free survival, or overall survival and there was no relationship between RAS mutations and high risk clinical features (9).…”

RasGRP Ras guanine nucleotide exchange factors in cancer

“…Early studies investigating the prevalence of oncogenic N- or K- Ras mutations in childhood T-ALL showed that these are relatively rare and present in only 4%–10% of patients, which is much lower than in other tumor types such as pancreatic or colorectal cancer (Ahuja et al, 1990; Yokota et al, 1998; Kawamura et al, 1999; Friday and Adjei, 2005). Significantly, it has also been shown that roughly 50% of patients have increased Ras activation levels in bone marrow cells from punctures or in peripheral blood cells, as compared to healthy controls (von Lintig et al, 2000).…”