LOSS OF MULTIPLE POINT MUTATIONS OF RAS GENES ASSOCIATED WITH ACQUISITION OF CHROMOSOMAL ABNORMALITIES DURING DISEASE PROGRESSION IN MYELODYSPLASTIC SYNDROME

Nakagawa, Toshio; S, Saitoh; Imoto, Shion; Itoh, Masae; Tsutsumi, Masayoshi; Hikiji, Kazumasa; Nakao, Yoshinobu; Fujita, Takeshi

doi:10.1111/j.1365-2141.1991.tb07988.x

Cited by 18 publications

(11 citation statements)

References 8 publications

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“…In this study we commonly found multiple point mutations of ras genes (7 cases out of 19; table 2). Since somatic mutations of ras genes have been postulated to serve as clonal marker of hematological neoplasms [12], our data suggest two pos sibilities; (1) that the malignant process initially had developed from several clones or (2) that the malignant process of AML had developed from a single clone and progressed to serveral clones [17], The first possibility ap pears unlikely, since a previous report showed that a mal ignant process of AML had developed from a single cell in 27 patients [18]. Hirai et al [4] also reported 2 cases in which chromosomal abnormality preceded activation of the N -ras gen. Senn et al [19] reported a case where the relapsed cell population differed from the onset clone by using N-ra.v oncogene mutation.…”

Section: Discussionmentioning

confidence: 89%

“…DN As from case 59 at various time points were am plified by PCR and hybridized with various probes simul taneously. The radioautogram was shown elsewhere as a case report [17], These observations may indicate that one clone carrying no mutated codon of the ras gene acquired chromosomal abnormalities and progressed the disease fatally. Case 74, acute monocytic leukemia, showed point mutation of N-ras codon 13 at the initial presentation but lost the mutation of the ras gene at complete remission.…”

Section: Clinical Course and Ras Mutationmentioning

confidence: 99%

“…Bone marrow cells were collected at diagnosis, then every 3-5 months, or as soon as the hematological parameters changed. Among these 14 cases, case number 59. where AML developed from RAEB-t, presented with distinct five point mutations in ras genes and lost these ras m uta tions at the end of the clinical course [ 17], The loss of these mutations was associated with acquisition of the chro mosomal abnormalities, 46.XY,-17,-f der(17)t(17;?) (pl3;?).del(9)(ql3q22).…”

Section: Clinical Course and Ras Mutationmentioning

confidence: 99%

“…Our experimental conditions do not allow an oligonucleo tide probe with a single base mutation to hybridize with an allele containing two or more mutations of codon 12 and codon 13 of the same ras gene. Therefore, when two or more mutations were detected in these 7 cases, we hypothe sized that they were present in either two separate alleles or separate cell populations [17], To confirm this, 101 bp of amplified DNAs containing codons 12 and 13 of N-ras from case 59 were ligated to the Sma I site of plasmid pUC19 and transfected into the E. co//XLl-Blue. Eighty colonies of transfected XL 1-Blue through selection medium Xgal/IPTG with ampicillin were cloned.…”

Section: Multiple Point Mutations O F Ras Genesmentioning

confidence: 99%

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Multiple Point Mutation of N-ras and K-ras Oncogenes in Myelodysplastic Syndrome and Acute Myelogenous Leukemia

Nakagawa

S²,

Imoto³

et al. 1992

Oncology

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We analyzed activating mutations of N-ras and K-ras by the polymerase chain reaction and oligonucleotide hybridization in hematological disorders. Activating mutations of these codons were detected in 4 of 20 cases of myelodysplastic syndrome (MDS) and 15 of 77 cases of acute myelogenous leukemia (AML). Out of 19 cases of MDS and AML who carried active mutations, 7 cases were found to have two or more distinct mutations in activating codons of N-ras and K-ras. Ras mutation was found preferentially in progressive disease such as refractory anemia with excess of blasts (RAEB) of RAEB in transformation (RAEB-t). A relatively high incidence of ras mutation was found in M₅ AML (40%). No ras mutations were found in other hematological disorders, such as acute lymphoblastic leukemia and chronic myelogenous-leukemia. The most frequent amino acid substitution was that of an aspartate for glycine at codon 12 of N-ras resulting from G to A mutation (11/35). The survival of AML patients who carried ras mutations showed no significant differences from those without ras mutations calculated by Kaplan-Meier. Seven cases of MDS and 7 cases of AML patients could be investigated at various points during their clinical course. Among these 14 cases, we found 2 interesting cases of MDS. The first case lost multiple clones carrying ras mutations during disease progression, the second case acquired mutation of the ras gene during disease progression. These results suggested that multiple point mutations of ras genes may not be initiating events but may contribute to a clonal evolution of MDS and AML.

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Section: Discussionmentioning

confidence: 89%

Section: Clinical Course and Ras Mutationmentioning

confidence: 99%

Section: Clinical Course and Ras Mutationmentioning

confidence: 99%

Section: Multiple Point Mutations O F Ras Genesmentioning

confidence: 99%

See 2 more Smart Citations

Multiple Point Mutation of N-ras and K-ras Oncogenes in Myelodysplastic Syndrome and Acute Myelogenous Leukemia

Nakagawa

S²,

Imoto³

et al. 1992

Oncology

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“…Kiras mutations are thought to occur as a relatively early event in the developmental sequence of colorectal adenocarcinoma (Vogelstein et al, 1988), and may therefore be expressed early on by most of the tumour cells. The cancer present at the time of biopsy may have progressed further, and may not harbour the same mutation because the cancer cells harbouring the earlier mutation were eliminated by the immune system in an early event of tumour development (Nakagawa et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

Specific T-cell immunity against Ki-ras peptides in patients with pancreatic and colorectal cancers

et al. 2003

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Mutations of codon 12 in the Ki-ras gene are frequently found in pancreatic and colorectal cancers. It has been demonstrated that human T-cells have the potential to recognise tumours expressing mutated ras-derived peptides. However, it remains unclear whether T-cells from a given individual can recognise the mutant peptides, which are expressed in that individual's tumour tissues. Mutations of the Ki-ras oncogene were analysed by the mutant-allele-specific amplification (MASA) method in pancreatic and colorectal tumour tissues, and T-cell responses against mutated Ki-ras-derived peptides were measured by [3 H]thymidine incorporation and IFN-g production assays. Specific T-cell responses against Ki-ras-products were found in cancer patients, whereas no immune response was observed in normal individuals (Po0.01). Six of the eight pancreatic cancer patients (75%) and nine of 26 colorectal cancer patients (35%) had T-cell responses to mutated Ki-ras-derived-peptides. T-cell response in a given individual cannot recognise the same mutated ras peptide, which is expressed in that individual's tumour tissues. However, pancreatic and colorectal cancer patients have T-cell immunity against Ki-ras-peptides, and this provides potential target for cancer immunotherapy.

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Possible co-existence of RAS activation and monosomy 7 in the leukaemic transformation of myelodysplastic syndromes

Stephenson

Mufti

1995

Leukemia Research

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LOSS OF MULTIPLE POINT MUTATIONS OF RAS GENES ASSOCIATED WITH ACQUISITION OF CHROMOSOMAL ABNORMALITIES DURING DISEASE PROGRESSION IN MYELODYSPLASTIC SYNDROME

Cited by 18 publications

References 8 publications

Multiple Point Mutation of N-<i>ras</i> and K-<i>ras</i> Oncogenes in Myelodysplastic Syndrome and Acute Myelogenous Leukemia

Multiple Point Mutation of N-<i>ras</i> and K-<i>ras</i> Oncogenes in Myelodysplastic Syndrome and Acute Myelogenous Leukemia

Specific T-cell immunity against Ki-ras peptides in patients with pancreatic and colorectal cancers

Possible co-existence of RAS activation and monosomy 7 in the leukaemic transformation of myelodysplastic syndromes

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