Differential U2AF1 mutation sites, burden and co-mutation genes can predict prognosis in patients with myelodysplastic syndrome

Abstract To investigate the U2AF1 gene mutation site, mutation load and co-mutations genes in patients with myelodysplastic syndrome (MDS) and their effects on prognosis. Gene mutation detection by next-generation sequence and related clinical data of 234 MDS patients were retrospectively collected and analyzed for the relationship between the clinical characteristics, treatment efficacy and prognosis of U2AF1 gene mutation. Among the 234 MDS patients, the U2AF1 gene mutation rate was 21.7% (51 cases), and the median variant allele frequency was 39.5%. Compared with the wild type, the U2AF1 mutant had a higher incidence of chromosome 8 aberration, and was positively correlated with the occurrence of ASXL1, RUNX1, SETBP1 gene mutation, negatively correlated with SF3B1, NPM1 genes mutation (p < 0.05). The most common mutation site of U2AF1 was S34F (32 cases), while U2AF1 Q157P site mutations had a higher incidence of chromosome 7 abnormalities (p = 0.003). The U2AF1 gene mutation more frequently coincided with signal pathway related gene mutations (p = 0.043) with a trend of shortened overall survival. Among patients with U2AF1 gene mutations, those with ASXL1 mutations were prone to develop into acute myeloid leukemia, those with RUNX1 mutations had an increased risk of relapse, and those with TET2 mutations had higher 1-year survival rate. Compared with the patient group of lower mutation load (VAF ≤ 40%), the group with higher mutation load of U2AF1 (VAF > 40%) had a significantly lower 1-year survival rate (46.1% and 80.5%, p = 0.027). The criteria of U2AF1 VAF > 40% is an independent indicator for poor prognosis of MDS patients. VAF > 40% of U2AF1 is an independent factor of short OS in MDS patients. MDS patients with a mutation in the Q157P site of U2AF1 and a higher U2AF1 mutation load suggests poor prognosis, and co-mutated genes in U2AF1 can affect disease progression and prognosis.

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N-ras mutations are associated with poor prognosis and increased risk of leukemia in myelodysplastic syndrome

Blood ◽

10.1182/blood.v82.2.590.bloodjournal822590 ◽

1993 ◽

Vol 82 (2) ◽

pp. 590-599 ◽

Cited By ~ 1

Author(s):

RL Paquette ◽

EM Landaw ◽

RV Pierre ◽

J Kahan ◽

M Lubbert ◽

...

Keyword(s):

Bone Marrow ◽

Myelodysplastic Syndrome ◽

Poor Prognosis ◽

Polymerase Chain Reaction Amplification ◽

Myelogenous Leukemia ◽

Survival Period ◽

Ras Mutation ◽

Ras Mutations ◽

Increased Risk ◽

Oligonucleotide Hybridization

To evaluate the clinical significance of N-ras mutations in the myelodysplastic syndrome (MDS) archival bone marrow samples from 252 patients were studied for the presence of N-ras exon I mutations using polymerase chain reaction amplification and differential oligonucleotide hybridization. Subsequently, clinical information about these patients was obtained and analyzed. Of 220 evaluable patients, 20 (9%) had point mutation of N-ras involving codon 12. Individuals with N- ras mutation had a significantly shorter survival period than those who were N-ras negative (P = .02). An increased risk of acute myelogenous leukemia (AML) was also found in patients with N-ras mutations (P = .005). N-ras mutations were not associated with any French-American- British (FAB) subtype, with the presence of increased myeloblasts, or with chromosomal aberrations in the bone marrow. However, the presence of increased bone marrow blasts was strongly associated with poor survival rate and risk of AML (P < .001 for each). After stratifying for the percentage of blasts, N-ras mutations remained significantly associated with shorter survival period (P = .04) and increased risk of AML (P = .02). Bone marrow cytogenetic abnormalities, particularly when multiple abnormalities were present, were significantly associated with a poor prognosis (P < .001). In conclusion, N-ras mutation, although relatively infrequent in MDS, is associated with short survival period and increased probability of developing AML.

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Significance of MTHFR gene mutation with normal homocysteine level in vascular events

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e20520 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e20520-e20520

Author(s):

V. K. Gadiyaram ◽

M. A. Khan ◽

T. Hogan ◽

R. Altaha ◽

E. Crowell ◽

...

Keyword(s):

Risk Factors ◽

Gene Mutation ◽

Gene Polymorphisms ◽

Homocysteine Level ◽

Fetal Loss ◽

Gene Mutations ◽

Mthfr Gene ◽

Vascular Events ◽

Laboratory Test Results ◽

Increased Risk

e20520 Background: Hyperhomocysteinemia, due to a combination of genetic and environmental factors, is considered to be a risk factor for vascular disease. Two common variations of the MTHFR gene (C677T and A1298C) result in amino acid substitutions and enhanced thermolability of the enzyme. Individuals with MTHFR gene mutations appear to have raised plasma level of homocysteine which may lead to increased risk of vascular events. However, significance of MTHFR gene mutations with normal homocysteine levels is unknown. Objective: To assess the relation of MTHFR gene mutations with normal homocysteine level and risk of Vascular events (deep venous thrombosis (DVT), pulmonary embolism (PE), Ischemic Heart disease (IHD), cerebrovascular accidents (CVA),recurrent fetal loss). Methods: We reviewed the records of 90 patients referred to our benign hematology clinic for thrombophilia evaluation between 2006 and 2008. All available medical history for risk factors and laboratory test results, obtained from first vascular event through time of consultation, including genetic testing, were reviewed. Anti-cardiolipin antibody, MTHFR genotyping and Protein C and Protein S assays were performed at Warde Medical Laboratory, Ann Arbor, MI. Results: 61 patients with documented vascular events were tested for MTHFR gene mutations. Forty one of these patients also had homocysteine levels available. Thirty-eight of these 41 (92 %) patients had an MTHFR gene mutation with normal homocysteine levels. Eighteen (47%) of these 38 patients had only an MTHFR gene mutation with normal homocysteine level and no other congenital or acquired risk factors for vascular events identified. Conclusions: In our clinic population, many patients with documented vascular events had MTHFR gene polymorphisms with normal homocysteine levels with no other thrombophilia risk factors identified, raising the question of whether MTHFR gene polymorphisms alone, without hyperhomocysteinemia, may somehow contribute to thrombophilia. [Table: see text] No significant financial relationships to disclose.

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PREVALENCE OF SPINK 1 AND CASR GENE MUTATIONS IN ACUTE AND RECURRENT ACUTE PANCREATITIS : A STUDY FROM CENTRAL INDIA

10.36106/ijar/2508292 ◽

2021 ◽

pp. 62-65

Author(s):

Mohd Talha Noor ◽

Rahul Sudan ◽

Vipin Goyal ◽

Susmit Kosta ◽

Ravindra Kumar ◽

...

Keyword(s):

Risk Factors ◽

Acute Pancreatitis ◽

Gene Mutation ◽

Genetic Factors ◽

Receptor Gene ◽

Gene Mutations ◽

Recurrent Acute Pancreatitis ◽

Casr Gene ◽

Increased Risk ◽

Spink 1

Background: Genetic factors may play an important role in the pathogenesis of acute pancreatitis. It has been observed in various studies that the presence of risk factors alone like alcohol abuse or gall bladder stones does not lead to attacks of pancreatitis in all the patients. This leads to assumption that genetic factors may decrease the threshold for the development of pancreatitis in presence of one or more risk factors. We observed that there is a paucity of data regarding the role of genetics in acute pancreatitis (AP) and recurrent acute pancreatitis (RAP) in our part of the world and we aimed at studying the prevalence of genetic mutations in such patients. Methods: Our study intended to nd the prevalence of SPINK1 N34S (Serine protease inhibitor kazal type 1) and CaSR (Calcium sensing receptor) gene mutations in patients of AP and RAP. A total of 50 patients and 25 age and gender matched controls entered our study. Blood samples were obtained from all the cases and controls for routine investigations and genetic analysis. SPINK 1 N34S and CaSR gene mutation studies were done in all the patients and controls. Results: Alcohol (64%) followed by gallbladder stone disease (20%) was the most common aetiology of pancreatitis. SPINK 1 N34S mutation was present in 21 patients and 2 controls whereas CaSR gene mutation was present in 13 patients and 2 controls. Patients with SPINK 1 N34S and CaSR gene mutations were younger than the patients without these mutations. Prevalence of both SPINK1 N34S and CaSR gene mutations was higher in patients of RAP than AP. These mutations were not associated with aetiology or severity of pancreatitis. Conclusion: The prevalence SPINK 1 N34S and CaSR gene mutations was higher in patients of AP and RAP. Identication of these mutations in patients of AP can help in the identication of patients who are at increased risk of recurrent attacks of AP

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N-RAS gene mutation in patients with aplastic anemia and aplastic anemia/ paroxysmal nocturnal hemoglobinuria during evolution to clonal disease

Blood ◽

10.1182/blood.v95.2.646 ◽

2000 ◽

Vol 95 (2) ◽

pp. 646-650 ◽

Cited By ~ 19

Author(s):

Y. Mortazavi ◽

J. A. Tooze ◽

E. C. Gordon-Smith ◽

T. R. Rutherford

Keyword(s):

Aplastic Anemia ◽

Gene Mutation ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Clonal Evolution ◽

Gene Mutations ◽

Early Event ◽

Ras Gene ◽

Ras Mutations ◽

Increased Risk ◽

Long Term Survivors

Long-term survivors of aplastic anemia (AA) have a high incidence of clonal disorders, in particular paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndromes (MDS), and acute nonlymphocytic leukemia. To investigate the potential involvement of N-RAS gene mutations in the predisposition to leukemic evolution, a subset of patients at potentially increased risk for clonal disease was selected based on evidence of existing clonal evolution. Nine patients showed a monoclonal pattern of X-chromosome inactivation, 18 demonstrated a PNH clone, and in 3 MDS developed during the course of this study. No mutations were detected during the aplastic phase of disease; 2 of 3 patients with MDS after AA also showed no mutations. However, in 1 patient in whom the disease transformed from AA/PNH to MDS, a mutation of GGT → GAT at N-RAS codon 13 became detectable, whereas the PNH mutation disappeared. The authors conclude that N-RAS mutations are not an early event preceding transformation of AA or AA/PNH to leukemia. In a subset of patients, RAS mutations may occur at the time of evolution to MDS, but preexisting RAS mutations do not explain the propensity of AA to leukemogenesis. Although PNH is also associated with leukemia, this may arise in the non-PNH cells, indicating that PIG-A gene mutation is not per se oncogenic.

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Novel gene mutation in von Hippel-Lindau disease – a report of two cases

BMC Medical Genetics ◽

10.1186/s12881-019-0930-8 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 1

Author(s):

Jitian Wang ◽

Wenjie Cao ◽

Zhaoxia Wang ◽

Hong Zhu

Keyword(s):

Gene Mutation ◽

Autosomal Dominant ◽

Novel Mutation ◽

Gene Mutations ◽

Neoplastic Disease ◽

Malignant Tumours ◽

Mutation Site ◽

Vhl Gene ◽

Von Hippel Lindau ◽

Clinical Phenotypes

Abstract Background Von Hippel-Lindau (VHL) syndrome is a familial autosomal dominant hereditary neoplastic disease caused by mutations in the VHL gene. Approximately 503 kinds of VHL gene mutations have been reported. Different types of mutations manifest various clinical phenotypes, from benign to malignant tumours or coexisting cysts. Thus, a gene mutation test is essential in the diagnosis of VHL syndrome. Case presentation We reported two cases in which a novel mutation site in the c530-536delGACTGGA region in exon 3 of the VHL gene resulted in the development of VHL syndrome. According to the ACMG guidelines, this variation is pathogenic and consistent with autosomal dominant inheritance. This variation has not been reported anywhere in the databases or literature. Conclusion This report will add a new mutation site to VHL gene databases. The newly added gene mutation and its associated clinical phenotypes will help improve the accuracy of VHL diagnosis and benefit the community of VHL gene mutation carriers.

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Detection of Factor V Leiden and Prothrombin Gene Mutations in Patients Who Died With Thrombotic Events

Archives of Pathology & Laboratory Medicine ◽

10.5858/2002-126-1193-dofvla ◽

2002 ◽

Vol 126 (10) ◽

pp. 1193-1196

Author(s):

Rostislav D. Ranguelov ◽

Nancy Rosenthal ◽

Christine Bromley ◽

Mohammad A. Vasef

Keyword(s):

At Risk ◽

Gene Mutation ◽

Gene Mutations ◽

Factor V Leiden ◽

Factor V ◽

Wild Type ◽

Increased Risk ◽

Factor V Gene ◽

Prothrombin Gene ◽

V Gene

Abstract Context.—Individuals with factor V or prothrombin gene mutations are at increased risk for thrombotic events. Furthermore, the risk of recurrent deep venous thrombosis in heterozygous carriers of both factor V Leiden and prothrombin gene mutations is high enough that some investigators suggest lifelong warfarin prophylaxis for these individuals, even with a single spontaneous thrombotic event. Objectives.—To assess the incidence of factor V Leiden and prothrombin gene mutations in an autopsy population and to determine if these tests can prove useful in identification of at-risk family members. Design.—We analyzed factor V Leiden and prothrombin gene mutations in 45 patients who died with or of thrombotic events, using archival tissue and multiplex allele-specific polymerase chain reaction amplification. The wild-type factor V gene was amplified in all 45 patients, whereas the wild-type prothrombin gene was amplified in 29 patients. Results.—Two patients (4.4%) who died with thrombotic events at the ages of 35 and 92 years were heterozygous for factor V gene mutation. Two additional patients (6.7%), who died with thrombotic events at the ages of 26 and 39 years, were heterozygous for prothrombin gene mutation. Patients homozygous for either factor V or prothrombin gene or simultaneously heterozygous for both genes were not detected in our study. Conclusions.—Our findings suggest that screening the relatives of elderly patients who die with thrombotic events would not be cost-effective because of the low incidence of these mutations in the autopsy population. However, because the incidence of these mutations appeared significantly more frequently among individuals who died at 39 years or younger, testing the relatives of this subset of patients may prove useful for detection of at-risk individuals who would benefit from preventive anticoagulation therapy.

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MON-436 Cribriform-morular Variant of Papillary Thyroid Carcinoma: A Case Report

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.161 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Zainab Shaheen ◽

Nesreen Aburrahman BenHamed ◽

Rawan Mehiar Elhamdani

Keyword(s):

Thyroid Cancer ◽

Gene Mutation ◽

Gene Mutations ◽

Left Lobe ◽

Apc Gene ◽

Follicular Neoplasm ◽

Pathology Report ◽

Recurrence Rates ◽

Increased Risk ◽

Cribriform Morular Variant

Abstract Background: Cribriform - morular variant is a rare variant of papillary cancer with 1–2 % prevalence. There are no established guidelines to screen for thyroid cancer in patients with APC gene mutations and FAP. We present a case of a young female with APC gene mutation and thyroid cancer. Case: Female, 25 years-old, without anemia, underwent colonoscopy at age 22 and multiple polyps were seen. One polyp showed intramucosal carcinoma with high-grade dysplasia. She was diagnosed with FAP. She was found to have APC gene mutation on genetic analysis. No family history of FAP was reported. Chest and abdominal CT showed multiple thyroid nodules. Thyroid ultrasound showed 3 nodules. The largest is in the mid R lobe, measuring 1 cm, and is isoechoic to hypoechoic, containing some small central cystic areas. The nodules in the left lobe measure 0.6 and 0.7 cm. FNA of the right thyroid nodule showed follicular neoplasm. Afirma was suspicious. She underwent total thyroidectomy. Pathology report showed multifocal tumor in both right (0.8 cm) and left lobe (0.5 cm). Histologic type was Papillary carcinoma, cribriform - morular variant. All surgical margins were negative. No angio-lymphatic invasion or extra thyroidal extension was identified. Pathologic stage classification was m pT1a pN0 pM0. Patient did not receive RAI ablation. Patient doing well and no further recurrence of thyroid cancer is noted. Discussion: Patients with FAP have a greatly increased risk for colorectal cancer and also have an elevated risk for other cancers including thyroid cancer (1%-2% compared to 1% in general population). According to ACG guidelines of 2015, annual thyroid screening by ultrasound should be recommended to individuals affected with FAP. Additionally, thyroid cancer found in unscreened patients with FAP was more advanced as compared to patients screened for cancer requiring less aggressive approaches. On ultrasonography, most nodules had benign-looking features (well-defined, hypoechoic, oval to round shapes without calcification), but some nodules had capsular invasion and larger height: width shape. In preoperative FNA, they were diagnosed as CMV-PTC/PTC but could also present as follicular neoplasm or PTC-follicular variant. Compared to conventional PTC, CMV-PTC had a lower frequency of lymph node metastases at presentation (12%) and distant metastases (3%) as well as lower recurrence rates (8.5%) and patient mortality rates (2%). Physical exam and clinical history is not sufficient to screen for cancer. In patients with APC gene mutations and FAP, there should be high suspicion for diagnosing thyroid cancer as the nodules are usually benign looking and small in size. As noted in the case, nodules were found incidentally, and tumor size was small with benign looking nodules. Additionally, screening should be focused more on young females below the age of 35 because of the high prevalence of cancer.

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DNMT3A mutations in De Novo Myelodysplastic Syndrome: Distinct Clinico-Biological Features and Prognostic Relevance

Blood ◽

10.1182/blood.v120.21.3799.3799 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3799-3799

Author(s):

Ming-En Lin ◽

Hsin-An Hou ◽

Yuan-Yeh Kuo ◽

Wen-Chien Chou ◽

Ming Cheng Lee ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Poor Prognosis ◽

Who Classification ◽

De Novo ◽

Gene Mutations ◽

Refractory Anemia ◽

Single Mutation ◽

Idh Mutation ◽

Biological Features ◽

Fab Classification

Abstract Abstract 3799 Background and Purpose Mutations of the DNMT3A gene, which encodes the enzyme DNA methyltransferase 3A, were identified in patients with myeloid malignancies and are associated with poor prognosis in primary AML patients. However, the clinical and prognostic implications of these mutations in myelodysplastic syndrome (MDS) remain to be determined. Methods and Materials A total of 328 de novo MDS patients diagnosed according to French-American-British (FAB) criteria at the National Taiwan University Hospital who had cryopreserved bone marrow cells for study were recruited into mutational analyses. Mutations in DNMT3A gene at exon 2–23 were analyzed by polymerase chain reaction and direct sequencing. The results were correlated with clinical features, cytogenetics, gene mutations and treatment outcomes. Results Among the 328 patients, 115 patients (35.0%) had refractory anemia (RA), 19 (5.8%) had RA with ring sideroblasts (RARS), 122 (37.2%) had RA with excess blasts (RAEB), 35 (10.7%) had RAEB in transformation (RAEBT), and 37 (11.3 %) had chronic myelomonocytic leukemia (CMMoL). DNMT3A mutations at 20 different positions were identified in 33 patients, including thirteen missense mutations, two nonsense mutations and five frame-shift mutations. Among these 33 patients, 31 had single mutation of DNMT3A, and the other 2 patients had double mutations. The most common mutation was R882H (n = 8), followed by R882C (n = 7), Y735C (n=2), and R720H (n=2). All other mutations were detected in only one patient each. Totally, DNMT3A mutations were identified in 33 (10.1%) of 328 patients diagnosed according to the FAB classification and in 25 (9.8%) of 256 diagnosed according to 2008 WHO classification. DNMT3A-mutated patients were older (median age, 74 years vs. 66 years, P=0.048) and had higher platelet counts at diagnosis than DNMT3A-wild patients (median, 123.5×103/μL vs. 73 ×103/μL, P=0.016). According to FAB classification, patients with RARS had the highest incidence (26.3%) of DNMT3A mutations, followed by RAEBT (14.3%), RAEB (11.5%), and CMMoL (8.1%), whereas those with RA had the lowest incidence (5.2%, P=0.035). Chromosome data were available in 308 patients (93.9%) at diagnosis and clonal chromosomal abnormalities were detected in 155 patients (50.3%). There was no difference in the distribution of 2008 WHO classification, karyotype and international prognostic scoring system (IPSS) between patients with and without DNMT3A mutations. To investigate the association of gene mutations in the pathogenesis of MDS, a mutational screening of 10 other genes was also performed. Among the 33 patients with DNMT3A mutations, 16 patients (48.5%) showed additional molecular abnormalities at diagnosis, including seven with concurrent IDH1/IDH2 mutations, seven ASXL1 mutations, five AML1/RUNX1 mutations, two MLL-PTD, two RAS mutations and one JAK2 mutation. Eight of these 16 patients (50%) had two other concurrent mutations, and the others had one additional mutation. It's clear that DNMT3A mutation was closely interacted with IDH mutation in MDS (IDH mutation occurring in 21.2% of DNMT3A-mutated patients vs. 3.4% in DNMT3A-wild ones, P=0.001). With a median follow-up of 57.6 months (range, 0.1–250.7 months), there was no significant difference in overall survival (OS) between patients with and without DNMT3A mutation by either FAB or 2008 WHO classifications (median, 22.5 months vs. 30.9 months, P=0.669 and 25.2 months vs. 34.9 months, P=0.538, respectively) as well as in the rate of acute transformation. However, among the subgroup of patients with RA by FAB classification or refractory cytopenia with unilineage dysplasia by 2008 WHO classification, DNMT3A-mutated patients had significantly shorter OS than DNMT3A-wild patients (median, 28.3 months vs. 39.8 months, P<0.001 and 23.8 months vs. 40.3 months, P=0.026, respectively). Further, DNMT3A mutation is an independent poor prognostic factor in these two subgroups. Conclusion Our findings provided evidence that DNMT3A mutations could be detected in a substantial portion of de novo MDS patients. DNMT3A mutations are associated with distinct clinical and biological features and poor prognosis in selected groups of patients. Disclosures: No relevant conflicts of interest to declare.

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Pathological Signature and Therapeutic Status of NSCLC Patients with Common or Rare Driver Gene Alterations in North China：A real world retrospective study

10.21203/rs.3.rs-30399/v1 ◽

2020 ◽

Author(s):

Hui Zhang ◽

Xinjie Yang ◽

Xiaodie Qu ◽

Kun Li ◽

Jinghui Wang ◽

...

Keyword(s):

Gene Mutation ◽

Gene Mutations ◽

Stage Iv ◽

Population Based ◽

Driver Gene ◽

Common Mutation ◽

Driver Genes ◽

Rare Mutation ◽

Nsclc Patients ◽

Gene Alterations

Abstract Background: Although guidelines recommended to test EGFR/ALK/ROS-1 gene alterations in advanced non-small cell lung cancer (NSCLC) patients before treatment, there is now growing evidence that rare driver genes and mutations also can inform targeted therapy and improve outcomes for this traditionally underrepresented population. This study aimed to describe mutational patterns and linked clinical parameters in a Chinese population-based NSCLC cohort.Methods: This study included patients with pathologically confirmed NSCLC, who were routinely screened for EGFR, KRAS, BRAF, ALK, ROS1, RET, MET, HER2, and PIK3CA mutations by the NMPA approved multi-gene detection kit. The demographic and clinicopathological data, treatment information, clinical outcomes after first-line treatment, as well as nine driver gene mutation statuses and PD-L1 expression level of these patients were retrospectively collected.Results: Finally, 431 patients were enrolled, most patients were male (55.9%), with adenocarcinoma or adenosquamous carcinoma (80.7%) and in stage IV (50.6%). Among all the 431 patients, 61.5% patients were identified with gene mutation including 101 with rare mutation, 164 with 19del or with L858R mutation. Adenocarcinoma patients have a higher mutation rate (73.6%), and the mutations mainly occur in EGFR, KRAS, ALK and HER2. While, the gene mutation characteristics in squamous cell carcinoma patients with were relatively simple, only 2 patients with EGFR 19del and 2 patients with PIK3CA mutation. More PD-L1 expression could detected in patients with rare mutation. The median PFS1 of patients with common mutation (13 months, 95% CI: 9.9-16) was longer than the patients with rare mutation (5 months, 95 % CI: 0-10.5). Conclusions: The clinicopathologic features and clinical treatment status among NSCLC patients with common or rare driver gene mutations were different. The survival of patients with rare mutation was worse than that of patients with common mutation. Therefore, more attention should be paid to the treatment strategy and survival status of patients with rare mutations in clinical practice.

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N-ras mutations are associated with poor prognosis and increased risk of leukemia in myelodysplastic syndrome

Blood ◽

10.1182/blood.v82.2.590.590 ◽

1993 ◽

Vol 82 (2) ◽

pp. 590-599 ◽

Cited By ~ 135

Author(s):

RL Paquette ◽

EM Landaw ◽

RV Pierre ◽

J Kahan ◽

M Lubbert ◽

...

Keyword(s):

Bone Marrow ◽

Myelodysplastic Syndrome ◽

Poor Prognosis ◽

Polymerase Chain Reaction Amplification ◽

Myelogenous Leukemia ◽

Survival Period ◽

Ras Mutation ◽

Ras Mutations ◽

Increased Risk ◽

Oligonucleotide Hybridization

Abstract To evaluate the clinical significance of N-ras mutations in the myelodysplastic syndrome (MDS) archival bone marrow samples from 252 patients were studied for the presence of N-ras exon I mutations using polymerase chain reaction amplification and differential oligonucleotide hybridization. Subsequently, clinical information about these patients was obtained and analyzed. Of 220 evaluable patients, 20 (9%) had point mutation of N-ras involving codon 12. Individuals with N- ras mutation had a significantly shorter survival period than those who were N-ras negative (P = .02). An increased risk of acute myelogenous leukemia (AML) was also found in patients with N-ras mutations (P = .005). N-ras mutations were not associated with any French-American- British (FAB) subtype, with the presence of increased myeloblasts, or with chromosomal aberrations in the bone marrow. However, the presence of increased bone marrow blasts was strongly associated with poor survival rate and risk of AML (P < .001 for each). After stratifying for the percentage of blasts, N-ras mutations remained significantly associated with shorter survival period (P = .04) and increased risk of AML (P = .02). Bone marrow cytogenetic abnormalities, particularly when multiple abnormalities were present, were significantly associated with a poor prognosis (P < .001). In conclusion, N-ras mutation, although relatively infrequent in MDS, is associated with short survival period and increased probability of developing AML.

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