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

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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Paroxysmal Nocturnal Hemoglobinuria Clones Are Infrequent in Hepatitis-Associated Aplastic Anemia at the Time of Diagnosis

Blood ◽

10.1182/blood-2019-125620 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5016-5016

Author(s):

Wenrui Yang ◽

Xin Zhao ◽

Guangxin Peng ◽

Li Zhang ◽

Liping Jing ◽

...

Keyword(s):

Aplastic Anemia ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Conflicts Of Interest ◽

Bone Marrow Failure ◽

Clonal Evolution ◽

Extrinsic Factors ◽

Clone Size ◽

Hematopoietic Stem ◽

Over Time ◽

Pnh Clone

Aplastic anemia (AA) is an immune-mediated bone marrow failure, resulting in reduced number of hematopoietic stem and progenitor cells and pancytopenia. The presence of paroxysmal nocturnal hemoglobinuria (PNH) clone in AA usually suggests an immunopathogenesis in patients. However, when and how PNH clone emerge in AA is still unclear. Hepatitis associated aplastic anemia (HAAA) is a special variant of AA with a clear disease course and relatively explicit immune pathogenesis, thus serves as a good model to explore the emergence and expansion of PNH clone. To evaluate the frequency and clonal evolution of PNH clones in AA, we retrospectively analyzed the clinical data of 90 HAAA patients that were consecutively diagnosed between August 2006 and March 2018 in Blood Diseases Hospital, and we included 403 idiopathic AA (IAA) patients as control. PNH clones were detected in 8 HAAA patients (8.9%,8/90) at the time of diagnosis, compared to 18.1% (73/403) in IAA. Eight HAAA patients had PNH clone in granulocytes with a median clone size of 3.90% (1.09-12.33%), and 3 patients had PNH clone in erythrocytes (median 4.29%, range 2.99-10.8%). Only one HAAA patients (1/8, 12.5%) had a PNH clone larger than 10%, while 24 out of 73 IAA patients (32.9%) had larger PNH clones. Taken together, we observed a less frequent PNH clone with smaller clone size in HAAA patients, compared to that in IAAs. We next attempted to find out factors that associated with PNH clones. We first split patients with HAAA into two groups based on the length of disease history (≥3 mo and < 3mo). There were more patients carried PNH clone in HAAA with longer history (21.4%, 3/14) than patients with shorter history (6.6%, 5/76), in line with higher incidence of PNH clone in IAA patients who had longer disease history. Then we compared the PNH clone incidence between HAAA patients with higher absolute neutrophil counts (ANC, ≥0.2*109/L) and lower ANC (< 0.2*109/L). Interestingly, very few VSAA patients developed PNH clone (5%, 3/60), while 16.7% (5/30) of non-VSAA patients had PNH clone at diagnosis. We monitored the evolution of PNH clones after immunosuppressive therapy, and found increased incidence of PNH clone over time. The overall frequency of PNH clone in HAAA was 20.8% (15/72), which was comparable to that in IAA (27.8%, 112/403). Two thirds of those new PNH clones occurred in non-responders in HAAA. In conclusion, PNH clones are infrequent in HAAA compared to IAA at the time of diagnosis, but the overall frequency over time are comparable between the two groups of patients. In SAA/VSAA patients who are under the activated abnormal immunity, longer clinical course and relatively adequate residual hematopoietic cells serve as two important extrinsic factors for HSCs with PIGA-mutation to escape from immune attack and to expand. Disclosures No relevant conflicts of interest to declare.

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Mutational activation of the K-ras oncogene and the effect of chemotherapy in advanced adenocarcinoma of the lung: a prospective study.

Journal of Clinical Oncology ◽

10.1200/jco.1997.15.1.285 ◽

1997 ◽

Vol 15 (1) ◽

pp. 285-291 ◽

Cited By ~ 63

Author(s):

S Rodenhuis ◽

L Boerrigter ◽

B Top ◽

R J Slebos ◽

W J Mooi ◽

...

Keyword(s):

Lung Cancer ◽

Clinical Characteristics ◽

Gene Mutations ◽

Close Relative ◽

Ras Gene ◽

Ras Mutation ◽

Ras Mutations ◽

Adenocarcinoma Of The Lung ◽

Response To Chemotherapy ◽

Mutational Activation

PURPOSE To determine whether the clinical course and the response to chemotherapy of patients with advanced adenocarcinoma of the lung depends on the presence or absence of a ras mutation in the tumor. Mutational activation of K-ras is a strong adverse prognostic factor in stage I or II lung cancer and laboratory studies have suggested that ras mutations lead to resistance against ionizing radiation and chemotherapy. PATIENTS AND METHODS Patients with advanced adenocarcinoma of the lung with measurable or assessable disease received chemotherapy with mesna, ifosfamide, carboplatin, and etoposide (MICE). Archival biopsies, fresh biopsies, or fine-needle aspirations were tested for the presence of ras gene mutations. Associations of ras mutations with clinical characteristics, response to chemotherapy, and survival were studied. RESULTS The presence or absence of ras gene mutations could be established in 69 of 83 patients (83%). A total of 261 courses of MICE were administered to 62 informative patients, 16 of whom were shown to have a K-ras mutation-positive tumor. The frequency of mutations (26%) and the type of mutations closely matched the pattern we have previously reported in operable disease. Patients with a ras mutation in their tumor were more likely to have a close relative with lung cancer, but other clinical characteristics, such as pattern of metastases, response, and survival, were similar between the ras mutation-positive and ras mutation-negative groups. CONCLUSION Patients with advanced lung adenocarcinoma who harbor a ras mutation may have major responses to chemotherapy and have similar progression-free and overall survival as patients with ras mutation-negative tumors. K-ras mutations may represent one of several ways in which early tumors are enabled to metastasize to distant sites.

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Very long-term follow-up of aplastic anemia treated with immunosuppressive therapy or allogeneic hematopoietic cell transplantation

Annals of Hematology ◽

10.1007/s00277-020-04271-4 ◽

2020 ◽

Vol 99 (11) ◽

pp. 2529-2538

Author(s):

Beatrice Drexler ◽

Felicitas Zurbriggen ◽

Tamara Diesch ◽

Romaine Viollier ◽

Joerg P. Halter ◽

...

Keyword(s):

Aplastic Anemia ◽

Immunosuppressive Therapy ◽

Hematopoietic Cell Transplantation ◽

Clonal Evolution ◽

University Hospital ◽

Term Outcome ◽

Long Term Outcome ◽

Long Term Survivors

Abstract Introduction Since the 1970s outcome of aplastic anemia (AA) patients has improved significantly due to the introduction of immunosuppressive therapy (IST) and allogeneic hematopoietic transplantation (HCT). However, patients may suffer from persistent disease, relapse, clonal evolution, graft-versus-host disease and other late effects. Here, we analyse very long-term outcome of all AA patients at our institution comparing not only survival, but also response status and complications. Methods Patient charts of all 302 AA patients treated between 1973 and 2017 at the University Hospital Basel, Switzerland, were retrospectively analysed. Results First line treatment was IST in 226 (75%) and HCT in 76 (25%) patients. Overall survival at 30 years was similar in patients treated initially by HCT and IST (44% (±14%), and 40% (± 9%) respectively, with better results in more recent years. Partial and no response occurred more frequently after IST, relapse incidence after IST was 24 %, whereas non-engraftment and graft failure was documented in 15 patients (19 %) after HCT. Clonal evolution to myelodysplastic syndrome / acute myeloid leukemia was 16 % at 25 years in IST patients, 1.3 % in HCT patients, iron overload (18 versus 4 %, p = 0.002) and cardiovascular events (11 versus 1 %, p=0.011) occured significantly more often in IST than HCT treated patients. The majority of long-term survivors, 96% of those alive at 25 years, were in complete remission at last follow up, irrespective of the initial treatment modality. Conclusion Very long term survivors after AA are those with stable hematopoietic recovery.

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

Scientific Reports ◽

10.1038/s41598-020-74744-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Haiqiong Wang ◽

Yongbo Guo ◽

Zhenkun Dong ◽

Tao Li ◽

Xinsheng Xie ◽

...

Keyword(s):

Survival Rate ◽

Myelodysplastic Syndrome ◽

Gene Mutation ◽

Poor Prognosis ◽

Gene Mutations ◽

Chromosome 8 ◽

Common Mutation ◽

Mutation Load ◽

Mutation Site ◽

Increased Risk

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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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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K-ras gene mutation as an early prognostic marker of colon cancer

Polish Journal of Surgery ◽

10.1515/pjs-2016-0021 ◽

2016 ◽

Vol 88 (1) ◽

Cited By ~ 3

Author(s):

Łukasz Szpon ◽

Aleksander Stal ◽

Marcin Zawadzki ◽

Anna Lis-Nawara ◽

Wojciech Kielan ◽

...

Keyword(s):

Colorectal Cancer ◽

Gene Mutation ◽

Cancer Incidence ◽

Early Stage ◽

Tnm Classification ◽

Gene Mutations ◽

Diagnostic Methods ◽

Female Group ◽

Ras Gene ◽

Colorectal Cancer Incidence

AbstractDue to increased colorectal cancer incidence there is a necessity of seeking new both prognostic and prediction factors that will allow to evolve new diagnostic tests. K-ras gene seems to be such a factor and its mutations are considered to be an early marker of progression of colorectal cancer.was to find a correlation between K-ras gene mutation in patients with diagnosed colorectal cancer and selected clinical parameters.A total of 104 patients (41 women and 63 men) with diagnosed colorectal cancer were included in this study. The average age of male group was 68.3 and in female group − 65.9. Samples were taken from paraffine blocks with tissue from diagnosed patients and K-ras gene mutation were identified. Afterwards the statistical analysis was made seeking the correlation between K-ras gene mutation incidence and clinical TNM staging system, tumour localisation, histological type, sex, age.K-ras gene mutations were detected in 20.1% of all colorectal cancers. Significantly higher rate of K-ras gene mutations were diagnosed among patients classified at stage I (40%), stage IIC (50%) and stage IV (50%) according to the TNM classification.The results of our study are compatible with other studies and indicate the correlation between K-ras gene mutation and colorectal cancer incidence. Identification of K-ras gene mutation may complement other diagnostic methods at early stage of colorectal cancer.

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18 CANDIDATE GENE MUTATIONS IN ACQUIRED APLASTIC ANEMIA CORRELATION WITH SURVIVAL AND CLONAL EVOLUTION TO MYELODYSPLASTIC SYNDROME

Leukemia Research ◽

10.1016/s0145-2126(15)30019-9 ◽

2015 ◽

Vol 39 ◽

pp. S8

Author(s):

B. Dumitriu ◽

T. Yoshizato ◽

K. Yoshida ◽

D.M. Townsley ◽

D. Liu ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Aplastic Anemia ◽

Candidate Gene ◽

Clonal Evolution ◽

Gene Mutations

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K-ras gene mutations in the diagnosis of fine-needle aspirates of pancreatic masses: prospective study using two techniques with different detection limits

Clinical Chemistry ◽

10.1093/clinchem/44.11.2243 ◽

1998 ◽

Vol 44 (11) ◽

pp. 2243-2248 ◽

Cited By ~ 17

Author(s):

Josefina Mora ◽

Pere Puig ◽

Jaume Boadas ◽

Eulàlia Urgell ◽

Enric Montserrat ◽

...

Keyword(s):

Pancreatic Cancer ◽

Gene Mutations ◽

Detection Limits ◽

Standard Technique ◽

Diagnostic Sensitivity ◽

Ras Gene ◽

Fine Needle ◽

Ras Mutations ◽

Fine Needle Aspirates ◽

Pancreatic Masses

Abstract Detection of K-ras mutations may be useful in the evaluation of pancreatic cancer. The aim of this study was to assess, in a prospective design, the diagnostic utility of K-ras mutation analysis in 62 consecutive fine-needle aspirates of pancreatic masses, using two PCR-based techniques—standard and enriched—with detection limits of a mutant allele in the presence of 102 or 103 wild-type alleles, respectively. Cytology alone offered a diagnostic sensitivity of 75%. The enriched higher sensitivity detection technique, in combination with cytology, offered a diagnostic sensitivity of 91% without false positives. The molecular analysis would have contributed to diagnosis in an additional 14 cases of pancreatic cancer. The standard technique contributed to diagnosis in an additional 9 cases. These results strongly support the use of the enriched method of detecting K-ras mutations as a complement to cytology in the evaluation of pancreatic masses.

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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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