The Relationship <i>BRCA1/2</i> Genes and Family History in Ovarian Cancers

BRCA1/2 genes are responsible for the hereditary breast and ovarian cancer syndrome. In this study, Turkish women with ovarian cancer were investigated in terms of demographic, clinicopathologic and family cancer stories according to their condition of the BRCA1/2 genes mutation carrier. During 2011 to 2017 in Turkey, BRCA1 and BRCA2 genes were analyzed in 38 women, who were diagnosed with cancer using Next Generation Sequencing technique. Pathogenic mutations were detected in 9 (23.7%) of patients. The diagnosis age for Ovarian cancer patients for BRCA1/2 mutation carriers was found higher. It was seen that mutations mostly occurred in the BRCA2 gene and frameshift mechanism and they were located in exon10 in the BRCA1 gene and especially in exon11 in the BRCA2 gene. According to the applied logistic regression model, it was found that patients with more than two relatives having cancer would have a 12.844 fold and high risk of being a BRCA1/2 mutation carrier. In women with ovarian cancer, BRCA1/2 gene mutations are observed more frequently in certain exons of these genes. BRCA1 mutation carriers are diagnosed with ovarian cancer earlier than BRCA2 mutation carriers. In hereditary ovarian cancers, besides BRCA1/2, many identified genes and many modifier candidate genes that are waiting to be discovered can cause this condition. In the family history, the numerical increase of cancerous relatives significantly increases the risk of BRCA1/2 carrying mutation.     

Comparison of <i>UGT1A1</i> Polymorphism as Guidance of Irinotecan Dose Escalation in RAS Wild-Type Metastatic Colorectal Cancer Patients Treated With Cetuximab or Bevacizumab Plus FOLFIRI as the First-Line Therapy

Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism plays a crucial role in the increased susceptibility and toxicity of patients to irinotecan. This retrospective, observational study compared the clinical outcomes and adverse events (AEs) in RAS wild-type metastatic colorectal cancer (mCRC) patients treated with cetuximab or bevacizumab plus FOLFIRI with UGT1A1 genotyping and irinotecan dose escalation as the first-line therapy. In total, 173 patients with mCRC with RAS wild-type were enrolled. Among them, 98 patients were treated with cetuximab, whereas 75 patients were treated with bevacizumab. All patients received irinotecan dose escalation based on UGT1A1 genotyping. We compared the progression-free survival (PFS), overall survival (OS), objective response rates (ORRs), disease control rates (DCRs), metastatectomy, and severe adverse events (SAEs) between the two groups. The clinical effects of primary tumor sidedness and target therapy crossover were further analyzed. Over a median follow-up of 23.0 months [interquartile range (IQR), 15.0–32.5 months], no significant differences were observed between the cetuximab and bevacizumab groups in PFS [18.0 months vs. 14.0 months; 95% confidence interval (CI), 0.517–1.027; hazard ratio (HR), 0.729; p = 0.071], OS (40.0 months vs. 30.0 months; 95% CI, 0.410–1.008; HR, 0.643; p = 0.054), ORR (65.3% vs. 62.7%; p = 0.720), DCR (92.8% vs. 86.7%; p = 0.175), metastatectomy (36.7% vs. 29.3%; p = 0.307), and SAEs (p = 0.685). Regardless of primary tumor sidedness and target therapy crossover, no significant differences were noted in efficacy and safety between the two groups (all p > 0.05). Our results revealed that patients with wild-type RAS mCRC, regardless of biologics, with UGT1A1 genotyping can tolerate escalated doses of irinotecan and potentially achieve a more favorable clinical outcome without significantly increased toxicity.     

Mutational analysis of DNMT3A improves the prognostic stratification of patients with acute myeloid leukemia

Nucleophosmin1 (NPM1) mutations are the most frequently detected gene mutations in acute myeloid leukemia (AML) and are considered a favorable prognostic factor. We retrospectively analyzed the prognosis of 605 Japanese patients with de novo AML, including 174 patients with NPM1-mutated AML. Although patients with NPM1-mutated AML showed a high remission rate, this was not a favorable prognostic factor for overall survival (OS); this is contrary to generally accepted guidelines. Comprehensive gene mutation analysis showed that mutations in codon R882 of DNA methyltransferase 3A (DNMT3A^R882 mutations) were a strong predicative factor indicating poor prognosis in all AML (p < 0.0001) and NPM1-mutated AML cases (p = 0.0020). Furthermore, multivariate analysis of all AML cases showed that DNMT3A^R882 mutations and the co-occurrence of internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD), NPM1 mutations, and DNMT3A^R882 mutations (triple mutations) were independent factors predicting a poor prognosis related to OS, with NPM1 mutations being an independent factor for a favorable prognosis (hazard ratios: DNMT3A^R882 mutations, 1.946; triple mutations, 1.992, NPM1 mutations, 0.548). Considering the effects of DNMT3A^R882 mutations and triple mutations on prognosis and according to the classification of NPM1-mutated AML into three risk groups based on DNMT3A^R882/FLT3-ITD genotypes, we achieved the improved stratification of prognosis (p < 0.0001). We showed that DNMT3A^R882 mutations are an independent factor for poor prognosis; moreover, when confounding factors that include DNMT3A^R882 mutations were excluded, NPM1 mutations were a favorable prognostic factor. This revealed that ethnological prognostic discrepancies in NPM1 mutations might be corrected through prognostic stratification based on the DNMT3A status.     

Anticancer Effects of <i>Gleditsia sinensis</i> Extract in Rats Transplanted With Hepatocellular Carcinoma Cells

The thorns of Gleditsia sinensis have been historically used in Chinese medicine and are considered one of the fundamental therapeutic herbs. Its anticancer effects are currently being explored. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and still requires the development of new drugs with higher efficiency. By using a rat HCC model implanted with cancerous Walker-256 cells, the therapeutic effects of G. sinensis extract (GSE) were assessed, as well as its regulatory effects on miRNAs. GSE significantly restored liver morphology and dramatically induced cell apoptosis in HCC rats. In addition, miR-21/181b/183 was upregulated in the HCC liver, and the elevation of these miRNAs could be alleviated by both GSE and sorafenib. PTEN/TIMP3/PDCD4 downregulation was consistent with the targets of miR-21/181b/183 in the HCC liver, and the alteration of these target genes was restored by both GSE and sorafenib. TIMP3 effects on MMP-2/9 expression were also determined. Our present findings indicate the potential of GSE in HCC treatment, and expand the understanding of miRNA-related mechanisms in the anticancer effects of GSE.     

Mutations of NPM1 gene in de novo acute myeloid leukaemia: determination of incidence,distribution pattern and identification of two novel mutations in Indian population

Mutations in the nucleophosmin (NPM1) gene have been recently described to occur in about one‐third of acute myeloid leukaemias (AMLs) and represent the most frequent genetic alteration currently known in this subset, specially in those with normal karyotype. This study explored the prevalence and clinical profile of NPM1 mutations in a cohort of 200 Indian adult and children with AML. NPM1 mutations were observed in 19.5% of all population and 34.2% of those with normal karyotype. Adults had a significantly higher incidence of NPM1 mutations than children [38 of 161 (23.6%) vs. 1 of 39 (2.5%), p = 0.002]. NPM1 mutations were significantly associated with normal karyotype (p = 0.001), high WBC count (p = 0.034), AML‐M4 subtype (p = 0.039) and a gradient increase of mutation rate with the increase in age groups. Sequence analysis of 39 mutated cases revealed typical mutations (types A, B, D, Nm and H*) as well as two novel variations (types F1 and F2). Majority of the patients had mutation type A (69.2%), followed by B (5.1%), D (15.3%), H* (2.5%) and Nm (2.5%) all involving COOH terminal of the NPM1 protein. In conclusion, this study represents the first report of NPM1 mutation from Indian population and confirms that the incidence of NPM1 mutations varies considerably globally, with slightly lower incidence in Indian population compared to western countries. The current study also served to identify two novel NPM1 mutants that add new insights into the heterogeneity of genomic insertions at exon 12. More ongoing larger studies are warranted to elucidate the molecular pathogenesis of AML that arises in this part of the world. Furthermore, we believe that in light of its high prevalence worldwide, inclusion of NPM1 mutation detection assay in diagnostic evaluations of AML may improve the efficacy of routine genetic characterization and allow assignment of patients to better‐defined risk categories. Copyright © 2009 John Wiley & Sons, Ltd.     

A gain-of-function mutation in microRNA 142 is sufficient to cause the development of T-cell leukemia in mice

MicroRNAs (miRNAs) play a crucial role in regulating gene expression. MicroRNA expression levels fluctuate, and point mutations and methylation occur in cancer cells; however, to date, there have been no reports of carcinogenic point mutations in miRNAs. MicroRNA 142 (miR-142) is frequently mutated in patients with follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia (CLL), and acute myeloid leukemia/myelodysplastic syndrome (AML/MDS). To understand the role of miR-142 mutation in blood cancers, the CRISPR-Cas9 system was utilized to successfully generate miR-142-55A>G mutant knock-in (Ki) mice, simulating the most frequent mutation in patients with miR-142 mutated AML/MDS. Bone marrow cells from miR-142 mutant heterozygous Ki mice were transplanted, and we found that the miR-142 mutant/wild-type cells were sufficient for the development of CD8⁺ T-cell leukemia in mice post-transplantation. RNA-sequencing analysis in hematopoietic stem/progenitor cells and CD8⁺ T-cells revealed that miR-142-Ki/+ cells had increased expression of the mTORC1 activator, a potential target of wild-type miR-142-3p. Notably, the expression of genes involved in apoptosis, differentiation, and the inhibition of the Akt–mTOR pathway was suppressed in miR-142-55A>G heterozygous cells, indicating that these genes are repressed by the mutant miR-142-3p. Thus, in addition to the loss of function due to the halving of wild-type miR-142-3p alleles, mutated miR-142-3p gained the function to suppress the expression of distinct target genes, sufficient to cause leukemogenesis in mice.     

Cytoplasmic localization of nucleophosmin in bone marrow blasts of acute myeloid leukemia patients is not completely concordant with NPM1 mutation and is not predictive of prognosis

BACKGROUND:

Nucleophosmin (NPM1) gene mutations are reported to predict a favorable prognosis in acute myeloid leukemia (AML) patients. Aberrant cytoplasmic localization of nucleophosmin (NPM) protein is reported be a surrogate for NPM1 gene mutation.

METHODS:

Using immunohistochemical (IHC) analysis, we assessed for NPM (clone 376) expression in formalin‐fixed, formic acid‐decalcified bone marrow biopsy specimens. DNA sequencing of exon 12 of NPM1 gene was performed in 104 patients.

RESULTS:

The study included 252 AML patients: 192 de novo AML, 33 AML preceded by either myelodysplastic syndrome or chronic myelomonocytic leukemia, and 27 therapy‐related AML. The median age was 62 years and 115 patients were ≤60 years old. All patients received intensive chemotherapy. Cytoplasmic NPM was detected in 59 of 252 (23%) patients, including 48 of 192 (25%) de novo AML and 33 of 94 (35%) with a normal karyotype. DNA sequencing identified NPM1 mutations in 30 of 38 cases with cytoplasmic NPM and 10 of 66 cases with nuclear NPM. Cytoplasmic NPM was associated with young patient age (P = .024), FLT3/ITD (P = .005), CD34 negative blasts (P < .001), high peripheral blood blast count (P = .041), and high serum albumin level (P = .028). No statistical differences in overall or event‐free survival were found on the basis of NPM localization. Similar results were obtained in patients ≤60 years old with normal karyotype and wild‐type FLT3 (P = .768).

CONCLUSIONS:

IHC assessment for NPM localization did not predict prognosis in this patient cohort. The discordance between immunohistochemistry and DNA sequencing results indicates that DNA sequencing cannot be replaced by IHC assessment. Cancer 2009. © 2009 American Cancer Society.     

Analysis of Antioxidant Potential of <i>Trigonella foenum-graecum</i> (L.) Extract Against Tumorigenesis

Background: Trigonella foenum-graecum Linn. has been extensively used for medicinal purposes. The current study deals with in vitro and in vivo correlation of free radical quenching activity and anticancer potential of seed extracts of Trigonella. Materials and methods: Antioxidant activity was evaluated against DPPH, NO and ABTS via in vitro radical scavenging assay. Cytotoxicity effect of Trigonella seed extract was studied in human embryonic kidney HEK 293 cell line by alamar blue assay. In vivo antioxidant activity in Swiss albino mice model was assessed by studying endogenous antioxidant enzymes such as GSH, GPx, SOD and LPO. Antitumor effect was observed by studying parameters like total number of tumors, tumor size in mice. Further, expression of tumor suppressor gene, p53 in treated mice was investigated. Results: In vitro antioxidant assays had shown methanolic extract to possess higher radical scavenging activity than aqueous and to be minimal cytotoxic. In vivo study has shown a significant reduction in total number of tumors and tumor size for the mice group treated with extract in comparison to DMBA-TPA treated group. An increase in the levels of GSH, SOD and GPx was observed with a significant reduction in LPO levels. Expression of p53 was found to be upregulated in Swiss albino mice treated with extract emphasizing possible antitumor effect of Trigonella. Conclusion: The present study helped in understanding the reducing potential and antitumorigenic activity of Trigonella seed extract and its probable therapeutic effect in skin papillomagenesis.     

Mutation Analysis of IDH1/2 Genes in Unselected De novo Acute Myeloid Leukaemia Patients in India - Identification of A Novel IDH2 Mutation

IDH1/2 mutations which result in alternation in DNA methylation pattern are one of the most commonmethylation associated mutations in Acute myeloid leukaemia. IDH1/2 mutations frequently associated withhigher platelet level, normal cytogentics and NPM1 mutations. Here we analyzed IDH1/2 mutations in 200 newlydiagnosed unselected Indian adult AML patients and investigated their correlation with clinical, cytogeneticparameters along with cooperating NPM1 mutation. We detected 5.5% and 4% mutations in IDH1/2 genes,respectively. Except IDH2 c.515_516GG>AA mutation, all the other identified mutations were reported mutations.Similar to reported c.515G>A mutation, the novel c.515_516GG>AA mutation replaces 172nd arginine to lysinein the active site of the enzyme. Even though there was a preponderance of IDH1/2 mutations in NK-AML,cytogenetically abnormal patients also harboured IDH1/2 mutations. IDH1 mutations showed significant higherplatelet count and NPM1 mutations. IDH2 mutated patients displayed infrequent NPM1 mutations and lowerWBC count. All the NPM1 mutations in the IDH1/2 mutated cases showed type A mutation. The present datasuggest that IDH1/2 mutations are associated with normal cytogenetics and type A NPM1 mutations in adultIndian AML patients.     

NPM1基因突变的急性髓系白血病免疫表型研究

 【摘要】 目的 研究伴有NPM1基因突变的急性髓系白血病(AML)患者的免疫表型特征。方法 采用流式细胞术检测237例初诊AML患者的免疫表型,并采用实时定量PCR方法对NPM1基因突变进行筛查,比较NPM1突变型和野生型患者的免疫表型差异。结果 NPM1突变型患者占所有AML患者的19.0 %（45／237）,与野生型相比其CD34、CD117、HLA-DR、CD15、CD19表达降低（均P＜0.05）。在正常核型AML患者中,NPM1突变率37.7 %（40／106）,突变型患者CD34、HLA-DR、CD15和CD7表达降低（均P＜0.05）。伴NPM1突变的正常核型AML患者的免疫表型在M1中表现为CD34、HLA-DR、CD7表达降低（均P＜0.05）,在M2中为HLA-DR表达降低和CD9表达升高（均P＜0.05）,在M5中为CD117表达降低（P＜0.05）。结论 NPM1突变能对AML患者的免疫表型特征造成影响,不同FAB分型的AML患者免疫表型改变存在差异。     

Double Heterozygosity in the <i>BRCA1/2</i> Genes in a Turkish Patient with Bilateral Breast Cancer: A Case Report

BRCA1 and BRCA2 tumor suppressor genes are responsible for a quarter of hereditary breast cancers. Double heterozygous (DH) pathogenic variant carrier status in these genes is an extremely rare condition, especially in non-Askenazi individuals. We report a woman patient with bilateral breast cancer that carries DH disease-causing variants in BRCA1/2 genes. The 45-year-old patient who was followed up with the diagnosis of metachronous bilateral breast cancer was diagnosed with cancer at the age of 39 and 43, respectively. BRCA1/2 genes of the patient were evaluated using Next-Generation Sequencing. In the patient, the c.2800C>T (p.Gln934Ter) pathogenic variant in BRCA1 and the c.9648+1G>C likely pathogenic variant in BRCA2 were detected as DH. Segregation analysis in family members revealed that her two healthy siblings available for testing were heterozygous for either BRCA1 or BRCA2 variants, but her mother, who had a past diagnosis of ovarian cancer, was heterozygous for both BRCA1 and BRCA2 variants. Germline double heterozygosity in inherited cancer is a rare condition, and as far as we know it is reported for the first time from patient population in Turkey. Large-scale patient series are needed to determine the impact of double heterozygosity on diseases course, such as prognosis and treatment responses.     

NPM1突变及H3K79甲基化的研究进展

白血病是一种常见的血液系统恶性肿瘤,其中急性髓系白血病（acute myeloid leukemia,AML）约占所有白血病的59%,其发病机理尚不十分清楚,现认为多种因素在多个层面、多个阶段的相互作用导致白血病的发生。NPM1蛋白可以穿梭于胞浆与胞核之间,并主要定位于细胞核内,与多种蛋白结合。NPM1突变在急性髓系白血病中占25～30%,产生的突变的NPM1蛋白因缺乏核定位肽段而滞留于细胞浆,对细胞核的稳定性以及某些癌基因的表达产生负面影响。在含有NPM1基因突变的AML中,约70%的病人同时含有DNA甲基化调节基因的突变（DNMT3A、IDH1、IDH2、TET2等）,并且已知表观遗传学的异常可以直接破坏核稳定性,上调某些白血病相关基因的高表达。NPM1突变基因的白血病细胞具有特殊的基因表达特征,如HOX家族基因、MEIS1基因在突变系统中显著高表达,这些基因不仅是引发白血病的关键调节子,而且是MLL融合蛋白的下游靶点。在携带有MLL融合蛋白的AML中,MLL的融合伴侣可以募集DOT1L,对MLL靶点基因上的H3K79位点进行甲基化,造成这些基因过度活化。同MLL基因的异常相比,NPM1突变保持着相似的转录特点,然而NPM1突变是否能够影响组蛋白H3K79甲基化的变化还不是很清楚。本综述着重探讨NPM1突变与H3K79甲基化的关系,以及H3K79甲基化转移酶DOT1L抑制剂对NPM1突变的AML的作用,从而为白血病发病寻求新的分子机制和治疗策略。     

The Clinicopathological Impact of Granulocyte-Macrophage Colony-Stimulating Factor Gene Expression and Different Molecular Prognostic Biomarkers in Egyptian Acute Myeloid Leukemia Patients

Background: Acute myeloid leukemia (AML) is characterized by clonal expansion of myeloid precursors with diminished capacity for differentiation. It develops as the consequence of a series of genetic changes in a hematopoietic precursor cell. Purpose This study aimed to investigate the correlation between GM-CSF gene expression and different molecular prognostic markers such as FLT3-ITD, NPM1 mutation A and CEBPA gene expression in 100 Egyptian AML patients. As well as, correlation with the response to induction therapy, DFS andOS in these patients. Methodology: Quantitative assessment of GM-CSF gene expression was performed by qRT-PCR. Additional prognostic molecular markers were determined as FLT3-ITD and NPM1 mutation A together with quantitative assessment of CEBPA gene expression by qRT-PCR. Results: Patients with high GM-CSF expression levels had better OS and DFS with p value 0.004 and 0.02, respectively. However, no statistically significant difference between low andhigh GM-CSF gene expression was found regarding the response to therapy (p value= 0.08). Most patients with low CEBPA expression had resistant disease together with poor OS and DFS (P value =     

Influence of FLT3‐internal tandem duplication allele burden and white blood cell count on the outcome in patients with intermediate‐risk karyotype acute myeloid leukemia

BACKGROUND:

In patients with acute myeloid leukemia (AML), testing for fms‐like tyrosine kinase‐3 (FLT3)–internal tandem duplication (FLT3‐ITD) and nucleophosmin‐1 (NPM1) mutations can allow for further prognostic subclassification, but less is known about the effects of FLT3‐ITD allele burden and presenting white blood cell count (WBC) within molecular subgroups.

METHODS:

The authors retrospectively assessed 206 adult patients who had AML with an intermediate‐risk karyotype and who received treatment on a uniform induction and consolidation chemotherapy regimen.

RESULTS:

The presenting WBC was a prognostic factor for survival only in patients who had an FLT3‐ITD mutation. On multivariate analysis, after correcting for age, WBC, secondary AML, and blast percentage, nucleophosmin‐1 (NPM1)‐mutated/FLT3‐ITD–negative patients had superior overall survival compared with patients in the other molecular subgroups. Patients who had FLT3‐ITD mutations had an inferior overall survival compared with patients who had NPM1 wild‐type/FLT3‐negative disease, and patients who had low or intermediate levels of the FLT‐ITD of mutant allele had overall and disease‐free survival similar to those in patients who had high‐level mutations.

CONCLUSIONS:

NPM1 and FLT3‐ITD status, age, WBC, and secondary AML were identified as important prognostic variables that can help to risk stratify patients with AML who have intermediate‐risk cytogenetics. FLT3 allele burden had no significant influence on outcomes after correcting for other variables. Cancer 2012. © 2012 American Cancer Society.     

Prognostic utility of six mutated genes for older patients with acute myeloid leukemia

Approximately 50% of older patients with acute myeloid leukemia (AML) do not obtain chromosomal abnormalities as an effective risk‐stratification, and present cytogenetically normal AML (CN‐AML). To develop a reliable prediction model for stratifying the risk of these elderly patients, we conducted a study with a discovery and validation design. As a result, we found the top 6 mutated genes in the discovery cohort of 26 case by the whole exome sequencing, and verified as recurrent mutations in the large cohort of 329 patients by Sanger sequencing. The top 6 genes were NPM1, FLT3‐ITD, DNMT3A, CEBPA double allele, IDH1 and IDH2 mutations, and the frequency of each gene in the combining cohort was 36.8%, 19.8%, 20.1%, 5.8%, 14.9% and 22.5%, respectively. In addition, clinical variables such as age, white blood cell counts, genes of IDH1 and DNMT3A mutations, European LeukemiaNet genotype (NPM1 mutations and lacking FLT3‐ITD or CEBPA double allele mutations) and treatment protocols were independent factors for predicting the probabilities of overall and event‐free survival. The prediction nomograms based on these significant factors showed accurate discrimination. In conclusion, we developed a reliable prediction model for stratifying the risk of elderly patients with CN‐AML.     

CEBPA single mutation can be a possible favorable prognostic indicator in NPM1 and FLT3-ITD wild-type acute myeloid leukemia patients with intermediate cytogenetic risk

The aim of this study was to evaluate the prognostic impact of CEBPA single mutation in acute myeloid leukemia (AML) patients with intermediate cytogenetic risk. CEBPA single and double mutations were detected in 11 (9.7%) and 17 (15.1%) of 113 NPM1 wild-type patients, but no CEBPA mutations were detected in a group of 44 NPM1 mutated patients. Among patients with NPM1/FLT3-ITD wild-type, those with CEBPA double mutations (P = 0.013 and 0.007 for overall survival and relapse-free survival, respectively) or a single mutation (P = 0.039 and 0.020 for overall survival and relapse-free survival, respectively) demonstrated a favorable prognosis compared with CEBPA wild-type patients. Subsequent multivariate analysis confirmed the favorable prognostic impact of CEBPA single and double mutations. Despite the low statistical power of this study due to the small number of patients, our preliminary data suggest that CEBPA single mutation may be associated with favorable clinical outcomes in NPM1/FLT3-ITD wild-type AML patients with intermediate cytogenetic risk.     

Nucleophosmin (NPM1) mutations in adult and childhood acute myeloid leukaemia: towards definition of a new leukaemia entity

Nucleophosmin (NPM) is a ubiquitously expressed chaperone protein that shuttles rapidly between the nucleus and cytoplasm, but predominantly resides in the nucleolus. It plays key roles in ribosome biogenesis, centrosome duplication, genomic stability, cell cycle progression and apoptosis. Somatic mutations in exon 12 of the NPM gene (NPM1) are the most frequent genetic abnormality in adult acute myeloid leukaemia (AML), found in approximately 35% of all cases and up to 60% of patients with normal karyotype (NK) AML. In children, NPM1 mutations are far less frequent, occurring in 8–10% of all AML cases, and in approximately 25% of those with a NK. NPM1 mutations lead to aberrant localization of the NPM protein into the cytoplasm, thus the designation, NPMc+ AML. NPMc+ AML is seen predominantly in patients with a NK and is essentially mutually exclusive of recurrent chromosomal translocations. Patients with NPM1 mutations are twice as likely as those who lack an NPM1 mutation to also have a FMS‐like tyrosine kinase (FLT3) internal tandem duplication (ITD) mutation. NPMc+ AML is also characterized by a unique gene expression signature and microRNA signature. NPMc+ AML has important prognostic significance, as NPMc+ AML, in the absence of a coexisting FLT3‐ITD mutation, is associated with a favourable outcome. NPM1 mutations have also shown great stability during disease evolution, and therefore represent a possible marker for minimal residual disease detection. Given its distinctive biologic and clinical features and its clear clinical relevance, NPMc+ AML is included as a provisional entity in the 2008 WHO classifications. There is still much to be learned about this genetic alteration, including its exact role in leukaemogenesis, how it interacts with other mutations and why it confers a more favourable prognosis. Further, it represents a potential therapeutic target warranting research aimed at identifying novel small molecules with activity in NPMc+ AML. Copyright © 2009 John Wiley & Sons, Ltd.     

Clinical Characteristics and Molecular Patterns of <i>RET</i>-Rearranged Lung Cancer in Chinese Patients

RET rearrangement has been proven as an oncogenic driver in patients with lung cancer. However, the prevalence, clinical characteristics, molecular features, and therapeutic options in RET-rearranged patients remain unclear, especially in Chinese lung cancer patients. We retrospectively collected 6,125 Chinese lung cancer patients who have been profiled using next-generation sequencing (NGS). The clinical demographics and molecular features of RET rearrangement-positive patients were analyzed. RET rearrangements were identified in 84 patients with a proportion of 1.4% in our cohort. The median age at diagnosis was 58 years, and it mainly occurred in females with adenocarcinoma histology. KIF5B-RET was the most frequent fusion type and accounted for 53.8% (57/106) of all RET fusions identified, with K15-R12 as the most frequent variant (71.9%). Among 47 RET+ patients profiled with larger panels, 72.3% (34/47) harbored concurrent alterations. TP53 ranked as the most common concurrent alteration, and concomitant EGFR oncogenic alterations were identified in seven patients. Moreover, an adenocarcinoma patient harboring concurrent RET fusion and EGFR L858R responded to combinatorial treatment of cabozantinib and osimertinib, with a progression-free survival of 5 months. Our study improved knowledge of clinical characteristics and molecular features of RET-rearranged lung cancers in China. It might be helpful to guide clinicians for more effective personalized diagnostic and therapeutic approaches.