Gene Summary

Gene:PTPN11; protein tyrosine phosphatase non-receptor type 11
Summary:The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains two tandem Src homology-2 domains, which function as phospho-tyrosine binding domains and mediate the interaction of this PTP with its substrates. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome as well as acute myeloid leukemia. [provided by RefSeq, Aug 2016]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:tyrosine-protein phosphatase non-receptor type 11
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (45)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • DNA Mutational Analysis
  • Infant
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • fms-Like Tyrosine Kinase 3
  • Intracellular Signaling Peptides and Proteins
  • SOS1 Protein
  • Germ-Line Mutation
  • src Homology Domains
  • Tumor Suppressor Proteins
  • Thrombocythemia, Essential
  • Stomach Cancer
  • Autologous Transplantat
  • Acute Myeloid Leukaemia
  • Noonan Syndrome
  • Genetic Predisposition
  • ras Proteins
  • Single Nucleotide Polymorphism
  • Missense Mutation
  • Phosphorylation
  • Cell Proliferation
  • Mutation
  • PTPN11
  • siRNA
  • Gene Expression Profiling
  • Leukemia, Myelomonocytic, Juvenile
  • Protein Tyrosine Phosphatases
  • Childhood Cancer
  • SH2 Domain-Containing Protein Tyrosine Phosphatases
  • Translocation
  • Signal Transduction
  • Receptor Protein-Tyrosine Kinases
  • Cancer Gene Expression Regulation
  • DNA Sequence Analysis
  • Chromosome 12
  • Threonine
  • Neoplastic Cell Transformation
  • Antineoplastic Agents
  • RAS Genes
  • Transfection
  • Adolescents
  • Leukaemia
  • Spain
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
LeukaemiaPTPN11 and Myeloid Leukemia View Publications138
Noonan SyndromePTPN11 and Noonan Syndrome
Noonan Syndrome is an autosamal dominant multi-system disorder, characterised by facial anomalies, short stature, developmental delay, cardiac abnormalities and other symptoms. The syndrome pre-disposes to myeloproliferative disorders ( mainly chronic myeolomonocytic leukemia / juvenile myelomonocytic leukemia and acute lymphoblastic leukemia), with reports of neuroblastoma, rhabdomyosarcoma and a wide range of other tumors.
View Publications70
-PTPN11 and Noonan Syndrome View Publications70
Acute Myeloid Leukaemia (AML)PTPN11 and Acute Myeloid Leukaemia View Publications46
Stomach CancerPTPN11 and Stomach Cancer View Publications13

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PTPN11 (cancer-related)

Fabri O, Horakova J, Bodova I, et al.
Diagnosis and treatment of juvenile myelomonocytic leukemia in Slovak Republic: novel approaches.
Neoplasma. 2019; 2019 [PubMed] Related Publications
Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive clonal myeloproliferative disorder of infancy and early childhood caused by oncogenic mutations in genes involved in the Ras pathway. Long-term survival has only been achieved with hematopoietic stem cell transplantation (HSCT), being able to cure more than 50% patients. To manage the disease before HSCT remains an important issue with constant searching for optimal treatment modalities. According to several retrospective analyses, azacytidine (AZA) induced clinical and molecular responses in patients with relapsed JMML pre-transplant and post-transplant, suggesting its use as a promising "bridging" therapy before HSCT. In this paper we report our first consecutive cohort of patients with JMML treated at our institution as well as our experience with the diagnosis, novel treatment and management of these patients before the HSCT. We present 6 patients with JMML, harboring different somatic mutations (PTPN11 and NRAS), with distinct clinical features; 3 of them had been treated with AZA 75mg/m2 i.v. on days 1 to 7 of a 28-day cycle before the HSCT. Response to therapy was evaluated after each cycle in accordance with the International response criteria. One patient had a progression of splenomegaly during the treatment and after three cycles he was urgently transplanted. At present, he is remaining in complete remission 3 years after HSCT. Two patients showed impressive response following the first cycle of the therapy with a regression of splenomegaly and monocyte count, normalized leukocytes, platelets, and absent blasts in peripheral blood. The treatment was well-tolerated with no adverse effect recorded. The clinical activity and favorable toxicity of AZA in JMML provide a rationale for its use as a "bridging" therapy before HSCT. Prospective trials with accompanying translational studies are required to provide further information regarding individual factors that may direct the most appropriate choice of pretransplantation therapy.

Tatiana S, Marta J, Monika M, Pavel V
Noonan syndrome from a fetopathologist perspective.
Cesk Patol. 2019; 55(1):48-52 [PubMed] Related Publications
We present our experience with four cases of fetal autopsies with abnormal prenatal ultrasound findings and suspicion of Noonan syndrome. These were fetuses from the 17th to the 24th age of gestation (GA). In all cases, prenatal ultrasound examination recorded increased nuchal translucency (NT) and presence of lymphatic neck sacs. Some fetuses showed signs of fetal hydrops and polyhydramnion was found. Similar signs and congenital developmental defects were confirmed in the autopsy examination. These were primarily signs of developing fetal hydrops with increased nuchal edema, in some cases up to the character of cystic hygroma, pleural and abdominal effusions, congenital heart and kidney defects, skeletal defects and facial dysmorphism. A karyotype was examined in all cases without chromosome aneuploidy. The diagnosis of NS was confimed by subsequent genetic analysis of causal gene mutations (mainly PTPN11, KRAS, RAF 1,). Our cases demonstrate a wide range of signs of prenatal presentation of this syndrome. Because of wide differential diagnosis, summarizing prenatal ultrasound findings, autopsy examination and molecular genetic testing is essential.

Bao H, Gao J, Chen YH, et al.
Rare myeloid sarcoma with KMT2A (MLL)-ELL fusion presenting as a vaginal wall mass.
Diagn Pathol. 2019; 14(1):26 [PubMed] Free Access to Full Article Related Publications
BACKGROUD: Myeloid sarcoma (MS) is a rare neoplasm of immature myeloid precursors that form tumor mass outside the bone marrow. The diagnosis of de novo MS can be challenging, particularly in patients with no prior history of hematologic malignancies or when MS involves unusual anatomic sites.
CASE PRESENTATION: The patient was a 53-year-old woman with a history of uterine fibroids and vaginal bleeding for many years who presented with a vaginal wall mass. The tumor had histologic and phenotypic features of histiocytic sarcoma, however, overlapping with a possible extramedullary MS. Using a comprehensive genomic profiling, we were able to identify recurrent chromosomal aberrations associated with MS including a rare KMT2A-ELL fusion, losses of chromosomes 1p, 9, 10, 15, 18, and gain of chromosome 1q and mutations in FLT3 and PTPN11, and achived the final diagnosis of a de novo MS. The patient received standard treatment for acute myeloid leukemia regimen with stem cell transplantation and achieved complete remission.
CONCLUSION: Our case illustrates the clinical utility of comprehensive genomic profiling in assisting the diagnosis or differential diagnosis of challenging MS or histiocytic sarcoma cases, and in providing important information in tumor biology for appropriate clinical management.

Zhao J, Chen AX, Gartrell RD, et al.
Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma.
Nat Med. 2019; 25(3):462-469 [PubMed] Related Publications
Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor's clonal evolution during treatment.

Kano Y, Gebregiworgis T, Marshall CB, et al.
Tyrosyl phosphorylation of KRAS stalls GTPase cycle via alteration of switch I and II conformation.
Nat Commun. 2019; 10(1):224 [PubMed] Free Access to Full Article Related Publications
Deregulation of the RAS GTPase cycle due to mutations in the three RAS genes is commonly associated with cancer development. Protein tyrosine phosphatase SHP2 promotes RAF-to-MAPK signaling pathway and is an essential factor in RAS-driven oncogenesis. Despite the emergence of SHP2 inhibitors for the treatment of cancers harbouring mutant KRAS, the mechanism underlying SHP2 activation of KRAS signaling remains unclear. Here we report tyrosyl-phosphorylation of endogenous RAS and demonstrate that KRAS phosphorylation via Src on Tyr32 and Tyr64 alters the conformation of switch I and II regions, which stalls multiple steps of the GTPase cycle and impairs binding to effectors. In contrast, SHP2 dephosphorylates KRAS, a process that is required to maintain dynamic canonical KRAS GTPase cycle. Notably, Src- and SHP2-mediated regulation of KRAS activity extends to oncogenic KRAS and the inhibition of SHP2 disrupts the phosphorylation cycle, shifting the equilibrium of the GTPase cycle towards the stalled 'dark state'.

Singla H, Kaur RP, Shafi G, et al.
Genomic alterations associated with HER2+ breast cancer risk and clinical outcome in response to trastuzumab.
Mol Biol Rep. 2019; 46(1):823-831 [PubMed] Related Publications
Human epidermal growth factor receptor 2 positive (HER2+) breast cancer (BC) is an aggressive BC subtype characterized by HER2 overexpression/amplification. Genomic alterations of HER2 and others have been reported to be associated with, HER2 overexpression and prediction of trastuzumab-response. Here, we aimed at identifying germline and somatic alterations associated with HER2+ BC and evaluating their association with clinical outcome in response to trastuzumab therapy given to HER2+ BC patients. Global Sequencing Array (GSA) and polymerase chain reaction-restriction length polymorphism (PCR-RFLP) techniques were used to determine alterations in HER2 and other HER2-interacting as well as signaling-related genes in HER2+ BC. In addition, 20 formalin fixed paraffin-embedded tissue samples were also evaluated by GSA for identifying significant variations associated with HER + BC as well as response to trastuzumab therapy. A germline variant in HER2 (I655V) was found to be significantly associated with the risk of the disease (p < 0.01). A nonsense mutation in PTPN11 (K99X), a pathogenic CCND1 splice site variant (P241P), a hotspot missense mutation in PIK3CA (E542K) and a hotspot missense mutation in TP53 (R249S); were observed in 25%, 75%, 30% and 40% of the HER2+ BC tissue samples, respectively. Mutant CCND1 (P241P) and PIK3CA (E542K) were found to be significantly associated with reduced disease-free survival (DFS) in patients treated with trastuzumab (p: 0.018 and 0.005, respectively). These results indicate that HER2, PTPN11, CCND1 and PIK3CA genes are important biomarkers in HER2+ BC. Moreover, the patients harboring mutant CCND1 and PIK3CA exhibit a poorer clinical outcome as compared to those carrying wild-type CCND1 and PIK3CA.

Niemeyer CM
JMML genomics and decisions.
Hematology Am Soc Hematol Educ Program. 2018; 2018(1):307-312 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
Juvenile myelomonocytic leukemia (JMML) is a unique clonal hematopoietic disorder of early childhood characterized by hyperactivation of the RAS signal transduction pathway. Approximately 90% of patients harbor molecular alteration in 1 of 5 genes (

Karachaliou N, Cardona AF, Bracht JWP, et al.
Integrin-linked kinase (ILK) and src homology 2 domain-containing phosphatase 2 (SHP2): Novel targets in EGFR-mutation positive non-small cell lung cancer (NSCLC).
EBioMedicine. 2019; 39:207-214 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
BACKGROUND: The activation of multiple signaling pathways jeopardizes the clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutation positive non-small cell lung cancer (NSCLC). Integrin-linked kinase (ILK) regulates the interactions between tumor cells and extracellular environment to activate signaling pathways and promote cell proliferation, migration, and epithelial-mesenchymal transition. Src homology 2 domain-containing phosphatase 2 (SHP2) is essential for receptor tyrosine kinase signaling and mitogen-activated protein kinase (MAPK) pathway activation.
METHODS: We analyzed tumor ILK, β-receptor subunit glycoprotein 130 (gp130), SHP2, and stromal hepatocyte growth factor (HGF) and interleukin-6 (IL-6) mRNA expression in baseline tumor specimens of advanced EGFR-mutation positive NSCLC patients treated with EGFR TKIs.
RESULTS: ILK, when highly expressed, was an independent poor prognostic factor for the progression-free survival of the patients, both in the univariate (hazard ratio [HR for disease progression, 2.49; 95% CI, 1.37-4.52; P = .0020]) and in the multivariate (HR 3.74; 95% CI, 1.33-10.56; P = .0126) Cox regression model. Patients with high SHP2 expression had an almost 13-month shorter progression-free survival (P = .0094) and an 18-month shorter overall survival (P = .0182) in comparison to those with low SHP2 mRNA expression.
INTERPRETATION: The levels of ILK and SHP2 could be predictive for upfront combinatory therapy of EGFR TKIs plus SHP2 or ILK inhibitors. FUND: A grant from La Caixa Foundation, an Instituto de Salud Carlos III grant (RESPONSE, PIE16/00011), an Instituto de Salud Carlos III grant (PI14/01678), a Marie Skłodowska-Curie Innovative Training Networks European Grant (ELBA No 765492) and a Spanish Association Against Cancer (AECC) grant (PROYE18012ROSE).

Zhao H, Martin E, Matalkah F, et al.
Conditional knockout of SHP2 in ErbB2 transgenic mice or inhibition in HER2-amplified breast cancer cell lines blocks oncogene expression and tumorigenesis.
Oncogene. 2019; 38(13):2275-2290 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
Overexpression of the human epidermal growth factor receptor 2 (HER2) is the cause of HER2-positive breast cancer (BC). Although HER2-inactivating therapies have benefited BC patients, development of resistance and disease recurrence have been the major clinical problems, pointing to a need for alternative therapeutic strategies. For that to happen, proteins that play critical roles in the biology of HER2-induced tumorigenesis have to be identified and characterized. Here, we show that the Src homology phosphotyrosyl phosphatase 2 (Shp2) encoded by the Ptpn11 gene is a requisite for ErbB2-induced tumorigenesis. We report that conditional knockout of Shp2 alleles in the ErbB2 BC model mice abrogates mammary tumorigenesis by blocking the expression of the ErbB2 transgene. We also show that inhibition of SHP2 encoded by the PTPN11 gene in the HER2-amplified BC cells induces a normal-like cellular phenotype and suppresses tumorigenesis and metastasis by blocking HER2 overexpression. These findings demonstrate that ErbB2-induced tumors in mice or xenograft tumors induced by transplantation of HER2-amplified BC cells are vulnerable to SHP2 inhibition since it abrogates the expression of the very oncogene that causes of the disease. This report paves the way for developing SHP2-targeting therapies for BC treatment in the future.

Bejar R
What biologic factors predict for transformation to AML?
Best Pract Res Clin Haematol. 2018; 31(4):341-345 [PubMed] Related Publications
Transformation of myelodysplastic syndromes (MDS) into secondary acute myeloid leukemia (sAML) is defined by an arbitrary boundary of ≥20% bone marrow blasts but does not necessarily reflect a defined biological transition. The more obvious distinction lies between MDS patients that have an isolated bone marrow failure phenotype and those with excess blasts. Subtyping of MDS might be more accurately stratified into clonal cytopenias and oligoblastic leukemias, using the degree of dysplasia and blast percentage as risk features, respectively, rather than as diagnostic criteria. Transformation from MDS to sAML often involves clonal evolution or expansion of existing subclones that can be assessed by changes in variant allele frequencies of the somatic mutations that define them. There are a number of predictors for transformation that have been identified: these include mutations of genes in growth signaling pathways (NRAS, KRAS, PTPN11, FLT3), mutations in genes more commonly observed in AML (NPM1, WT1, IDH2), certain cytogenetic abnormalities (monosomy 7, complex karyotype, loss of 17p). Gene expression profiles that divide MDS into two major categories identify a progenitor gene signature subtype associated with a high risk of AML transformation. Assessing for these genetic abnormalities may better identify MDS patients at greatest risk of transformation.

Shao H, Ma L, Jin F, et al.
Immune inhibitory receptor LILRB2 is critical for the endometrial cancer progression.
Biochem Biophys Res Commun. 2018; 506(1):243-250 [PubMed] Related Publications
Although leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) is known as an immune inhibitory receptor to suppress the immune system, its function in cancer development remains largely unknown. Herein, we provide the first body of information showing that LILRB2 is highly expressed in the endometrial cancer. More importantly, the expression levels of LILRB2 are inversely correlated with the overall patients' survival. Knockdown of LILRB2 results in a dramatic decrease in the proliferation, colony formation and migration in several endometrial cancer cell lines in vitro. Furthermore, in vivo xenograft experiments reveal a notable reduction of tumor cell growth. Mechanistically, LILRB2 enhances the SHP2/CaMK1/CREB signaling pathways to support the expansion and migration of the endometrial cancer cells. These findings unravel an unexpected role of LILRB2 in solid cancers except for its canonical role in immune surveillance, which may serve as a potential endometrial stem cell marker and may benefit the development of novel strategies for the treatment of endometrial cancers.

Wang Y, Luo T
LINC00673 rs11655237 Polymorphism Is Associated With Increased Risk of Cervical Cancer in a Chinese Population.
Cancer Control. 2018 Jan-Dec; 25(1):1073274818803942 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
Cervical cancer is the fourth most commonly diagnosed cancer and the fourth leading cause of cancer deaths in women worldwide. Few single-nucleotide polymorphisms associated with risk of cervical cancer have been identified, yet genetic predisposition contributes significantly to this malignancy. Long noncoding RNA LINC00673 has been widely explored for its role in the development and prognosis of many tumors, and 2 genome-wide association studies identified that LINC00673 rs11655237 was associated with susceptibility to pancreatic cancer. In the current study, using a case-control study design, we found rs11655237 significantly increased susceptibility of cervical cancer in a Chinese population (odds ratio = 1.27; 95% confidence interval = 1.08-1.50; P = .005). Expression of LINC00673 was significantly higher in adjacent normal tissues than in paired cancer tissues ( P < .01) and significantly lower in the cancer or paired adjacent normal tissues of patients with cervical cancer having rs11655237 allele A than in those having rs11655237 allele G ( P < .001). Our results indicate that LINC00673 rs11655237 is associated with increased risk of cervical cancer, possibly by downregulating LINC00673 expression in cervical tissues.

Zhao W, Wang L, Yu Y
Gene module analysis of juvenile myelomonocytic leukemia and screening of anticancer drugs.
Oncol Rep. 2018; 40(6):3155-3170 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
Juvenile myelomonocytic leukemia (JMML) is a rare but severe primary hemopoietic system tumor of childhood, most frequent in children 4 years and younger. There are currently no specific anticancer therapies targeting JMML, and the underlying gene expression changes have not been revealed. To define molecular targets and possible biomarkers for early diagnosis, optimal treatment, and prognosis, we conducted microarray data analysis using the Gene Expression Omnibus, and constructed protein‑protein interaction networks of all differentially expressed genes. Modular bioinformatics analysis revealed four core functional modules for JMML. We analyzed the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway functions associated with these modules. Using the CMap database, nine potential anticancer drugs were identified that modulate expression levels of many JMML‑associated genes. In addition, we identified possible miRNAs and transcription factors regulating these differentially expressed genes. This study defines a new research strategy for developing JMML‑targeted chemotherapies.

Kotani S, Yoda A, Kon A, et al.
Molecular pathogenesis of disease progression in MLL-rearranged AML.
Leukemia. 2019; 33(3):612-624 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
Leukemic relapse is frequently accompanied by progressively aggressive clinical course. To understand the molecular mechanism of leukemic relapse, MLL/AF9-transformed mouse leukemia cells were serially transplanted in C57BL/6 mice (N = 96) by mimicking repeated recurrences, where mutations were monitored by exome sequencing (N = 42). The onset of leukemia was progressively promoted with advanced transplants, during which increasing numbers of somatic mutations were acquired (P < 0.005). Among these, mutations in Ptpn11 (p.G60R) and Braf (p.V637E) corresponded to those identified in human MLL-AML, while recurrent mutations affecting Msn (p.R295C) were observed only in mouse but not in human MLL-AML. Another mutated gene of interest was Gnb2 which was reported to be recurrently mutated in various hematological neoplasms. Gnb2 mutations (p.G77R) were significantly increased in clone size (P = 0.007) and associated with earlier leukemia onset (P = 0.011). GNB2 transcripts were significantly upregulated in human MLL-AML compared to MLL-negative AML (P < 0.05), which was supported by significantly increased Gnb2 transcript induced by MLL/AF9 overexpression (P < 0.001). In in vivo model, both mutation and overexpression of GNB2 caused leukemogenesis, and downregulation of GNB2 expression reduced proliferative potential and survival benefit, suggesting a driver role of GNB2. In conclusion, alterations of driver genes over time may play an important role in the progression of MLL-AML.

Kanayama T, Imamura T, Kawabe Y, et al.
KMT2A-rearranged infantile acute myeloid leukemia masquerading as juvenile myelomonocytic leukemia.
Int J Hematol. 2018; 108(6):665-669 [PubMed] Related Publications
Mixed lineage leukemia [MLL; now known as lysine methyltransferase 2A (KMT2A)] rearrangement-positive acute myeloid leukemia (AML) and juvenile myelomonocytic leukemia (JMML) are distinct diseases, although age of susceptibility (infancy or early childhood) and abnormal monocytosis are common clinical features. Here, we report two cases of KMT2A-rearranged infantile AML masquerading as JMML at initial presentation. Both cases showed leukocytosis accompanied by atypical monocytosis. However, in both cases, leukemic blasts were absent at the initial examination. Thus, a diagnosis of JMML was suspected. However, initial cytogenetic analysis revealed that both cases had an 11q23 rearrangement, which is atypical in JMML. Eventually, due to the emergence of leukemic blasts and further cytogenetic studies, both cases were diagnosed with infantile AML with a KMT2A rearrangement. Although one patient remains in complete remission after the completion of AML appropriate chemotherapy, the other died of AML due to treatment failure. Our experience suggests that AML with KMT2A rearrangement should be considered for the differential diagnosis of infantile cases with atypical monocytosis suggestive of JMML. Cytogenetic studies, including fluorescence in situ hybridization analysis of KMT2A, may be helpful in distinguishing between AML with KMT2A rearrangement and JMML.

Gagne AL, Maguire JA, Gandre-Babbe S, et al.
Generation of a human Juvenile myelomonocytic leukemia iPSC line, CHOPi001-A, with a mutation in CBL.
Stem Cell Res. 2018; 31:157-160 [PubMed] Related Publications
Juvenile myelomonocytic leukemia (JMML) is a rare myeloproliferative disorder of early childhood characterized by expansion of clonal myelomonocytic cells and hyperactive Ras/MAPK signaling. The disorder is caused by somatic and/or germline mutations in genes involved in the Ras/MAPK and JAK/STAT signaling pathways, including CBL. Here we describe the generation of an iPSC line with a homozygous CBL c.1111T->C (Y371H) mutation, designated CHOPJMML1854.

Yao R, Yu T, Xu Y, et al.
Concurrent somatic KRAS mutation and germline 10q22.3-q23.2 deletion in a patient with juvenile myelomonocytic leukemia, developmental delay, and multiple malformations: a case report.
BMC Med Genomics. 2018; 11(1):60 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
BACKGROUND: The proto-oncogene KRAS performs an essential function in normal tissue signaling, and the mutation of KRAS gene is a key step in the development of many cancers. Somatic KRAS mutations are often detected in patients with solid and non-solid tumors, whereas germline KRAS mutations are implicated in patients with the Noonan syndrome, cardio-facio-cutaneous (CFC) syndrome and Costello syndrome. The deletion of chromosome 10q22.3-q23.2 is a rare cytogenetic abnormality, which often leads to distinct facial appearance and delays in speech and global development.
CASE PRESENTATION: Herein, we report the case of a 4-year-old boy diagnosed with juvenile myelomonocytic leukemia. The boy also had syndromic features, such as speech and motor developmental delay, multiple congenital malformations, including distinct facial features, club feet, and cryptorchidism. Using whole-exome sequencing, we identified a pathogenic mutation in KRAS [c.34G > A, p.Gly12Ser] isolated from peripheral blood DNA. Sanger sequencing confirmed the wild-type sequence in the parents and patient's salivary cell DNA indicating its somatic state. A 7311-kb deletion in 10q22.3-q23.2 was also revealed by chromosomal microarray analysis, which was later proved as a germline de novo variant.
CONCLUSION: Juvenile myelomonocytic leukemia in the patient was attributed to a somatic KRAS mutation, whereas the syndromic features of the patient were considered a consequence of germline chromosome 10q22.3-q23.2 deletion. Genetic testing for patients with complicated phenotypes can be valuable in detecting multiple pathogenic variants.

Yuan Y, Qi G, Shen H, et al.
Clinical significance and biological function of WD repeat domain 54 as an oncogene in colorectal cancer.
Int J Cancer. 2019; 144(7):1584-1595 [PubMed] Related Publications
In recent years, protein-protein interactions have become an attractive candidate for identifying biomarkers and drug targets for various diseases. However, WD40 repeat (WDR) domain proteins, some of the most abundant mediators of protein interactions, are largely unexplored. In our study, 57 of 361 known WDR proteins were identified as hub nodes, and a hub (WDR54) with elevated mRNA in colorectal cancer (CRC) was selected for further study. Immunohistochemistry of specimens from 945 patients confirmed the elevated expression of WDR54 in CRC, and we found that patients with WDR54-high tumors typically had a shorter disease-specific survival (DSS) than those with WDR54-low tumors, especially for the subgroup without well-differentiated tumors. Multivariate analysis showed that WDR54-high tumors were an independent risk factor for DSS, with a hazard ratio of 2.981 (95% confidence interval, 1.425-6.234; p = 0.004). Knockdown of WDR54 significantly inhibited the growth and aggressiveness of CRC cells and reduced tumor growth in a xenograft model. Each WDR54 isoform (a, b, and c) was found to reverse the inhibitory effect of WDR54 knockdown; however, only isoform c, which exhibited the highest expression, was increased in CRC cells. Sensitization of WDR54 knockdown to an SHP2 inhibitor was consistently found in CRC cells, and the underlying mechanism involved their common function in regulating AKT and ERK signaling. In conclusion, the present study is the first to investigate the significance of WDR54 in cancer and to conclude that WDR54 serves as an oncogene in CRC and may be a potential prognostic marker and therapeutic target.

Sklarz LM, Wittke C, Krohn S, et al.
Genetic Mutations in a Patient with Chronic Myeloid Leukemia Showing Blast Crisis 10 Years After Presentation.
Anticancer Res. 2018; 38(7):3961-3966 [PubMed] Related Publications
Since the introduction of tyrosine kinase inhibitors (TKI), the prospects for patients with chronic myeloid leukemia (CML) have improved significantly. Herein we present the case of a patient with CML who experienced blast crisis and development of acute myeloid leukemia (AML) 10 years after presentation. The CML was characterized by the gene fusion of breakpoint cluster region BCR and tyrosine-protein kinase ABL1. During treatment different therapeutic protocols including imatinib, nilotinib, dasatinib and ponatinib were applied due to development of resistance or non-response. Fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) were used to describe cytogenetic and molecular aberrations elucidating the development into AML: A loss of chromosome 7, as well as an arising frequency of variants in the gene met proto-oncogene MET (p.T110I) and tyrosine-protein phosphatase non-receptor type 11 PTPN11 (p.Q510L) was observed. This report describes the comprehensive characterization of a clinical case showing multiple therapeutic resistances correlated with genetic aberrations.

Ressa A, Bosdriesz E, de Ligt J, et al.
A System-wide Approach to Monitor Responses to Synergistic BRAF and EGFR Inhibition in Colorectal Cancer Cells.
Mol Cell Proteomics. 2018; 17(10):1892-1908 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Intrinsic and/or acquired resistance represents one of the great challenges in targeted cancer therapy. A deeper understanding of the molecular biology of cancer has resulted in more efficient strategies, where one or multiple drugs are adopted in novel therapies to tackle resistance. This beneficial effect of using combination treatments has also been observed in colorectal cancer patients harboring the BRAF(V600E) mutation, whereby dual inhibition of BRAF(V600E) and EGFR increases antitumor activity. Notwithstanding this success, it is not clear whether this combination treatment is the only or most effective treatment to block intrinsic resistance to BRAF inhibitors. Here, we investigate molecular responses upon single and multi-target treatments, over time, using BRAF(V600E) mutant colorectal cancer cells as a model system. Through integration of transcriptomic, proteomic and phosphoproteomics data we obtain a comprehensive overview, revealing both known and novel responses. We primarily observe widespread up-regulation of receptor tyrosine kinases and metabolic pathways upon BRAF inhibition. These findings point to mechanisms by which the drug-treated cells switch energy sources and enter a quiescent-like state as a defensive response, while additionally compensating for the MAPK pathway inhibition.

Giacaman A, Bauzá Alonso A, Salinas Sanz JA, et al.
Cutaneous involvement in an 8-year-old boy with Ras-associated autoimmune leucoproliferative disorder (RALD).
Clin Exp Dermatol. 2018; 43(8):913-916 [PubMed] Related Publications
Ras-associated autoimmune leucoproliferative disorder (RALD) is a nonmalignant syndrome associated with somatic KRAS mutations. We report a patient with RALD and cutaneous lesions, the first such case reported, to our knowledge. An 8-year-old boy presented with erythematous plaques on his face and body, along with lymphadenopathies and spleen enlargement without systemic symptoms. An increased number of monocytes were found in skin biopsy, peripheral blood and bone marrow (BM). Juvenile myelomonocytic leukaemia (JMML) was suspected. Genetic study using peripheral blood showed no mutations in the KRAS, PTPN11, NRAS, CBL or BCR-ABL genes, but bone marrow analysis revealed a mutation (p-G12S/c.34 G>A) in the KRAS gene. The karyotype was normal. No KRAS mutations were found using molecular analysis of saliva. The diagnosis of RALD was proposed. The differential diagnosis between RALD and JMML is challenging because there are no established criteria to differentiate between them. The clinical course of RALD is uncertain, so long-term follow-up is recommended.

Walker BA, Mavrommatis K, Wardell CP, et al.
Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma.
Blood. 2018; 132(6):587-597 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Understanding the profile of oncogene and tumor suppressor gene mutations with their interactions and impact on the prognosis of multiple myeloma (MM) can improve the definition of disease subsets and identify pathways important in disease pathobiology. Using integrated genomics of 1273 newly diagnosed patients with MM, we identified 63 driver genes, some of which are novel, including

Melo-Cardenas J, Xu Y, Wei J, et al.
USP22 deficiency leads to myeloid leukemia upon oncogenic Kras activation through a PU.1-dependent mechanism.
Blood. 2018; 132(4):423-434 [PubMed] Article available free on PMC after 01/10/2019 Related Publications

Wong GS, Zhou J, Liu JB, et al.
Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition.
Nat Med. 2018; 24(7):968-977 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
The role of KRAS, when activated through canonical mutations, has been well established in cancer

Zhang Y, Mi X, Song Z, et al.
Cripto-1 promotes resistance to drug-induced apoptosis by activating the TAK-1/NF-κB/survivin signaling pathway.
Biomed Pharmacother. 2018; 104:729-737 [PubMed] Related Publications
Cripto-1 is an oncogenic protein that belongs to the epidermal growth factor (EGF)-cripto-1/FRL1/cryptic (CFC) family. It has been shown to stimulate tumorigenesis and metastasis by promoting cancer cell proliferation, epithelial-to-mesenchymal transition (EMT), and tumor angiogenesis. However, the role of Cripto-1 in cell survival and apoptosis remains largely undefined. In the present study, we found that Cripto-1 is significantly upregulated in a number of human cancer cell lines. The membrane-associated but not the soluble form of Cripto-1 promotes resistance to drug-induced caspase-3 cleavage, an indicator of apoptosis. Consequently, Cripto-1 silencing sensitizes human cancer cells to chemotherapy drugs including cytarabine, cisplatin and taxol. Our mechanistic studies revealed that Cripto-1 promotes apoptosis resistance by inducing NF-κB-mediated Survivin expression through activation of TAK-1. We also found that Cripto-1 silencing does not affect growth of un-treated cancer cells, and Cripto-1 forms self-assembled punctiforms and changes its subcellular distribution upon cytarabine treatment. Thus, the anti-apoptotic activity of Cripto-1 could be an inducible function that can be activated by external stimuli such as drug stimulation. Our findings suggested that targeting the Cripto-1/TAK-1/NF-κB/Survivin pathway may be an effective approach to combat apoptosis resistance in cancer.

Wang Z, Zou Y, Chen Y, Chen Y
Multiple unexpected lesions of metachondromatosis detected by technetium-99m methylene diphosphonate SPECT/CT: A case report.
Medicine (Baltimore). 2018; 97(17):e0512 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
RATIONALE: Metachondromatosis (MC) is a very rare genetic disease, which is infrequently reported worldwide, which leads to osteochondroma and enchondromatosis. The disease has been shown to be associated with loss of function of the tumor suppressor gene "protein tyrosine phosphatase, non-receptor type 11" (PTPN11).
PATIENT CONCERNS: A 12-year-old female was admitted to the hospital with pain due to an enlarged mass in her left fifth finger.
DIAGNOSIS: Examination of the left hand by computed tomography (CT) revealed an expanding type of round and low-density lesion in the fifth proximal phalanx. The patient then underwent technetium-99m methylene diphosphonate single-photon emission CT/CT (Tc-MDP SPECT/CT) to assess the nature of the lesion. The SPECT/CT image revealed dilated osteopathy and increased activity of the fifth proximal phalanx on the left hand. Unexpectedly, the examination of the right hand revealed slight expanded lesions and increased activities of the third metacarpal and proximal phalange, as well as the fourth proximal phalange and the middle phalanx. On the basis of the patient's symptoms and the results of the above-mentioned examinations, we diagnosed the patient as having MC in her hands.
INTERVENTION: Considering the pain of the fifth finger of the left hand, the patient underwent debridement of the fifth proximal phalanx of the left hand and internal fixation with bone graft taken from the body.
OUTCOMES: The patient was discharged after a week of observation. One year later, she was admitted to the hospital again for removal of the bone healing internal fixation after osteoma surgery. Preoperative Tc-MDP SPECT/CT revealed that the left-handed lesions displayed postoperative changes, while the multiple lesions in the right hand increased in volume but remained unchanged in number.
LESSONS: This case revealed the CT and Tc-MDP SPECT/CT imaging features of MC. Specifically, SPECT/CT imaging contributed to the diagnosis of clinically asymptomatic bone lesions, and the 3D SPECT/CT fusion allowed a more comprehensive and intuitive view of the lesion by combining anatomy and function.

Bins S, Basak EA, El Bouazzaoui S, et al.
Association between single-nucleotide polymorphisms and adverse events in nivolumab-treated non-small cell lung cancer patients.
Br J Cancer. 2018; 118(10):1296-1301 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: Treatment with PD-1 inhibitors can be hampered by severe auto-immune-related toxicities. Our objective was to identify single-nucleotide polymorphisms (SNPs) in genes previously associated with auto-immunity, which are associated with toxicities in nivolumab-treated NSCLC patients. This was in order to identify patients prone to develop severe toxicities and to gain more insight into the underlying pathobiology.
METHODS: We analysed 322 nivolumab-treated patients and assessed the association with toxicities for seven SNPs in four genes, which are considered contributors to PD-1-directed T-cell responses, i.e., PDCD1, PTPN11, ZAP70 and IFNG. Every SNP was tested for its association with toxicity endpoints. Significant associations were tested in a validation cohort.
RESULTS: A multivariable analysis in the exploration cohort showed that homozygous variant patients for PDCD1 804C>T (rs2227981) had decreased odds for any grade treatment-related toxicities (n = 96; OR 0.4; 95% CI 0.2-1.0; p = 0.039). However, this result could not be validated (n = 85; OR 0.9; 95% CI 0.4-1.9; p = NS).
CONCLUSIONS: Our results show that it is unlikely that the investigated SNPs have a clinical implication in predicting toxicity. A finding, even though negative, that is considered timely and instructive towards further research in biomarker development for checkpoint inhibitor treatments.

Jiang H, Dong L, Gong F, et al.
Inflammatory genes are novel prognostic biomarkers for colorectal cancer.
Int J Mol Med. 2018; 42(1):368-380 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Inflammatory genes serve a crucial role in the pathogenesis of inflammation‑associated tumors. However, as recent studies have mainly focused on the effects of single inflammatory genes on colorectal cancer (CRC), but not on the global interactions between genes, the underlying mechanisms between inflammatory genes and CRC remain unclear. In the current study, two inflammation‑associated networks were constructed based on inflammatory genes, differentially expressed genes (DEGs) in CRC vs. normal samples, and protein‑protein interactions (PPIs). These networks included an inflammation‑related neighbor network (IRNN) and an inflammation‑related DEG network (IRDN). Notably, the results indicated that the inflammatory genes served as important CRC‑associated genes in the IRNN. Certain inflammatory genes were more likely to be network hubs and exhibited higher betweenness centralities, indicating that these inflammatory hub genes had central roles in the communication between genes in the IRNN. By contrast, in the IRDN, functional enrichment analysis revealed that genes were enriched in numerous cancer‑associated functions and pathways. Subsequently, 14 genes in a module were identified in the IRDN as the potential biomarkers associated with disease‑free survival (DFS) in CRC patients in the GSE24550 dataset, the prognosis of which was further validated using three independent datasets (GSE24549, GSE34551 and GSE103479). All 14 genes (including BCAR1, CRK, FYN, GRB2, LCP2, PIK3R1, PLCG1, PTK2, PTPN11, PTPN6, SHC1, SOS1, SRC and SYK) in this module were inflammatory genes, emphasizing the critical role of inflammation in CRC. In conclusion, these findings based on integrated inflammation‑associated networks provided a novel insight that may help elucidate the inflammation‑mediated mechanisms involved in CRC.

Huang KL, Mashl RJ, Wu Y, et al.
Pathogenic Germline Variants in 10,389 Adult Cancers.
Cell. 2018; 173(2):355-370.e14 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.

Dardaei L, Wang HQ, Singh M, et al.
SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors.
Nat Med. 2018; 24(4):512-517 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Most anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung tumors initially respond to small-molecule ALK inhibitors, but drug resistance often develops. Of tumors that develop resistance to highly potent second-generation ALK inhibitors, approximately half harbor resistance mutations in ALK, while the other half have other mechanisms underlying resistance. Members of the latter group often have activation of at least one of several different tyrosine kinases driving resistance. Such tumors are not expected to respond to lorlatinib-a third-generation inhibitor targeting ALK that is able to overcome all clinically identified resistant mutations in ALK-and further therapeutic options are limited. Herein, we deployed a shRNA screen of 1,000 genes in multiple ALK-inhibitor-resistant patient-derived cells (PDCs) to discover those that confer sensitivity to ALK inhibition. This approach identified SHP2, a nonreceptor protein tyrosine phosphatase, as a common targetable resistance node in multiple PDCs. SHP2 provides a parallel survival input downstream of multiple tyrosine kinases that promote resistance to ALK inhibitors. Treatment with SHP099, the recently discovered small-molecule inhibitor of SHP2, in combination with the ALK tyrosine kinase inhibitor (TKI) ceritinib halted the growth of resistant PDCs through preventing compensatory RAS and ERK1 and ERK2 (ERK1/2) reactivation. These findings suggest that combined ALK and SHP2 inhibition may be a promising therapeutic strategy for resistant cancers driven by several different ALK-independent mechanisms underlying resistance.

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