Gene Summary

Gene:TPM3; tropomyosin 3
Aliases: TM3, TM5, TRK, CFTD, NEM1, TM-5, TM30, CAPM1, TM30nm, TPM3nu, TPMsk3, hscp30, HEL-189, HEL-S-82p, OK/SW-cl.5
Summary:This gene encodes a member of the tropomyosin family of actin-binding proteins. Tropomyosins are dimers of coiled-coil proteins that provide stability to actin filaments and regulate access of other actin-binding proteins. Mutations in this gene result in autosomal dominant nemaline myopathy and other muscle disorders. This locus is involved in translocations with other loci, including anaplastic lymphoma receptor tyrosine kinase (ALK) and neurotrophic tyrosine kinase receptor type 1 (NTRK1), which result in the formation of fusion proteins that act as oncogenes. There are numerous pseudogenes for this gene on different chromosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:tropomyosin alpha-3 chain
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 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.

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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

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

Latest Publications: TPM3 (cancer-related)

Miao Q, Ma K, Chen D, et al.
Targeting tropomyosin receptor kinase for cancer therapy.
Eur J Med Chem. 2019; 175:129-148 [PubMed] Related Publications
NTRKs and their expression product tropomyosin receptor kinases (Trks) are widely distributed in mammals. While neural growth factor (NGF)-induced normal Trk activation plays a key role in nerve growth, NTRK alternations occurring in tumor cells were highly correlated to tumor progression and invasion. Recent clinical data from several pan-Trk inhibitors have demonstrated potential and broad applications in various cancers. This intrigues us to summarize the development of inhibitors targeting Trks with different mechanisms of action and their applications in cancer therapy. We believe that this perspective would be of great help in investigating novel anticancer drugs with better therapeutic index.

Penault-Llorca F, Rudzinski ER, Sepulveda AR
Testing algorithm for identification of patients with TRK fusion cancer.
J Clin Pathol. 2019; 72(7):460-467 [PubMed] Free Access to Full Article Related Publications
The neurotrophic tyrosine receptor kinase (

Antunes LCM, Cartell A, de Farias CB, et al.
Tropomyosin-Related Kinase Receptor and Neurotrophin Expression in Cutaneous Melanoma Is Associated with a Poor Prognosis and Decreased Survival.
Oncology. 2019; 97(1):26-37 [PubMed] Related Publications
OBJECTIVE: Normally, activation of tropomyosin-related kinase (TRK) receptors by neurotrophins (NTs) stimulates intracellular pathways involved in cell survival and proliferation. Dysregulation of NT/TRK signaling may affect neoplasm prognosis. Data on NT and TRK expression in melanomas are limited, and it is unclear whether NT/TRK signaling pathways are involved in the origin and progression of this neoplasm.
METHODS: We examined whether NT/TRK expression differs across different cutaneous melanoma grades and subtypes, and whether it is associated with melanoma prognosis and survival. A cross-sectional study was performed in which the expression of TrkA, TrkB, nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) was analyzed by immunohistochemistry of 154 melanoma samples. We investigated NT/TRK expression associations with prognostic factors for melanoma, relapse-free survival (RFS), and overall survival (OS).
RESULTS: Of the 154 melanoma samples, 77 (55.4%) were TrkA immunopositive, 81 (58.3%) were TrkB immunopositive, 113 (81.3%) were BDNF immunopositive, and 104 (75.4%) were NGF immunopositive. We found NT/TRK expression associated strongly with several clinical prognostic factors, including the tumor-node-metastasis stage (p < 0.001), histological subtype (p < 0.001), and Clark level (p < 0.05), as well as with a worse OS (p < 0.05 for all, except TrkB) and RFS (p < 0.05 for all).
CONCLUSIONS: Our results show strong associations of NT/TRK expression with melanoma stage progression and a poor prognosis.

Humayun-Zakaria N, Arnold R, Goel A, et al.
Tropomyosins: Potential Biomarkers for Urothelial Bladder Cancer.
Int J Mol Sci. 2019; 20(5) [PubMed] Free Access to Full Article Related Publications
Despite the incidence and prevalence of urothelial bladder cancer (UBC), few advances in treatment and diagnosis have been made in recent years. In this review, we discuss potential biomarker candidates: the tropomyosin family of genes, encoded by four loci in the human genome. The expression of these genes is tissue-specific. Tropomyosins are responsible for diverse cellular roles, most notably based upon their interplay with actin to maintain cellular processes, integrity and structure. Tropomyosins exhibit a large variety of splice forms, and altered isoform expression levels have been associated with cancer, including UBC. Notably, tropomyosin isoforms are detectable in urine, offering the potential for non-invasive diagnosis and risk-stratification. This review collates the basic knowledge on tropomyosin and its isoforms, and discusses their relationships with cancer-related phenomena, most specifically in UBC.

Brooks RA, Tritchler DS, Darcy KM, et al.
GOG 8020/210: Risk stratification of lymph node metastasis, disease progression and survival using single nucleotide polymorphisms in endometrial cancer: An NRG oncology/gynecologic oncology group study.
Gynecol Oncol. 2019; 153(2):335-342 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: The ability to stratify a patient's risk of metastasis and survival permits more refined care. A proof of principle study was undertaken to investigate the relationship between single nucleotide polymorphisms (SNPs) in literature based candidate cancer genes and the risk of nodal metastasis and clinical outcome in endometrioid endometrial cancer (EEC) patients.
METHODS: Surgically-staged EEC patients from the Gynecologic Oncology Group or Washington University School of Medicine with germline DNA available were eligible. Fifty-four genes represented by 384 SNPs, were evaluated by Illumina Custom GoldenGate array. Association with lymph node metastases was the primary outcome. Progression-free survival (PFS) and overall survival (OS) was also evaluated.
RESULTS: 361 SNPs with high quality genotype data were evaluated in 337 patients with outcome data. Five SNPs in CXCR2 had an odds ratio (OR) between 0.68 and 0.70 (p-value ≤ 0.025). The A allele rs946486 in ABL had an OR of 1.5 (p-value = 0.01) for metastasis. The G allele in rs7795743 in EGFR had an OR for metastasis of 0.68 (p-value = 0.02) and hazard ratio (HR) for progression of 0.66 (p-value = 0.004). Importantly, no SNP met genome wide significance after adjusting for multiple test correcting and clinical covariates. The A allele in rs2159359 SNP in NME1 and the G allele in rs13222385 in EGFR were associated with worse OS. Both exhibited genome wide significance; rs13222385 remained significant after adjusting for prognostic clinical variables.
CONCLUSION: SNPs in cancer genes including rs2159359 SNP in NME1 and rs13222385 in EGFR may stratify risk in EEC and are prioritized for further investigation.

Hannafon BN, Gin AL, Xu YF, et al.
Metastasis-associated protein 1 (MTA1) is transferred by exosomes and contributes to the regulation of hypoxia and estrogen signaling in breast cancer cells.
Cell Commun Signal. 2019; 17(1):13 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Exosomes are small membrane-bound vesicles that contribute to tumor progression and metastasis by mediating cell-to-cell communication and modifying the tumor microenvironment at both local and distant sites. However, little is known about the predominant factors in exosomes that contribute to breast cancer (BC) progression. MTA1 is a transcriptional co-regulator that can act as both a co-activator and co-repressor to regulate pathways that contribute to cancer development. MTA1 is also one of the most up-regulated proteins in cancer, whose expression correlates with cancer progression, poor prognosis and increased metastatic potential.
METHODS: We identified MTA1 in BC exosomes by antibody array and confirmed expression of exosome-MTA1 across five breast cancer cells lines. Ectopic expression of tdTomato-tagged MTA1 and exosome transfer were examined by fluorescent microscopy. CRISPR/Cas9 genetic engineering was implemented to knockout MTA1 in MCF7 and MDA-MB-231 breast cancer cells. Reporter assays were used to monitor hypoxia and estrogen receptor signaling regulation by exosome-MTA1 transfer.
RESULTS: Ectopic overexpression of tdTomato-MTA1 in BC cell lines demonstrated exosome transfer of MTA1 to BC and vascular endothelial cells. MTA1 knockout in BC cells reduced cell proliferation and attenuated the hypoxic response in these cells, presumably through its co-repressor function, which could be rescued by the addition of exosomes containing MTA1. On the other hand, consistent with its co-activator function, estrogen receptor signaling was enhanced in MTA1 knockout cells and could be reversed by addition of MTA1-exosomes. Importantly, MTA1 knockout sensitized hormone receptor negative cells to 4-hydroxy tamoxifen treatment, which could be reversed by the addition of MTA1-exosomes.
CONCLUSIONS: This is the first report showing that BC exosomes contain MTA1 and can transfer it to other cells resulting in changes to hypoxia and estrogen receptor signaling in the tumor microenvironment. These results, collectively, provide evidence suggesting that exosome-mediated transfer of MTA1 contributes to BC progression by modifying cellular responses to important signaling pathways and that exosome-MTA1 may be developed as a biomarker and therapeutic target for BC.

Wang Y, Zhang C, Mai L, et al.
PRR11 and SKA2 gene pair is overexpressed and regulated by p53 in breast cancer.
BMB Rep. 2019; 52(2):157-162 [PubMed] Free Access to Full Article Related Publications
Our previous study found that two novel cancer-related genes, PRR11 and SKA2, constituted a classic gene pair that was regulated by p53 and NF-Y in lung cancer. However, their role and regulatory mechanism in breast cancer remain elusive. In this study, we found that the expression levels of PRR11 and SKA2 were upregulated and have a negative prognotic value in breast cancer. Loss-of-function experiments showed that RNAi-mediated knockdown of PRR11 and/or SKA2 inhibited proliferation, migration, and invasion of breast cancer cells. Mechanistic experiments revealed that knockdown of PRR11 and/or SKA2 caused dysregulation of several downstream genes, including CDK6, TPM3, and USP12, etc. Luciferase reporter assays demonstrated that wild type p53 significantly repressed the PRR11-SKA2 bidirectional promoter activity, but not NF-Y. Interestingly, NF-Y was only essential for and correlated with the expression of PRR11, but not SKA2. Consistently, adriamycin-induced (ADR) activation of endogenous p53 also caused significant repression of the PRR11 and SKA2 gene pair expression. Notably, breast cancer patients with lower expression levels of either PRR11 or SKA2, along with wild type p53, exhibited better disease-free survival compared to others with p53 mutations and/or higher expression levels of either PRR11 or SKA2. Collectively, our study indicates that the PRR11 and SKA2 transcription unit might be an oncogenic contributor and might serve as a novel diagnostic and therapeutic target in breast cancer. [BMB Reports 2019; 52(2): 157-162].

Remoué A, Conan-Charlet V, Bourhis A, et al.
Non-secretory breast carcinomas lack NTRK rearrangements and TRK protein expression.
Pathol Int. 2019; 69(2):94-96 [PubMed] Related Publications
Anti-TRK targeted therapies offer opportunities to treat patients with advanced NTRK1/2/3-rearranged cancers. Beyond NTRK-rearranged secretory breast carcinomas, little is known about NTRK rearrangements and the expression of TRK proteins in non-secretory breast carcinomas. We search for TRK proteins expressions using pan-TRK immunohistochemistry and NTRK1, NTRK2 and NTRK3 rearrangements using fluorescent in situ hybridization (FISH) tests in a set of tissue microarray included breast carcinomas. Only 1/339 invasive breast carcinomas, the only example of secretory subtype, was positive using pan-TRK immunohistochemistry and harboured a NTRK-rearrangement (NTRK1 positive FISH test). According to our results, druggable NTRK rearrangements and related-TRK proteins expression are not encountered in non-secretory breast carcinomas.

Somasundaram DB, Aravindan S, Yu Z, et al.
Droplet digital PCR as an alternative to FISH for MYCN amplification detection in human neuroblastoma FFPE samples.
BMC Cancer. 2019; 19(1):106 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: MYCN amplification directly correlates with the clinical course of neuroblastoma and poor patient survival, and serves as the most critical negative prognostic marker. Although fluorescence in situ hybridization (FISH) remains the gold standard for clinical diagnosis of MYCN status in neuroblastoma, its limitations warrant the identification of rapid, reliable, less technically challenging, and inexpensive alternate approaches.
METHODS: In the present study, we examined the concordance of droplet digital PCR (ddPCR, in combination with immunohistochemistry, IHC) with FISH for MYCN detection in a panel of formalin-fixed paraffin-embedded (FFPE) human neuroblastoma samples.
RESULTS: In 112 neuroblastoma cases, ddPCR analysis demonstrated a 96-100% concordance with FISH. Consistently, IHC grading revealed 92-100% concordance with FISH. Comparing ddPCR with IHC, we observed a concordance of 95-98%.
CONCLUSIONS: The results demonstrate that MYCN amplification status in NB cases can be assessed with ddPCR, and suggest that ddPCR could be a technically less challenging method of detecting MYCN status in FFPE specimens. More importantly, these findings illustrate the concordance between FISH and ddPCR in the detection of MYCN status. Together, the results suggest that rapid, less technically demanding, and inexpensive ddPCR in conjunction with IHC could serve as an alternate approach to detect MYCN status in NB cases, with near-identical sensitivity to that of FISH.

van der Tuin K, Ventayol Garcia M, Corver WE, et al.
Targetable gene fusions identified in radioactive iodine refractory advanced thyroid carcinoma.
Eur J Endocrinol. 2019; 180(4):235-241 [PubMed] Related Publications
Objective Gene alterations leading to activation of the MAPK pathway are of interest for targeted therapy in patients with advanced radioactive iodine refractory (RAI-R) thyroid carcinoma. Due to technical reasons gene fusion analysis in RNA isolated from formalin-fixed tumor tissues has till now been limited. The objective of the present study was to identify targetable gene rearrangements in RNA isolated from formalin-fixed RAI-R thyroid carcinomas. Design Retrospective study in 132 patients with RAI-R thyroid carcinoma (59 papillary-, 24 follicular-, 35 Hürthle cell- and 14 anaplastic thyroid carcinoma). Methods Total nucleic acid (undivided DNA and RNA) was isolated from formalin-fixed tissue. Extensive gene fusion analysis was performed in all samples that tested negative for pathogenic BRAF, NRAS, HRAS and KRAS variants. Results Seven targetable gene fusions were identified in the remaining 60 samples without known DNA variants. This includes frequently reported gene fusions such as CCDC6/RET (PTC1), PRKAR1A/RET (PTC2) and ETV6/NTRK3 , and gene fusions that are less common in thyroid cancer (TPM3/NTRK1, EML4/ALK and EML4/NTRK3). Of note, most gene fusions were detected in papillary thyroid carcinoma and MAPK-associated alterations in Hürthle cell carcinomas are rare (2/35). Conclusion Targetable gene fusions were found in 12% of RAI-R thyroid carcinoma without DNA variants and can be effectively identified in formalin-fixed tissue. These gene fusions might provide a preclinical rationale to include specific kinase inhibitors in the treatment regimen for these patients. The latter intends to restore iodine transport and/or take advantage of the direct effect on tumor cell vitality once progressive disease is seen.

Montgomery MR, Hull EE
Alterations in the glycome after HDAC inhibition impact oncogenic potential in epigenetically plastic SW13 cells.
BMC Cancer. 2019; 19(1):79 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Defects in the type and degree of cellular glycosylation impact oncogenesis on multiple levels. Although the type of glycosylation is determined by protein sequence encoded by the genome, the extent and modifications of glycosylation depends on the activity of biosynthetic enzymes and recent data suggests that the glycome is also subject to epigenetic regulation. This study focuses on the ability of HDAC inhibition to alter glycosylation and to lead to pro-oncogenic alterations in the glycome as assessed by metastatic potential and chemoresistance.
METHODS: Epigenetically plastic SW13 adrenocortical carcinoma cells were treated with FK228, an HDAC inhibitor with high affinity for HDAC1 and, to a lesser extent, HDAC2. In comparing HDAC inhibitor treated and control cells, differential expression of glycome-related genes were assessed by microarray. Differential glycosylation was then assessed by lectin binding arrays and the ability of cellular proteins to bind to glycans was assessed by glycan binding arrays. Differential sensitivity to paclitaxel, proliferation, and MMP activity were also assessed.
RESULTS: Treatment with FK228 alters expression of enzymes in the biosynthetic pathways for a large number of glycome related genes including enzymes in all major glycosylation pathways and several glycan binding proteins. 84% of these differentially expressed glycome-related genes are linked to cancer, some as prognostic markers and others contributing basic oncogenic functions such as metastasis or chemoresistance. Glycan binding proteins also appear to be differentially expressed as protein extracts from treated and untreated cells show differential binding to glycan arrays. The impact of differential mRNA expression of glycosylation enzymes was documented by differential lectin binding. However, the assessment of changes in the glycome is complicated by the fact that detection of differential glycosylation through lectin binding is dependent on the methods used to prepare samples as protein-rich lysates show different binding than fixed cells in several cases. Paralleling the alterations in the glycome, treatment of SW13 cells with FK228 increases metastatic potential and reduces sensitivity to paclitaxel.
CONCLUSIONS: The glycome is substantially altered by HDAC inhibition and these changes may have far-reaching impacts on oncogenesis.

Dudás J, Riml A, Tuertscher R, et al.
Brain-Derived Neurotrophin and TrkB in Head and Neck Squamous Cell Carcinoma.
Int J Mol Sci. 2019; 20(2) [PubMed] Free Access to Full Article Related Publications
We hypothesized that in head and neck squamous cell carcinoma (HNSCC), the neurotrophin brain-derived neurotrophic factor (BDNF) and its high affinity receptor TrkB regulate tumor cell survival, invasion, and therapy resistance. We used in situ hybridization for

Fabbro M, Moore KN, Dørum A, et al.
Efficacy and safety of niraparib as maintenance treatment in older patients (≥ 70 years) with recurrent ovarian cancer: Results from the ENGOT-OV16/NOVA trial.
Gynecol Oncol. 2019; 152(3):560-567 [PubMed] Related Publications
OBJECTIVE: To analyze the safety and efficacy of niraparib in patients aged ≥70 years with recurrent ovarian cancer in the ENGOT-OV16/NOVA trial.
METHODS: The trial enrolled 2 independent cohorts with histologically diagnosed recurrent ovarian, fallopian tube, or peritoneal cancer who responded to platinum rechallenge, on the basis of germline breast cancer susceptibility gene mutation (gBRCAmut) status. Patients were randomized 2:1 to receive niraparib (300 mg) or placebo once daily until disease progression. The primary endpoint was progression-free survival (PFS) by blinded independent central review. Adverse events (AEs) of special interest were based on the known safety profile of poly(ADP-ribose) polymerase inhibitors.
RESULTS: Patients aged ≥70 years in the gBRCAmut cohort receiving niraparib (n = 14) had not yet reached a median PFS compared with a median PFS of 3.7 months for the same age group in the placebo arm (hazard ratio [HR], 0.09 [95% confidence interval (CI), 0.01 to 0.73]). Non-gBRCAmut patients aged ≥70 years receiving niraparib (n = 47) had a median PFS of 11.3 months compared with 3.8 months in the placebo arm (HR, 0.35 [95% CI, 0.18 to 0.71]). Median duration of follow-up in the niraparib arm was 17.3 months in patients ≥70 years and 17.2 months in patients <70 years. Frequency, severity of AEs, and dose reductions in the niraparib arm were similar in patients aged <70 and ≥ 70 years population. The most common grade ≥ 3 AEs in patients ≥70 years were hematologic: thrombocytopenia event (34.4%), anemia event (13.1%), and neutropenia event (16.4%).
CONCLUSIONS: For patients ≥70 years of age receiving niraparib as maintenance treatment in the ENGOT-OV16/NOVA trial, PFS benefits and incidence of any grade or serious treatment-emergent AEs were comparable to results in the younger population. Use of niraparib should be considered in this population.

Scott LJ
Larotrectinib: First Global Approval.
Drugs. 2019; 79(2):201-206 [PubMed] Related Publications
Larotrectinib (VITRAKVI

Mitchell CB, Black B, Sun F, et al.
Tropomyosin Tpm 2.1 loss induces glioblastoma spreading in soft brain-like environments.
J Neurooncol. 2019; 141(2):303-313 [PubMed] Related Publications
INTRODUCTION: The brain is a very soft tissue. Glioblastoma (GBM) brain tumours are highly infiltrative into the surrounding healthy brain tissue and invasion mechanisms that have been defined using rigid substrates therefore may not apply to GBM dissemination. GBMs characteristically lose expression of the high molecular weight tropomyosins, a class of actin-associating proteins and essential regulators of the actin stress fibres and focal adhesions that underpin cell migration on rigid substrates.
METHODS: Here, we investigated how loss of the high molecular weight tropomyosins affects GBM on soft matrices that recapitulate the biomechanical architecture of the brain.
RESULTS: We find that Tpm 2.1 is down-regulated in GBM grown on soft substrates. We demonstrate that Tpm 2.1 depletion by siRNA induces cell spreading and elongation in soft 3D hydrogels, irrespective of matrix composition. Tpm 1.7, a second high molecular weight tropomyosin is also down-regulated when cells are cultured on soft brain-like surfaces and we show that effects of this isoform are matrix dependent, with Tpm 1.7 inducing cell rounding in 3D collagen gels. Finally, we show that the absence of Tpm 2.1 from primary patient-derived GBMs correlates with elongated, mesenchymal invasion.
CONCLUSIONS: We propose that Tpm 2.1 down-regulation facilitates GBM colonisation of the soft brain environment. This specialisation of the GBM actin cytoskeleton organisation that is highly suited to the soft brain-like environment may provide novel therapeutic targets for arresting GBM invasion.

Zhang W, Li W, Han X
Skullcapflavone I inhibits proliferation of human colorectal cancer cells via down-regulation of miR-107 expression.
Neoplasma. 2019; 66(2):203-210 [PubMed] Related Publications
Colorectal cancer (CRC) is a common malignant tumor with high global increase and mortality. While Skullcapflavone I has been reported to exert anti-tumor effect in several cancers, its role in CRC has not previously been investigated. Recent studies have also demonstrated that microRNA-107 (miR-107) and tropomyosin alpha-1 (TPM1) are important regulators of cancer cell proliferation, but it remains unclear if these are involved in regulating the effect of Skullcapflavone I on CRC cells. This study therefore assessed the effects of Skullcapflavone I on CRC cell proliferation and investigated miR-107 and TPM1 regulatory effects on this process. The results showed that Skullcapflavone I significantly suppressed cell proliferation and viability and down-regulated PCNA and Cyclin D1protein levels. It also down-regulated miR-107 expression which then promoted TPM1 expression, but miR-107 over-expression abolished Skullcapflavone I anti-proliferative effects. Furthermore, Skullcapflavone I inhibited the activations of MEK/ERK and NF-κB signal pathway activation by regulating TPM1 in HCT116 cells. These results demonstrated that Skullcapflavone I increased the expression of TPM1 by down-regulating miR-107 and inhibiting the MEK/ERK and NF-κB signal pathways. It then inhibited HCT116 cell proliferation, and therefore Skullcapflavone I may provide new methodology in colorectal cancer treatment.

Nakano K, Takahashi S
Translocation-Related Sarcomas.
Int J Mol Sci. 2018; 19(12) [PubMed] Free Access to Full Article Related Publications
Chromosomal translocations are observed in approximately 20% of soft tissue sarcomas (STS). With the advances in pathological examination technology, the identification of translocations has enabled precise diagnoses and classifications of STS, and it has been suggested that the presence of and differences in translocations could be prognostic factors in some translocation-related sarcomas. Most of the translocations in STS were not regarded as targets of molecular therapies until recently. However, trabectedin, an alkylating agent, has shown clinical benefits against translocation-related sarcoma based on a modulation of the transcription of the tumor's oncogenic fusion proteins. Many molecular-targeted drugs that are specific to translocations (e.g., anaplastic lymphoma kinase and tropomyosin kinase related fusion proteins) have emerged. The progress in gene technologies has allowed researchers to identify and even induce new translocations and fusion proteins, which might become targets of molecular-targeted therapies. In this review, we discuss the clinical significance of translocation-related sarcomas, including their diagnoses and targeted therapies.

Ma C, Xie J, Luo C, et al.
OxLDL promotes lymphangiogenesis and lymphatic metastasis in gastric cancer by upregulating VEGF‑C expression and secretion.
Int J Oncol. 2019; 54(2):572-584 [PubMed] Free Access to Full Article Related Publications
Gastric cancer is one of the most malignant tumor types, and its metastasis is a notable cause of mortality. Among the methods of tumor metastasis, lymphatic metastasis is the predominant one in gastric cancer. A previous study reported that the plasma oxidized low‑density lipoprotein (oxLDL) is the risk factor associated with the development of tumors in patients with abnormal lipid metabolism, but the influence of plasma oxLDL in the lymphatic metastasis of gastric cancer remains unclear. In the present study, the concentration of plasma oxLDL from patients with gastric cancer was detected with an ELISA kit, and the lymphatic vessel density in gastric cancer tissues was determined by D2‑40 staining. The correlation analysis of oxLDL concentration and lymphatic vessel density demonstrated that plasma oxLDL was positively correlated with lymphatic metastasis in patients with gastric cancer. Subsequently, the popliteal lymph node metastasis animal experiment with nude mice confirmed that oxLDL could promote the lymphatic metastasis of gastric cancer. Following this, the western blotting and ELISA data demonstrated that oxLDL promoted the expression and secretion of vascular endothelia growth factor (VEGF)‑C in gastric cancer cell lines. Finally, blocking the lectin‑like oxLDL‑1 (LOX‑1) receptor, a specific receptor for oxLDL, and the nuclear factor (NF)‑κB signaling pathway following oxLDL (50 µg/ml) treatment in HGC‑27 cells revealed that oxLDL could activate the NF‑κB signaling pathway mediated by LOX‑1, with subsequent upregulation of VEGF‑C expression, and secretion in and from gastric cancer cells, and finally that it could promote the lymphatic metastasis of gastric cancer. These data indicate the association between the plasma oxLDL and the lymphatic metastasis of gastric cancer, and indicate that oxLDL elimination may be a potential therapeutic target for the prevention and intervention of early lymph node metastasis in gastric cancer.

Pratap S, Scordino TS
Molecular and cellular genetics of non-Hodgkin lymphoma: Diagnostic and prognostic implications.
Exp Mol Pathol. 2019; 106:44-51 [PubMed] Related Publications
Non-Hodgkin lymphoma (NHL) is a diverse collection of malignant neoplasms with lymphoid-cell origin which includes all the malignant lymphomas that are not classified as Hodgkin lymphoma. NHL is one of the most common types of cancer diagnosed in men and women in the developed world. In the United States of America, the past few decades have seen a significant rise in the incidence of NHL and it accounts for about 4% of all cancers now. The overall survival of NHL has improved drastically over the past ten years. This can be attributed to better understanding of pathogenesis, refined classification, enhanced supportive care, and data from collaborative clinical trials. The prognosis of a newly diagnosed NHL patient depends, among other factors, on the specific subtype of lymphoma, stage of the disease, and age of the patient. Advances in the fields of molecular biology and innovations in cytogenetic techniques have led to the discovery of several oncogenic pathways involved in lymphomagenesis, which in turn has amplified the diagnostic and therapeutic approaches available for NHL. Our comprehension of the genetic features that determine the character of NHL, and ultimately guide the therapy, has undergone significant shift and it is essential that scientists as well as clinicians stay in tune with this rapidly evolving knowledge. In this review we have summarized the current concepts about cellular and molecular genetics of the common subtypes of NHL and their clinical implications.

Lopez-Ramirez MA, Pham A, Girard R, et al.
Cerebral cavernous malformations form an anticoagulant vascular domain in humans and mice.
Blood. 2019; 133(3):193-204 [PubMed] Article available free on PMC after 17/01/2020 Related Publications
Cerebral cavernous malformations (CCMs) are common brain vascular dysplasias that are prone to acute and chronic hemorrhage with significant clinical sequelae. The pathogenesis of recurrent bleeding in CCM is incompletely understood. Here, we show that central nervous system hemorrhage in CCMs is associated with locally elevated expression of the anticoagulant endothelial receptors thrombomodulin (TM) and endothelial protein C receptor (EPCR). TM levels are increased in human CCM lesions, as well as in the plasma of patients with CCMs. In mice, endothelial-specific genetic inactivation of

Anderson WJ, Hornick JL
Immunohistochemical correlates of recurrent genetic alterations in sarcomas.
Genes Chromosomes Cancer. 2019; 58(2):111-123 [PubMed] Related Publications
Accurate diagnosis of sarcomas relies on the integration of clinical, histopathological and molecular features. Our understanding of the latter has increased dramatically in recent years with the application of high-throughput sequencing. Concomitantly, the role of immunohistochemistry has expanded as genomic alterations have been exploited by the development of diagnostic markers that serve as surrogates for their detection. Herein, we review selected immunohistochemical markers that can infer the presence of diverse molecular events. These include gene fusions in vascular neoplasms (FOSB, CAMTA1 and TFE3), round cell sarcomas (BCOR, DUX4 and WT1), and fibroblastic/myofibroblastic tumors (STAT6, ALK and Pan-TRK); amplifications in well-differentiated and dedifferentiated liposarcomas (MDM2 and CDK4); and deletions in several aggressive neoplasms (SMARCB1 and SMARCA4). Protein correlates of single nucleotide variants (beta-catenin in desmoid fibromatosis) and epigenetic alterations (histone H3K27me3 in malignant peripheral nerve sheath tumor) and markers discovered through gene expression profiling (NKX2.2 and MUC4) are also discussed.

Kuroda N, Sugawara E, Kusano H, et al.
A review of ALK-rearranged renal cell carcinomas with a focus on clinical and pathobiological aspects.
Pol J Pathol. 2018; 69(2):109-113 [PubMed] Related Publications
ALK-rearranged renal cell carcinoma (ALK-RCC) has been recently proposed and incorporated into the recent World Health Organisation Classification of renal tumours as a provisional entity. In this article, we review ALK-RCC with a focus on clinical and pathobiological aspects. Seventeen cases have been described to date. ALK-RCC accounts for less than 1% of all renal tumours. The age of patients ranges from 6 to 61 years with a mean age of 29.6 years. Grossly, the tumour forms were ill-demarcated or well demarcated solid mass in the renal medulla. Histologically, RCC with VCL-ALK translocation resembles renal medullary carcinoma and mucinous cribriform pattern, signet-ring cell pattern and solid rhabdoid pattern are often observed in RCC with non-VCL-ALK fusion. Immunohistochemically, ALK protein diffusely expresses and TFE3 is often expressed. ALK gene can fuse to VCL, TPM3, EML4, HOOK1 or STRN gene. A break-apart fluorescence in situ hybridisation study is clinically available for the practice of definite diagnosis. ALK inhibitor therapy will provide great benefit for patients with advanced stage of ALK-RCC in the near future.

Cocco E, Scaltriti M, Drilon A
NTRK fusion-positive cancers and TRK inhibitor therapy.
Nat Rev Clin Oncol. 2018; 15(12):731-747 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
NTRK gene fusions involving either NTRK1, NTRK2 or NTRK3 (encoding the neurotrophin receptors TRKA, TRKB and TRKC, respectively) are oncogenic drivers of various adult and paediatric tumour types. These fusions can be detected in the clinic using a variety of methods, including tumour DNA and RNA sequencing and plasma cell-free DNA profiling. The treatment of patients with NTRK fusion-positive cancers with a first-generation TRK inhibitor, such as larotrectinib or entrectinib, is associated with high response rates (>75%), regardless of tumour histology. First-generation TRK inhibitors are well tolerated by most patients, with toxicity profiles characterized by occasional off-tumour, on-target adverse events (attributable to TRK inhibition in non-malignant tissues). Despite durable disease control in many patients, advanced-stage NTRK fusion-positive cancers eventually become refractory to TRK inhibition; resistance can be mediated by the acquisition of NTRK kinase domain mutations. Fortunately, certain resistance mutations can be overcome by second-generation TRK inhibitors, including LOXO-195 and TPX-0005 that are being explored in clinical trials. In this Review, we discuss the biology of NTRK fusions, strategies to target these drivers in the treatment-naive and acquired-resistance disease settings, and the unique safety profile of TRK inhibitors.

Suurmeijer AJH, Dickson BC, Swanson D, et al.
A novel group of spindle cell tumors defined by S100 and CD34 co-expression shows recurrent fusions involving RAF1, BRAF, and NTRK1/2 genes.
Genes Chromosomes Cancer. 2018; 57(12):611-621 [PubMed] Related Publications
Tumors characterized by co-expression of S100 and CD34, in the absence of SOX10, remain difficult to classify. Triggered by a few index cases with monomorphic cytomorphology and distinctive stromal and perivascular hyalinization, immunopositivity for S100 and CD34, and RAF1 and NTRK1 fusions, the authors undertook a systematic review of tumors with similar features. Most of the cases selected were previously diagnosed as low-grade malignant peripheral nerve sheath tumors, while others were deemed unclassified. The tumors were studied with targeted RNA sequencing and/or FISH. A total of 25 cases (15 adults and 10 children) with kinase fusions were identified, including 8 cases involving RAF1, 2 BRAF, 14 NTRK1, and 1 NTRK2 gene rearrangements. Most tumors showed a monomorphic spindle cell proliferation with stromal and perivascular keloidal collagen, in a patternless architecture, with only occasional scattered pleomorphic or multinucleated cells. Most cases showed low cellularity, a low mitotic count, and absence of necrosis. Although a subset showed overlap with lipofibromatosis-like neural tumors, the study group showed distinctive hyalinization and overt malignant features, such as highly cellular fascicular growth and primitive appearance. All tumors showed co-expression of S100 and CD34, ranging from focal to diffuse. SOX10 was negative in all cases. NTRK1 immunohistochemistry showed high levels of expression in all tumors with NTRK1 gene rearrangements. H3K27me3 expression performed in a subset of cases was retained. These findings together with the recurrent gene fusions in RAF1, BRAF, and NTRK1/2 kinases suggest a distinct molecular tumor subtype with consistent S100 and CD34 immunoreactivity.

Ziegler DS, Wong M, Mayoh C, et al.
Brief Report: Potent clinical and radiological response to larotrectinib in TRK fusion-driven high-grade glioma.
Br J Cancer. 2018; 119(6):693-696 [PubMed] Related Publications
Genes encoding TRK are oncogenic drivers in multiple tumour types including infantile fibrosarcoma, papillary thyroid cancer and high-grade gliomas (HGG). TRK fusions have a critical role in tumourigenesis in 40% of infant HGG. Here we report the first case of a TRK fusion-driven HGG treated with larotrectinib-the first selective pan-TRK inhibitor in clinical development. This 3-year-old girl had failed multiple therapies including chemotherapy and radiotherapy. Tumour profiling confirmed an ETV6-NTRK3 fusion. Treatment with larotrectinib led to rapid clinical improvement with near total resolution of primary and metastatic lesions on MRI imaging. This is the first report of a TRK fusion glioma successfully treated with a TRK inhibitor.

Wu X, Kabalane H, Kahli M, et al.
Developmental and cancer-associated plasticity of DNA replication preferentially targets GC-poor, lowly expressed and late-replicating regions.
Nucleic Acids Res. 2018; 46(19):10157-10172 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
The spatiotemporal program of metazoan DNA replication is regulated during development and altered in cancers. We have generated novel OK-seq, Repli-seq and RNA-seq data to compare the DNA replication and gene expression programs of twelve cancer and non-cancer human cell types. Changes in replication fork directionality (RFD) determined by OK-seq are widespread but more frequent within GC-poor isochores and largely disconnected from transcription changes. Cancer cell RFD profiles cluster with non-cancer cells of similar developmental origin but not with different cancer types. Importantly, recurrent RFD changes are detected in specific tumour progression pathways. Using a model for establishment and early progression of chronic myeloid leukemia (CML), we identify 1027 replication initiation zones (IZs) that progressively change efficiency during long-term expression of the BCR-ABL1 oncogene, being twice more often downregulated than upregulated. Prolonged expression of BCR-ABL1 results in targeting of new IZs and accentuation of previous efficiency changes. Targeted IZs are predominantly located in GC-poor, late replicating gene deserts and frequently silenced in late CML. Prolonged expression of BCR-ABL1 results in massive deletion of GC-poor, late replicating DNA sequences enriched in origin silencing events. We conclude that BCR-ABL1 expression progressively affects replication and stability of GC-poor, late-replicating regions during CML progression.

Hung YP, Sholl LM
Diagnostic and Predictive Immunohistochemistry for Non-Small Cell Lung Carcinomas.
Adv Anat Pathol. 2018; 25(6):374-386 [PubMed] Related Publications
Non-small cell lung carcinoma (NSCLC) accounts for significant morbidity and mortality worldwide, with most patients diagnosed at advanced stages and managed increasingly with targeted therapies and immunotherapy. In this review, we discuss diagnostic and predictive immunohistochemical markers in NSCLC, one of the most common tumors encountered in surgical pathology. We highlight 2 emerging diagnostic markers: nuclear protein in testis (NUT) for NUT carcinoma; SMARCA4 for SMARCA4-deficient thoracic tumors. Given their highly aggressive behavior, proper recognition facilitates optimal management. For patients with advanced NSCLCs, we discuss the utility and limitations of immunohistochemistry (IHC) for the "must-test" predictive biomarkers: anaplastic lymphoma kinase, ROS1, programmed cell death protein 1, and epidermal growth factor receptor. IHC using mutant-specific BRAF V600E, RET, pan-TRK, and LKB1 antibodies can be orthogonal tools for screening or confirmation of molecular events. ERBB2 and MET alterations include both activating mutations and gene amplifications, detection of which relies on molecular methods with a minimal role for IHC in NSCLC. IHC sits at the intersection of an integrated surgical pathology and molecular diagnostic practice, serves as a powerful functional surrogate for molecular testing, and is an indispensable tool of precision medicine in the care of lung cancer patients.

Promthet S, Songserm N, Woradet S, et al.
Opisthorchiasis with proinflammatory cytokines (IL-1β and TNF-α) polymorphisms influence risk of intrahepatic cholangiocarcinoma in Thailand: a nested case-control study.
BMC Cancer. 2018; 18(1):846 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Chronic inflammation and repeated infection with Opisthorchis viverrini (O. viverrini) induces intrahepatic cholangiocarcinoma (ICC). Inflammatory cytokines such as interleukin (IL) and tumor necrosis factor (TNF) are substances in the immune system that promote inflammation and causes disease to progress. Genes that help express proinflammatory cytokines can affect an individual's susceptibility to disease, especially in cancer-related chronic inflammation. This study aimed to investigate risk factors for ICC with a focus on opisthorchiasis and polymorphisms of proinflammatory cytokines (IL-1β and TNF-α).
METHODS: This study was a nested case-control study within a cohort study. 219 subjects who developed a primary ICC were identified and matched with two non-cancer controls from the same cohort based on sex and age at recruitment (±3 years). An O. viverrini-IgG antibody was assessed using enzyme linked immunosorbent assay. IL-1β and TNF-α polymorphisms were analyzed using a polymerase chain reaction with high resolution melting analysis. Associations between variables and ICC were assessed using conditional logistic regression.
RESULTS: Subjects with a high infection intensity had higher risk of ICC than those who had a low level (OR = 2.1; 95% CI: 1.2-3.9). Subjects with all genotypes of TNF-α (GG, GA, AA) and high infection intensity were significantly related to an increased risk of ICC (p < 0.05).
CONCLUSIONS: Polymorphisms of IL-1β and TNF-α are not a risk of ICC, but an individual with O. viverrini infection has an effect on all genotypes of the TNF-α gene that might promote ICC. Primary prevention of ICC in high-risk areas is based on efforts to reduce O. viverrini infection.

Mi X, Griffin G, Lee W, et al.
Genomic and clinical characterization of B/T mixed phenotype acute leukemia reveals recurrent features and T-ALL like mutations.
Am J Hematol. 2018; 93(11):1358-1367 [PubMed] Related Publications
The B/T subtype of mixed phenotype acute leukemia (B/T MPAL) is defined by co-expression of antigens of both B- and T-cell lineages on leukemic blasts. Although it has been suggested that multilineage antigen expression portends poor response to chemotherapy, the clinical characteristics and driver mutations that underlie the pathogenesis of this rare subtype of acute leukemia are scarcely known. We identified nine cases of B/T MPAL from multiple institutions and correlated clinical and immunophenotypic findings with next-generation sequencing data. We report that B/T MPAL commonly presents with lymphadenopathy in adolescence and young adulthood. While the tumors have diverse cytogenetic and genomic perturbations, recurrent acquired aberrations include mutations in the putative transcriptional regulator PHF6 and the JAK-STAT and Ras signaling pathways. Alterations were also identified in genes encoding hematopoietic transcription factors, cell cycle regulators/tumor suppressors, and chromatin modifying enzymes. The genomic landscape of B/T MPAL strongly resembles that of T-ALL subgroups associated with early developmental arrest, while genetic alterations that are common in B-ALL were rarely seen. Two-thirds of the patients responded to ALL-based chemotherapy with or without stem cell transplantation. Our observations lay the groundwork for further study of the unique biology and clinical trajectory of B/T MPAL.

Vaughn CP, Costa JL, Feilotter HE, et al.
Simultaneous detection of lung fusions using a multiplex RT-PCR next generation sequencing-based approach: a multi-institutional research study.
BMC Cancer. 2018; 18(1):828 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Gene fusion events resulting from chromosomal rearrangements play an important role in initiation of lung adenocarcinoma. The recent association of four oncogenic driver genes, ALK, ROS1, RET, and NTRK1, as lung tumor predictive biomarkers has increased the need for development of up-to-date technologies for detection of these biomarkers in limited amounts of material.
METHODS: We describe here a multi-institutional study using the Ion AmpliSeq™ RNA Fusion Lung Cancer Research Panel to interrogate previously characterized lung tumor samples.
RESULTS: Reproducibility between laboratories using diluted fusion-positive cell lines was 100%. A cohort of lung clinical research samples from different origins (tissue biopsies, tissue resections, lymph nodes and pleural fluid samples) were used to evaluate the panel. We observed 97% concordance for ALK (28/30 positive; 71/70 negative samples), 95% for ROS1 (3/4 positive; 19/18 negative samples), and 93% for RET (2/1 positive; 13/14 negative samples) between the AmpliSeq assay and other methodologies.
CONCLUSION: This methodology enables simultaneous detection of multiple ALK, ROS1, RET, and NTRK1 gene fusion transcripts in a single panel, enhanced by an integrated analysis solution. The assay performs well on limited amounts of input RNA (10 ng) and offers an integrated single assay solution for detection of actionable fusions in lung adenocarcinoma, with potential savings in both cost and turn-around-time compared to the combination of all four assays by other methods.

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