Gene Summary

Gene:DMPK; DM1 protein kinase
Aliases: DM, DM1, DMK, MDPK, DM1PK, MT-PK
Summary:The protein encoded by this gene is a serine-threonine kinase that is closely related to other kinases that interact with members of the Rho family of small GTPases. Substrates for this enzyme include myogenin, the beta-subunit of the L-type calcium channels, and phospholemman. The 3' untranslated region of this gene contains 5-38 copies of a CTG trinucleotide repeat. Expansion of this unstable motif to 50-5,000 copies causes myotonic dystrophy type I, which increases in severity with increasing repeat element copy number. Repeat expansion is associated with condensation of local chromatin structure that disrupts the expression of genes in this region. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jul 2016]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:myotonin-protein kinase
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 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.

Tag cloud generated 30 August, 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: DMPK (cancer-related)

Osborne JR, Kondraciuk JD, Rice SL, et al.
Thyroid Cancer Brain Metastasis: Survival and Genomic Characteristics of a Large Tertiary Care Cohort.
Clin Nucl Med. 2019; 44(7):544-549 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
PURPOSE: Brain metastases (BMs) in patients with differentiated thyroid cancer (DTC) are rare but associated with poor prognosis. We examined risk factors for overall survival (OS) in this population and explored the pattern of genomic alterations.
METHODS: Single-institution, retrospective review of all patients with DTC from January 2000 to November 2016 identified 79 patients for analysis. Multiple prognostic factors, including age, gender, distal metastasis (DM), diagnosis time, DM sites, BM diagnosis time, BM number and size, genomic sequencing data, craniectomy, external beam radiation therapy, and kinase inhibitor therapies, were evaluated. Univariate and multivariate analyses were performed.
RESULTS: Median survival after BM was 18 months. One- and 3-year survival rates were 63% and 33%, respectively. Univariate analysis identified 4 covariates correlated with prolonged survival: time between DTC diagnosis and BM for less than 3 years (P = 0.01), time from initial DM diagnosis to BM for 22 months or less (P = 0.03), 3 BM sites or fewer (P = 0.002), and craniectomy (P = 0.05). Multivariate model revealed 3 variables associated with OS: DTC diagnosis to BM time of less than 3 years (P = 0.04), craniectomy (P = 0.06), and patients with fewer than 3 BM sites (P = 0.06). The majority of patients with BM had a telomerase reverse transcriptase promoter mutation, However, mutational status was not an independent predictor of survival.
CONCLUSIONS: For BM from DTC, time interval between DTC diagnosis and BM, number of BM sites, and craniectomy were independently associated with OS. Further studies are needed to define the role of genomic mutations in advanced cancer.

Su L, Gao S, Tan Y, et al.
CSF3R mutations were associated with an unfavorable prognosis in patients with acute myeloid leukemia with CEBPA double mutations.
Ann Hematol. 2019; 98(7):1641-1646 [PubMed] Related Publications
The aim of this study was to explore the clinical features and prognostic significance of CSF3R mutations in AML patients with CEBPA double mutations (CEBPA

Ben Hamou A, Espiard S, Do Cao C, et al.
Systematic thyroid screening in myotonic dystrophy: link between thyroid volume and insulin resistance.
Orphanet J Rare Dis. 2019; 14(1):42 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
BACKGROUND: Myotonic dystrophy (DM1), a neuromuscular disease related to DMPK gene mutations, is associated to endocrine disorders and cancer. A routine endocrine work-up, including thyroid ultrasound (US), was conducted in 115 genetically-proven DM1 patients in a neuromuscular reference center. The aim of this study was to determine the prevalence and the causes of US thyroid abnormalities in DM1.
RESULTS: In the whole population (age 45.1 ± 12.2 years, 61.7% female), palpable nodules or goiters were present in 29.2%. The percentage of US goiter (thyroid volume > 18 mL) and US nodules were, respectively, 38.3 and 60.9%. Sixteen of the 115 patients had a thyroidectomy, after 22 fine-needle aspiration cytology guided by thyroid imaging reporting and data system (TIRADS) classification. Six micro- (1/6 pT3) and 3 macro-papillary thyroid carcinoma (PTCs) (2/3 intermediate risk) were diagnosed (7.9% of 115). Thyroid US led to the diagnosis of 4 multifocal and 2 unifocal (including 1 macro-PTC) non-palpable PTCs. Ultrasound thyroid volume was positively correlated to body mass index (BMI) (p = 0.015) and parity (p = 0.036), and was inversely correlated to TSH (p < 0.001) and vitamin D levels (p = 0.023). The BMI, the frequencies of glucose intolerance and PTC were significantly higher in UsGoiter versus non-UsGoiter groups.
CONCLUSION: In this systematically screened DM1 cohort, the frequency of UsGoiter, mainly associated to BMI, was about 40%, US nodules 60%, thyroidectomies 13-14%, and PTCs 8%, two-thirds of them being micro-PTCs with good prognosis. Therefore, a systematic screening remains debatable. A targeted US screening in case of clinical abnormality or high BMI seems more appropriate.

Malinen MM, Ito K, Kang HE, et al.
Protein expression and function of organic anion transporters in short-term and long-term cultures of Huh7 human hepatoma cells.
Eur J Pharm Sci. 2019; 130:186-195 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
Human-derived hepatic cell lines are a valuable alternative to primary hepatocytes for drug metabolism, transport and toxicity studies. However, their relevance for investigations of drug-drug and drug-organic anion (e.g., bile acid, steroid hormone) interactions at the transporter level remains to be established. The aim of the present study was to determine the suitability of the Huh7 cell line for transporter-dependent experiments. Huh7 cells were cultured for 1 to 4 weeks and subsequently were analyzed for protein expression, localization and activity of solute carrier (SLC) and ATP-binding cassette (ABC) transporters involved in organic anion transport using liquid chromatography-tandem mass spectroscopy, immunocytochemistry, and model substrates [

Wang Y, Liu Z, Lian B, et al.
Integrative Analysis of Dysfunctional Modules Driven by Genomic Alterations at System Level Across 11 Cancer Types.
Comb Chem High Throughput Screen. 2018; 21(10):771-783 [PubMed] Related Publications
AIM AND OBJECTIVE: Integrating multi-omics data to identify driver genes and key biological functions for tumorigenesis remains a major challenge.
METHOD: A new computational pipeline was developed to identify the Driver Mutation-Differential Co-Expression (DM-DCE) modules based on dysfunctional networks across 11 TCGA cancers.
RESULTS: Functional analyses provided insight into the properties of various cancers, and found common cellular signals / pathways of cancers. Furthermore, the corresponding network analysis identified conservations or interactions across different types of cancers, thus the crosstalk between the key signaling pathways, immunity and cancers was found. Clinical analysis also identified key prognostic / survival patterns.
CONCLUSION: Taken together, our study sheds light on both cancer-specific and cross-cancer characteristics systematically.

Wang Y, Yang R, Wang X, et al.
Evaluation of the correlation of vasculogenic mimicry, Notch4, DLL4, and KAI1/CD82 in the prediction of metastasis and prognosis in non-small cell lung cancer.
Medicine (Baltimore). 2018; 97(52):e13817 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
Vasculogenic mimicry (VM) is a new blood supply style in tumors and has long been treated as a useful factor in malignant tumor metastasis and prognosis. Notch4 (a marker of Notch signaling pathway receptors), DLL4 (a marker of Notch signaling pathway ligands) and KAI1/CD82 (a suppressor gene of tumor metastasis) are all effective predictive factors for tumor metastasis. In this study, we analyzed correlations among VM, Notch4, DLL4, and KAI1/CD82 in non-small cell lung cancer (NSCLC), and their respective associations with patients' clinicopathological parameters and survival rate in NSCLC.Positive rates of VM, Notch4, DLL4, and KAI1/CD82 in 189 whole NSCLC specimens were detected by histochemical and immunohistochemical staining. Moreover, patients' clinicopathological information was also collected.Positive rates of VM, Notch4, and DLL4 were significantly higher, and levels of KAI1/CD82 were significantly lower in NSCLC than in normal lung tissues. Positive rates of VM, Notch4, and DLL4 were positively associated with tumor size, lymph node metastasis (LNM), distant metastasis (DM) and tumor-node-metastasis (TNM) stage, and inversely with patients, overall survival (OS) time and positive rate of DLL4 were positively associated with tumor grade. Levels of KAI1/CD82 were negatively associated with tumor size, LNM, DM, and TNM stage. The KAI1/CD82+ subgroup had significantly longer OS time than did the KAI1/CD82- subgroup. In multivariate analysis, high VM, Notch4, DLL4 levels, tumor size, LNM, DM, TNM stage, and low KAI1/CD82 levels were potential to be independent prognostic factors for overall survival time (OST) in NSCLC patients.VM and the expression of Notch4, DLL4, and KAI1/CD82 represent promising markers for tumor metastasis and prognosis, and maybe potential therapeutic targets for NSCLC.

Li H, Xu X, Liu Y, et al.
MMP7 Induces T-DM1 Resistance and Leads to the Poor Prognosis of Gastric Adenocarcinoma
Anticancer Agents Med Chem. 2018; 18(14):2010-2016 [PubMed] Related Publications
BACKGROUND: Gastric adenocarcinoma is one of the most common and lethal cancer types and is known as the second leading cause of cancer-related death of Asian adults, early diagnosis based on either pathology or molecular biology could be one of the most efficient ways to improve the outcomes of gastric adenocarcinoma patients.
METHODS: Quantitative Real-Time PCR and Western-blot were used in detection of mRNA and protein expression. Lentivirus infection was used to overexpression or knock down target gene. Alarma blue assay was used to monitor cells proliferation. Flow cytometry analysis was performed to test protein expression and apoptosis level. Immunohistochemistry was used to identify protein expression in tissue. Statistical differences between two groups are evaluated by two-tailed t-tests. The comparison among multiple groups is performed by one-way Analysis of Variance (ANOVA) followed by Dunnett's posttest. The statistical significance of the Kaplan-Meier survival plot is determined by log-rank analysis.
RESULTS: MMP7 as one of the most up-regulated genes in T-DM1 resistant NCI-N87 gastric adenocarcinoma cells compared to matched naïve cell lines. T-DM1 resistant NCI-N87 cell lines by exposed to T-DM1 in vitro. Exogenous overexpression of MMP7 promotes T-DM1 resistance and tumor growth in NCI-N87 cell lines while MMP7 knockdown enhanced sensitivity to T-DM1 in T-DM1 resistant NCI-N87 cell lines established previously. MMP7 was enriched in high WHO grade GC samples and implies poor outcomes for these patients. DKK1 as one of the most correlated genes to MMP7 in gastric adenocarcinoma and knock-down of DKK1 or inhibition of Wnt/β-catenin pathway led to a decreased expression of MMP7 and resistance to T-DM1.
CONCLUSION: DKK1 and Wnt/β-catenin-dependent activation of MMP7 induces T-DM1 resistance and leads to the poor prognosis of gastric adenocarcinoma, which might be a novel potential therapeutical target for T-DM1 resistant gastric adenocarcinoma.

Portaro S, Naro A, Guarneri C, et al.
Hemangiomas of the tongue and the oral cavity in a myotonic dystrophy type 1 patient: A case report.
Medicine (Baltimore). 2018; 97(48):e13448 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
RATIONALE: Myotonic dystrophy type 1 (DM1) is an autosomal dominant disease caused by a cytosine, guanine, thymine (CTG) trinucleotide repeat expansion in the non-coding region of dystrophia myotonica protein kinase gene, causing a multisystem involvement. To date, few studies have been performed to evaluate skin features in DM1 patients, but none reported on the possible association between the disease and tongue hemangiomas.
PATIENTS CONCERNS: We report a case of a 63-year-old woman affected by DM1 and presenting, at the intraoral examination, several swelling and buish lesions occurring on buccal and palatal mucosa, and in the anterior two-thirds and margins of the tongue.
DIAGNOSIS: Multiple tongue hemangiomas in DM1 patient.
INTERVENTIONS: Color Doppler ultrasound revealed hypoechoic lesions with intermittent color picking suggestive of vascular lesion. Surgical excision was performed under general anesthesia. Histopathological examination was compatible with the diagnosis of cavernous hemangiomas.
OUTCOMES: At 6 months follow-up, a part from the cosmetic deformity, patient's hemangiomas did not bleed, but caused functional problems with speaking, mastication, and deglutition, in addition to the same symptoms induced by DM1.
LESSONS: This case may add new details to better characterize the DM1 phenotype, suggesting that even tongue hemangiomas may be part of the DM1 multisystem involvement.

Zhou J, Yang Y, Zhang Y, et al.
A meta-analysis on the role of pleiotrophin (PTN) as a prognostic factor in cancer.
PLoS One. 2018; 13(11):e0207473 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
BACKGROUND: Some researchers reported that pleiotrophin (PTN) is associated with the development and metastasis of various tumors and it is a poor prognostic factor for the tumor patients. However, the results of other researches are inconsistent with them. It is obliged to do a meta-analysis to reach a definite conclusion.
METHODS: The published studies relevant to PTN were searched in the databases including PubMed, Embase and Web of Science until March 20, 2018. A meta-analysis was conducted to evaluate the role of PTN in clinicopathological characteristics and overall survival (OS) of cancer patients.
RESULTS: Our meta-analysis indicated that the high expression of PTN was remarkably associated with advanced TNM stage (OR = 2.79, 95%CI: 1.92-4.06, P<0.00001) and poor OS (HR = 1.77, 95%CI: 1.41-2.22, P<0.00001) in tumor patients. The expression of PTN was not associated with tumor size (OR = 1.12, 95% CI: 0.55-2.26, P = 0.76), lymph node metastasis (LNM) (OR = 1.95, 95%CI: 0.62-6.12, P = 0.25), distant metastasis (DM) (OR = 2.78, 95%CI: 0.72-10.74, P = 0.14) and histological grade (OR = 1.95, 95%CI: 0.98-3.87, P = 0.06).
CONCLUSION: The high expression of PTN is significantly relevant to the advanced TNM stage and poor OS in tumor patients. PTN can serve as a promising biomarker to predict unfavorable survival outcomes, and it may be a potential target for tumor treatment.

Gianferante DM, Rotunno M, Dean M, et al.
Whole-exome sequencing of nevoid basal cell carcinoma syndrome families and review of Human Gene Mutation Database PTCH1 mutation data.
Mol Genet Genomic Med. 2018; 6(6):1168-1180 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
BACKGROUND: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder with variable expression and nearly complete penetrance. PTCH1 is the major susceptibility locus and has no known hot spots or genotype-phenotype relationships.
METHODS: We evaluated 18 NBCCS National Cancer Institute (NCI) families plus PTCH1 data on 333 NBCCS disease-causing mutations (DM) reported in the Human Gene Mutation Database (HGMD). National Cancer Institute families underwent comprehensive genomic evaluation, and clinical data were extracted from NCI and HGMD cases. Genotype-phenotype relationships were analyzed using Fisher's exact tests focusing on mutation type and PTCH1 domains.
RESULTS: PTCH1 pathogenic mutations were identified in 16 of 18 NCI families, including three previously mutation-negative families. PTCH1 mutations were spread across the gene with no hot spot. After adjustment for multiple tests, a statistically significant genotype-phenotype association was observed for developmental delay and gross deletion-insertions (p = 9.0 × 10
CONCLUSION: Overall, 89% of our NCI families had a pathogenic PTCH1 mutation. The identification of PTCH1 mutations in previously mutation-negative families underscores the importance of repeated testing when new technologies become available. Additional clinical information linked to mutation databases would enhance follow-up and future studies of genotype-phenotype relationships.

Al-Saden N, Cai Z, Reilly RM
Tumor uptake and tumor/blood ratios for [
Nucl Med Biol. 2018; 67:43-51 [PubMed] Related Publications
INTRODUCTION: Our objective was to determine correlations between the tumor uptake and T/B ratios for
METHODS: The tumor and normal tissue uptake and T/B ratios for
RESULTS: Uptake of
CONCLUSIONS: Based on the direct correlations between the T/B ratio for

Wang Y, Qian M, Ruan P, et al.
Detection of epigenetic field defects using a weighted epigenetic distance-based method.
Nucleic Acids Res. 2019; 47(1):e6 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
Identifying epigenetic field defects, notably early DNA methylation alterations, is important for early cancer detection. Research has suggested these early methylation alterations are infrequent across samples and identifiable as outlier samples. Here we developed a weighted epigenetic distance-based method characterizing (dis)similarity in methylation measures at multiple CpGs in a gene or a genetic region between pairwise samples, with weights to up-weight signal CpGs and down-weight noise CpGs. Using distance-based approaches, weak signals that might be filtered out in a CpG site-level analysis could be accumulated and therefore boost the overall study power. In constructing epigenetic distances, we considered both differential methylation (DM) and differential variability (DV) signals. We demonstrated the superior performance of the proposed weighted epigenetic distance-based method over non-weighted versions and site-level EWAS (epigenome-wide association studies) methods in simulation studies. Application to breast cancer methylation data from Gene Expression Omnibus (GEO) comparing normal-adjacent tissue to tumor of breast cancer patients and normal tissue of independent age-matched cancer-free women identified novel epigenetic field defects that were missed by EWAS methods, when majority were previously reported to be associated with breast cancer and were confirmed the progression to breast cancer. We further replicated some of the identified epigenetic field defects.

Zhang YJ, Ma YS, Xia Q, et al.
MicroRNA‑mRNA integrated analysis based on a case of well‑differentiated thyroid cancer with both metastasis and metastatic recurrence.
Oncol Rep. 2018; 40(6):3803-3811 [PubMed] Related Publications
The incidence of well‑differentiated thyroid cancer (WDTC) is rapidly increasing. Poor survival follows distant metastasis (DM) and recurrence. In the present study, we aimed to analyze the expression alterations in different stages of WDTC and the regulatory mechanism of DM and the recurrence of DM. A male patient diagnosed with follicular thyroid cancer and distant metastasis in the eleventh thoracic vertebrae received total thyroidectomy and the removal of a metastatic lesion. A local relapse was found in the vertebrae after four‑time iodine‑131 treatment. We performed mRNA and microRNA microarray on the paracancerous, cancerous, metastatic and metastatic recurrent tissue. In combination with the data of The Cancer Genome Atlas (TCGA), we used bioinformatics approaches to analyze the common alterations and microRNA‑mRNA interactions among the processes of tumorigenesis and metastasis. Metastatic lesions and recurrent lesions were used to investigate the molecular mechanism of tumor evolution and recurrence in this case. A total of four mRNAs and two microRNAs were newly found to be related to patient survival in WDTC. The microRNA‑mRNA interactions were predicted for the overlapped mRNAs and microRNAs. Lineage deregulation of genes, such as C‑X‑C motif chemokine receptor 4 (CXCR4) and thyroglobulin (TG) were found from the tumorigenic stage to the metastatic stage. The ribosome pathway was highly enriched in the bone metastasis compared with the cancerous tissue. The downstreaming effects of p53 were impaired in the recurrent lesion due to deregulation of several functional genes. The integrated analysis with TCGA data indicated several prognostic markers and regulatory networks for potential treatment. Our results also provided possible molecular mechanisms in which the ribosome and p53 pathways may respectively contribute to bone metastasis and local recurrence of metastasis.

Cai M, Zhang H, Hou L, et al.
Inhibiting homologous recombination decreases extrachromosomal amplification but has no effect on intrachromosomal amplification in methotrexate-resistant colon cancer cells.
Int J Cancer. 2019; 144(5):1037-1048 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
Gene amplification, which involves the two major topographical structures double minutes (DMs) and homegeneously stained region (HSR), is a common mechanism of treatment resistance in cancer and is initiated by DNA double-strand breaks. NHEJ, one of DSB repair pathways, is involved in gene amplification as we demonstrated previously. However, the involvement of homologous recombination, another DSB repair pathway, in gene amplification remains to be explored. To better understand the association between HR and gene amplification, we detected HR activity in DM- and HSR-containing MTX-resistant HT-29 colon cancer cells. In DM-containing MTX-resistant cells, we found increased homologous recombination activity compared with that in MTX-sensitive cells. Therefore, we suppressed HR activity by silencing BRCA1, the key player in the HR pathway. The attenuation of HR activity decreased the numbers of DMs and DM-form amplified gene copies and increased the exclusion of micronuclei and nuclear buds that contained DM-form amplification; these changes were accompanied by cell cycle acceleration and increased MTX sensitivity. In contrast, BRCA1 silencing did not influence the number of amplified genes and MTX sensitivity in HSR-containing MTX-resistant cells. In conclusion, our results suggest that the HR pathway plays different roles in extrachromosomal and intrachromosomal gene amplification and may be a new target to improve chemotherapeutic outcome by decreasing extrachromosomal amplification in cancer.

Daniels B, Girosi F, Tervonen H, et al.
Adherence to prescribing restrictions for HER2-positive metastatic breast cancer in Australia: A national population-based observational study (2001-2016).
PLoS One. 2018; 13(7):e0198152 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
BACKGROUND: Targeted cancer therapy is often complex, involving multiple agents and chemotherapeutic partners. In Australia, prescribing restrictions are put in place to reflect existing evidence of cost-effectiveness of these medicines. As therapeutic options continue to expand, these restrictions may not be perceived to align with best practice and it is not known if their use in the real-world clinic adheres to these restrictions. We examined the treatment of women receiving trastuzumab for HER2-positive metastatic breast cancer (HER2+MBC) to determine the extent to which treatment adhered to national prescribing restrictions.
PATIENTS AND METHODS: Our population-based, retrospective cohort study used dispensing records for every Australian woman initiating publicly-subsidised trastuzumab for HER2+MBC between 2001-2013, followed through 2016. We used group-based trajectory models (GBTMs) to cluster patients, first on their patterns of trastuzumab exposure, and then on their patterns of lapatinib and chemotherapy exposure. We described the characteristics of patients within each cluster, and examined their treatments and combinations of treatments to determine restriction adherence.
RESULTS: Of 5,052 patients initiating trastuzumab, 1,795 (36%) received at least one non-adherent HER2-targeted treatment. The most common non-adherent treatments were trastuzumab combinations involving vinorelbine (24% of non-adherent treatments); capecitabine (24%); and anthracyclines (10%). Non-adherent lapatinib use was observed in 4% of patients. GBTM identified three trastuzumab exposure clusters, each containing three further sub-clusters. The largest proportions of non-adherent treatments were in sub-clusters with longer trastuzumab exposure and more non-taxane chemotherapy. Patients in these sub-clusters were younger than those in sub-clusters with less non-adherent treatment.
CONCLUSIONS: Our study highlights that, even during the relatively simpler treatment era of our study period, a substantial amount of treatment did not adhere to prescribing restrictions. As more trials are conducted exploring pertuzumab and T-DM1 in combination with different chemotherapies and other HER2-targeted therapies, the regulation and funding of HER2-targeted treatment will become more challenging.

Kim S, Park SG, Song YJ, et al.
Analysis of Anticancer Activity and Chemical Sensitization Effects of
Anticancer Res. 2018; 38(7):3853-3861 [PubMed] Related Publications
BACKGROUND/AIM: Dendropanax morbifera (DM) and Commersonia bartramia (CB) are possible candidates for immunotherapy. In this study, the cytotoxicity and chemical sensitization of DM and CB extracts on gynecologic and colon cancers were evaluated.
MATERIALS AND METHODS: The malignant cell lines were cultured and analyzed for cytotoxicity and chemical sensitization. A mouse model was also constructed to make the condition similar to in vivo. Reverse transcription-polymerase chain reaction was conducted to determine alterations in drug-resistant genes.
RESULTS: The extracts from DM and CB showed specific cytotoxicity to malignant cell lines. DM increased chemical sensitivity to cervical and ovarian cancer, while CB showed improved sensitization to endometrial cancer. The effects of the extracts were confirmed using a mouse model. The extracts induced differences in the expression levels of a number of genes related to drug resistance.
CONCLUSION: DM and CB extracts could be novel agents for immunotherapy and chemical sensitization in gynecologic and colon cancers.

Liu Z, Wu G, Lin C, et al.
IGF2BP1 over-expression in skin squamous cell carcinoma cells is essential for cell growth.
Biochem Biophys Res Commun. 2018; 501(3):731-738 [PubMed] Related Publications
The present study examined expression and potential functions of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in human skin squamous cell carcinoma (SCC). We show that IGF2BP1 mRNA and protein expression levels were upregulated in established (A431 line) and primary human skin SCC cells. Its expression was also increased in human skin SCC tissues, as compared to the normal skin tissues. In skin SCC cells, IGF2BP1 silencing or CRISPR/Cas9 knockout decreased levels of IGF2BP1-stablized mRNAs, including IGF2, CD44, Gli1 and Myc. Furthermore, skin SCC cell survival and proliferation were inhibited by IGF2BP1 silencing/knockout. Conversely, forced over-expression of IGF2BP1 further promoted A431 cell survival and proliferation. Furthermore, siRNA-mediated knockdown of IGF2BP1-bound long non-coding RNA THOR ("Lnc-THOR") similarly depleted IGF2BP1-dependent mRNAs, causing inhibition on A431 cell survival and proliferation. In vivo, IGF2BP1 silencing or knockout inhibited A431 tumor xenograft growth in mice. Together, we conclude that IGF2BP1 over-expression in skin SCC cells is essential for cell growth.

Sakai H, Tsurutani J, Iwasa T, et al.
HER2 genomic amplification in circulating tumor DNA and estrogen receptor positivity predict primary resistance to trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer.
Breast Cancer. 2018; 25(5):605-613 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
BACKGROUND: Trastuzumab emtansine (T-DM1) is approved for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC), and has high efficacy. However, some patients exhibit primary resistance to T-DM1, and thus methods that can predict resistance in clinical practice are needed. Genomic analysis of circulating tumor DNA (ctDNA) in plasma is a non-invasive and reproducible method. This study aimed to predict primary resistance to T-DM1 by combining genomic analysis of ctDNA and other clinicopathological features of patients with HER2-positive ABC.
METHODS: The study population comprised 34 patients with HER2-positive ABC who had been treated with T-DM1. Correlations between clinicopathological characteristics of patients and primary resistance to T-DM1 were examined, and HER2 gene copy number and PIK3CA gene mutations were analyzed using plasma ctDNA samples obtained from 16 patients before T-DM1 administration.
RESULTS: Among the 34 patients, nine (26.5%) had progressive disease at the first efficacy analysis; these patients were considered to have primary resistance to T-DM1. No significant difference was found in the rate of primary resistance to T-DM1 between groups. Among 16 patients whose ctDNA was analyzed, four showed primary resistance to T-DM1. These four patients showed negative HER2 gene amplification in ctDNA and were ER-positive and/or PR-positive by immunohistochemistry.
CONCLUSIONS: HER2 gene amplification in ctDNA and ER and PR status may predict primary resistance to T-DM1. A liquid biopsy before the initiation of T-DM1 treatment could be a non-invasive way to predict whether a patient would exhibit primary resistance to T-DM1.

Li G, Guo J, Shen BQ, et al.
Mechanisms of Acquired Resistance to Trastuzumab Emtansine in Breast Cancer Cells.
Mol Cancer Ther. 2018; 17(7):1441-1453 [PubMed] Related Publications
The receptor tyrosine kinase HER2 is overexpressed in approximately 20% of breast cancer, and its amplification is associated with reduced survival. Trastuzumab emtansine (Kadcyla, T-DM1), an antibody-drug conjugate that is comprised of trastuzumab covalently linked to the antimitotic agent DM1 through a stable linker, was designed to selectively deliver DM1 to HER2-overexpressing tumor cells. T-DM1 is approved for the treatment of patients with HER2-positive metastatic breast cancer following progression on trastuzumab and a taxane. Despite the improvement in clinical outcome, many patients who initially respond to T-DM1 treatment eventually develop progressive disease. The mechanisms that contribute to T-DM1 resistance are not fully understood. To this end, we developed T-DM1-resistant

Wu Y, Wan X, Ji F, et al.
Serum miR-658 induces metastasis of gastric cancer by activating PAX3-MET pathway: A population-based study.
Cancer Biomark. 2018; 22(1):111-118 [PubMed] Related Publications
BACKGROUND AND OBJECTIVE: MiR-658, paired box gene 3 (PAX3) and met proto-oncogene (MET) are overexpressed in gastric cancer while PAX3 and MET can be regulated by miRNA. Serum miR-658 may be associated with metastasis of gastric cancer (MGC) by affecting PAX3-MET pathway.
METHODS: Ninety-eight gastric carcinoma patients with distant MGC (DM group) and ninety-six gastric carcinoma patients with no MGC (NM group) were recruited. Serum miR-658 was validated between DM and NM groups by using quantitative reverse transcription PCR (qRT-PCR). PAX3 and MET levels were measured by Western Blot. The molecular mechanism for the function of serum miR-658 was further validated in gastric cell lines.
RESULTS: The results demonstrate that serum level of miR-658 is significantly lower in the NM group than in the DM group (P< 0.001). Meanwhile, the levels of PAX3 and MET are lower in the NM group than in the DM group too (P< 0.01). Both overexpression and silence of miR-658 significantly up-regulate or down-regulate the levels of PAX3 and MET in gastric cell lines (P< 0.05).
CONCLUSIONS: The present findings demonstrate that elevated circulating miR-658 is associated with MGC by activating PAX3-MET pathway.

Huang EY, Chang JC, Chen HH, et al.
Carcinoembryonic antigen as a marker of radioresistance in colorectal cancer: a potential role of macrophages.
BMC Cancer. 2018; 18(1):321 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
BACKGROUND: We sought to identify the carcinoembryonic antigen (CEA) as a marker of radioresistance in rectal cancer.
METHODS: From July 1997 to January 2008, 104 patients with stage II or III rectal cancer who were treated with post-operative radiotherapy (PORT) were included in this study. The doses of radiotherapy ranged from 45 to 54.6 Gy. The CEA levels were measured before surgery. We analyzed the actuarial rates of overall survival (OS), distant metastasis (DM), and local recurrence (LR) using Kaplan-Meier curves. Multivariate analyses were performed with Cox regression models. We used THP-1 monocyte cell lines for macrophage differentiation (M0, M1 or M2). The RNA extracted from the macrophages was analyzed via a genomic method in the core laboratory. The radiosensitivities of CEA-rich LS1034 cells were compared between cells with and without the conditioned media from CEA-stimulated macrophages.
RESULTS: Preoperative CEA levels ≥10 ng/mL were independent predictive factors for OS (p = 0.005), DM (p = 0.026), and LR (p = 0.004). The OS rates among the patients with pretreatment CEA levels < 10 ng/mL and ≥10 ng/mL were 64.5% and 35.9% (p = 0.004), respectively. The corresponding rates of DM were 40.6% and 73.1% (p = 0.024). The corresponding rates of LR were 6.6% and 33.9% (p = 0.002). In the M0 macrophages, exogenous CEA elicited a dose-response relationship with M2 differentiation. In the CEA-stimulated M0 cells, some mRNAs were upregulated by as much as 5-fold, including MMP12, GDF15, and JAG1. In the CEA-stimulated M2 cells, a 4-fold up-regulation of GADD45G mRNA was noted. The conditioned media from the CEA-stimulated M2 cells elicited an increase in the numbers of LS180, SW620, and LS1034 cells after irradiation. CEA caused the M2 differentiation of the macrophages.
CONCLUSION: Pretreatment CEA levels ≥10 ng/mL are a significant risk factor for OS, DM, and LR following PORT for rectal cancer. CEA causes radioresistance in the presence of M2 macrophages. More comprehensive examinations prior to surgery and intensive adjuvant therapy are suggested for patients with CEA levels ≥10 ng/mL. Further studies of these mechanisms are needed.

Zhou Q, Hu W, Zhu W, et al.
Long non coding RNA XIST as a prognostic cancer marker - A meta-analysis.
Clin Chim Acta. 2018; 482:1-7 [PubMed] Related Publications
BACKGROUND: The X inactivate-specific transcript (XIST), derived from XIST gene, is aberrantly expressed in various cancers. High-expression of XIST is related to poor clinical outcome. This meta-analysis evaluated the potential role of XIST as novel predictor of prognosis in human cancer.
MATERIALS AND METHODS: This meta-analysis collected eligible studies about XIST and tumor prognosis through retrieving keywords in Web of Science, PubMed, Embase and the CNKI database, from 1993 to August 21, 2017. The quantitative meta-analysis was carried out with Stata SE12.0 and RevMan3.23 software. The aim was to determine whether XIST expression is associated with cancer prognosis and clinicopathology.
RESULTS: A total of 858 patients from 10 eligible studies were included in the final meta-analysis. Overall, a significant negative association between XIST and overall survival (OS) time (HR = 2.62, 95% CI: 2.18-3.14) was observed. Statistical significance was also showed in subgroup meta-analysis stratified by the country, sample size, follow-up and publication year. It was reported that increased XIST was positively related to advanced clinical TNM stage (OR = 4.03, 95% CI: 2.22-7.30), lymph node metastasis (LNM) (OR = 2.70, 95% CI: 1.73-4.21), distant metastasis (DM) (OR = 2.61, 95% CI: 1.57-4.33) and tumor size (OR = 3.10, 95% CI: 2.24-4.30).
CONCLUSIONS: LncRNA XIST may serve as a potential biomarker to predict solid tumor prognosis. This molecule can be effectively used to predict the clinical and pathological features of cancers.

Fang Z, Cao B, Liao JM, et al.
SPIN1 promotes tumorigenesis by blocking the uL18 (universal large ribosomal subunit protein 18)-MDM2-p53 pathway in human cancer.
Elife. 2018; 7 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
Ribosomal proteins (RPs) play important roles in modulating the MDM2-p53 pathway. However, less is known about the upstream regulators of the RPs. Here, we identify SPIN1 (Spindlin 1) as a novel binding partner of human RPL5/uL18 that is important for this pathway. SPIN1 ablation activates p53, suppresses cell growth, reduces clonogenic ability, and induces apoptosis of human cancer cells. Mechanistically, SPIN1 sequesters uL18 in the nucleolus, preventing it from interacting with MDM2, and thereby alleviating uL18-mediated inhibition of MDM2 ubiquitin ligase activity toward p53. SPIN1 deficiency increases ribosome-free uL18 and uL5 (human RPL11), which are required for SPIN1 depletion-induced p53 activation. Analysis of cancer genomic databases suggests that SPIN1 is highly expressed in several human cancers, and its overexpression is positively correlated with poor prognosis in cancer patients. Altogether, our findings reveal that the oncogenic property of SPIN1 may be attributed to its negative regulation of uL18, leading to p53 inactivation.

Zuradelli M, Masci G, Ferraro E, et al.
Never too old to fight breast cancer: A case report.
Medicine (Baltimore). 2018; 97(9):e9981 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
RATIONALE: Breast cancer is the most common cancer affecting females worldwide and its lifetime risk increases with age. Human epidermal growth factor receptor gene-2 (HER-2) positive breast cancer represents about 20% of all breast cancers, 1 out of 10 is diagnosed in women over 70 years of age. It tends to be more aggressive and to spread more quickly than other subtypes, but the introduction in clinical practice of new anti-HER-2 agents combined with chemotherapy has significantly improved progression free and overall survival. Elderly patients are frequently undertreated because of concerns about their age, performance status, and comorbidities. Here, we report a case of an octogenarian patient treated with T-DM1 with brilliant results.
PATIENT CONCERNS: An 87 years old woman affected with HER-2 positive breast cancer presented progression of disease with lymph node and skin metastases after 3 lines of chemoimmunotherapy.
DIAGNOSES: Breast cancer in elderly patient, lymph node, and skin metastases.
INTERVENTIONS: Chemoimmunotherapy (trastuzumab emtansine).
OUTCOME: Objective response of the disease and significant clinical benefit.
LESSONS: This case clearly suggests that age and comorbidities do not always represent an absolute contraindication to combined treatments.

Dai YJ, Qiu YB, Jiang R, et al.
Concomitant high expression of ERα36, GRP78 and GRP94 is associated with aggressive papillary thyroid cancer behavior.
Cell Oncol (Dordr). 2018; 41(3):269-282 [PubMed] Related Publications
PURPOSE: Papillary thyroid cancer (PTC) is more common in women than in men. It has been suggested that estrogen may be involved in its development, as has previously been shown for breast, endometrial and ovarian cancer. The purpose of this study was to assess correlations between the expression of the estrogen receptor alpha36 (ERα36) and the glucose regulated proteins GRP78 and GRP94 (chaperones involved in glycoprotein folding) and various PTC clinicopathological features, as well as to evaluate the potential usefulness of these three potential oncogenic proteins in the prediction of aggressive PTC behavior.
METHODS: ERα36, GRP78 and GRP94 protein expression in 218 primary PTC tissues and PTC-derived BCPAP cells was examined using immunohistochemistry, Western blotting and immunocytochemistry. The proliferative, invasive and migrative capacities of BCPAP cells in which the respective genes were either exogenously over-expressed or silenced were assessed using BrdU incorporation and Transwell assays, respectively.
RESULTS: We found that ERα36, GRP78 and GRP94 protein expression was upregulated in the primary PTC tissues tested. We also found that ERα36, GRP78 and GRP94 expression modulation affected the proliferation, invasion and migration of PTC-derived BCPAP cells. A positive correlation and a positive feedback loop were noted between ERα36, GRP78 and GRP94 protein expression in the primary PTC tissues and in BCPAP cells, respectively. High ERα36 expression in combination with a high GRP78/ GRP94 expression was found to have a stronger correlation with extrathyroid extension (ETE), lymph node metastasis (LNM), distant metastasis (DM) and high TNM stage than high ERα36 expression in combination with either high GRP78 or high GRP94 expression (p = 0.028 for ETE, p = 0.002 for DM and p ≤ 0.001 for LNM and high TNM stage) or high ERα36 expression alone (p < 0.001 for ETE, LNM, DM and high TNM stage).
CONCLUSIONS: From our data we conclude that a concomitant high expression of ERα36, GRP78 and GRP94 is strongly associated with aggressive PTC behavior and may be used as a predictor for ETE, LNM, DM and high TNM stage.

Mercier KA, Al-Jazrawe M, Poon R, et al.
A Metabolomics Pilot Study on Desmoid Tumors and Novel Drug Candidates.
Sci Rep. 2018; 8(1):584 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
Desmoid tumors (aggressive fibromatosis) are locally invasive soft tissue tumors that lack the ability to metastasize. There are no directed therapies or standard treatment plan, and chemotherapeutics, radiation, and surgery often have temporary effects. The majority of desmoid tumors are related to T41A and S45F mutations of the beta-catenin encoding gene (CTNNB1). Using broad spectrum metabolomics, differences were investigated between paired normal fibroblast and desmoid tumor cells from affected patients. There were differences identified, also, in the metabolomics profiles associated with the two beta-catenin mutations, T41A and S45F. Ongoing drug screening has identified currently available compounds which inhibited desmoid tumor cellular growth by more than 50% but did not affect normal fibroblast proliferation. Two drugs were investigated in this study, and Dasatinib and FAK Inhibitor 14 treatments resulted in unique metabolomics profiles for the normal fibroblast and desmoid tumor cells, in addition to the T41A and S45F. The biochemical pathways that differentiated the cell lines were aminoacyl-tRNA biosynthesis in mitochondria and cytoplasm and signal transduction amino acid-dependent mTORC1 activation. This study provides preliminary understanding of the metabolic differences of paired normal and desmoid tumors cells, their response to desmoid tumor therapeutics, and new pathways to target for therapy.

Miao C, Zhao K, Zhu J, et al.
Clinicopathological and Prognostic Role of Long Noncoding RNA Linc00152 in Various Human Neoplasms: Evidence from Meta-Analysis.
Biomed Res Int. 2017; 2017:6010721 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
Recent researches have demonstrated that long noncoding RNA linc00152 was aberrantly upregulated in multiple tumor types. High expression of linc00152 was associated with poor outcomes in cancer patients. Therefore, we conducted this meta-analysis to evaluate its potential value as a prognostic predictor in various human neoplasms. Eligible studies were searched through several electronic databases including PubMed, Embase, Web of Science, and the Cochrane Library. Eight original studies including 752 cancer patients were ultimately enrolled. Statistical analysis suggested that overexpression of linc00152 was significantly correlated with unfavorable overall survival (OS) (HR = 2.05, 95% CI: 1.59-2.64) and disease-free/progression-free survival (DFS/PFS) (HR = 3.52, 95% CI: 1.82-6.79) in cancer patients. In addition, a significant correlation was observed between aberrant linc000152 expression and lymph node metastasis (LNM) (OR = 2.49, 95% CI: 1.57-3.94) but not in vessel invasion (VI) (OR = 1.02, 95% CI: 0.54-1.93) and distant metastasis (DM) (OR = 0.600, 95% CI: 0.213-1.689). Our meta-analysis demonstrated that high linc00152 expression significantly predicted inferior OS and DFS/PFS in multiple neoplasms, as well as advanced LNM and VI. Linc00152 may serve as a potential indicator in predicting poor outcomes and metastases of diverse cancers.

Saito T, Mizukami H, Umetsu S, et al.
Worsened outcome in patients with pancreatic ductal carcinoma on long-term diabetes: association with E-cadherin1 (CDH1) promoter methylation.
Sci Rep. 2017; 7(1):18056 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
Prevalence of pancreatic ductal carcinoma (PDC) is nearly twice in patients with diabetes mellitus, but the reason for this close association remains obscure. Recently promoter methylation of E-cadherin1 (CDH1) and CDKN2A genes, encoding E-cadherin and P16 respectively, are invoked in development of PDC. It is still unclear whether diabetes affects such epigenetic changes and malignant behavior in PDC. In this study, we studied whether diabetes influences the clinico-pathological profile and methylation status of CDH1 and CDKN2A genes in patients with PDC. PDC subjects were divided into 3 groups; 59 cases without diabetes (non-DM), 17 cases with short-term diabetes (short-DM)(diabetes duration 3 yrs>) and 33 cases with long-term diabetes (long-DM)(≧3 yrs). Compared to non-DM or short-DM, long-DM was associated with a higher histological grade of malignancy and a higher tumor stage. Promoter methylation of both CDH1 and CDKN2A was encountered more frequently in PDC patients with long-DM than non-DM or short DM. Cases with CDH1 promoter methylation showed reduced E-cadherin expression and worsened survival. We consider that the presence of long-DM has a negative impact on the prognosis of PDC patients which may be relevant to a high frequency of promoter methylation of CDH1.

Ivonne Wence-Chavez L, Palomares-Chacon U, Pablo Flores-Gutierrez J, et al.
Gene expression profiling demonstrates WNT/β-catenin pathway genes alteration in Mexican patients with colorectal cancer and diabetes mellitus.
J BUON. 2017 Sep-Oct; 22(5):1107-1114 [PubMed] Related Publications
PURPOSE: Several studies have shown a strong association between diabetes mellitus (DM) and increased risk of colorectal cancer (CRC). The fundamental mechanisms that support this association are not entirely understood; however, it is believed that hyperinsulinemia and hyperglycemia may be involved. Some proposed mechanisms include upregulation of mitogenic signaling pathways like MAPK, PI3K, mTOR, and WNT, which are involved in cell proliferation, growth, and cancer cell survival. The purpose of this study was to evaluate the gene expression profile and identify differently expressed genes involved in mitogenic pathways in CRC patients with and without DM.
METHODS: In this study, microarray analysis of gene expression followed by quantitative PCR (qPCR) was performed in cancer tissue from CRC patients with and without DM to identify the gene expression profiles and validate the differently expressed genes.
RESULTS: Among the study groups, some differently expressed genes were identified. However, when bioinformatics clustering tools were used, a significant modulation of genes involved in the WNT pathway was evident. Therefore, we focused on genes participating in this pathway, such as WNT3A, LRP6, TCF7L2, and FRA-1. Validation of the expression levels of those genes by qPCR showed that CRC patients without type 2 diabetes mellitus (T2DM) expressed significantly more WNT3Ay LRP6, but less TCF7L2 and FRA-1 compared to controls, while in CRC patients with DM the expression levels of WNT3A, LRP6, TCF7L2, and FRA-1 were significantly higher compared to controls.
CONCLUSIONS: Our results suggest that WNT/β-catenin pathway is upregulated in patients with CRC and DM, demonstrating its importance and involvement in both pathologies.

Wang Y, Pfeiffer RM, Alsaggaf R, et al.
Risk of skin cancer among patients with myotonic dystrophy type 1 based on primary care physician data from the U.K. Clinical Practice Research Datalink.
Int J Cancer. 2018; 142(6):1174-1181 [PubMed] Article available free on PMC after 15/03/2020 Related Publications
Myotonic dystrophy type 1 (DM1) is an inherited multisystem neuromuscular disorder caused by a CTG trinucleotide repeat expansion in the DMPK gene. Recent evidence documents that DM1 patients have an increased risk of certain cancers, but whether skin cancer risks are elevated is unclear. Using the U.K. Clinical Practice Research Datalink (CPRD), we identified 1,061 DM1 patients and 15,119 DM1-free individuals matched on gender, birth year (±2 years), attending practice and registration year (±1 year). We calculated the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of DM1 diagnosis with skin cancer risk using Cox proportional hazards models, for all skin cancers combined and by histological subtype. Follow-up started at the latest of the age at practice registration, DM1 diagnosis/control selection or January 1st 1988, and ended at the earliest of the age at first skin cancer diagnosis, death, transfer out of the practice, last date of data collection or the end of the CPRD record (October 31, 2016). During a median follow-up of 3.6 years, 35 DM1 patients and 108 matched DM1-free individuals developed a skin cancer. DM1 patients had an increased risk of skin cancer overall (HR = 5.44, 95% CI = 3.33-8.89, p < 0.0001), and basal cell carcinoma (BCC) (HR = 5.78, 95% CI = 3.36-9.92, p < 0.0001). Risks did not differ by gender, or age at DM1 diagnosis (p-heterogeneity > 0.5). Our data confirm suggested associations between DM1 and skin neoplasms with the highest risk seen for BCC. Patients are advised to minimize ultraviolet light exposure and seek medical advice for suspicious lesions.

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