Gene Summary

Gene:AKR1C2; aldo-keto reductase family 1 member C2
Aliases: DD, DD2, TDD, BABP, DD-2, DDH2, HBAB, HAKRD, MCDR2, SRXY8, DD/BABP, AKR1C-pseudo
Summary:This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols using NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity. This enzyme binds bile acid with high affinity, and shows minimal 3-alpha-hydroxysteroid dehydrogenase activity. This gene shares high sequence identity with three other gene members and is clustered with those three genes at chromosome 10p15-p14. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:aldo-keto reductase family 1 member C2
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (23)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

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

Literature Analysis

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

  • Aldehyde Reductase
  • Chromosome 10
  • Cell Proliferation
  • Case-Control Studies
  • Young Adult
  • Breast Cancer
  • Down-Regulation
  • Androgen Receptors
  • Cancer Gene Expression Regulation
  • AKR1C2
  • Stomach Cancer
  • Tumor Suppressor Proteins
  • Risk Factors
  • Messenger RNA
  • Hydroxyprostaglandin Dehydrogenases
  • Oligonucleotide Array Sequence Analysis
  • Alcohol Oxidoreductases
  • siRNA
  • 3-Hydroxysteroid Dehydrogenases
  • Testosterone
  • Adenocarcinoma
  • Hydroxysteroid Dehydrogenases
  • Esophageal Cancer
  • Apoptosis
  • Drug Resistance
  • RNA Interference
  • Aldo-Keto Reductase Family 1 Member C3
  • Gene Expression Profiling
  • Signal Transduction
  • 20-Hydroxysteroid Dehydrogenases
  • Oxidoreductases
  • Up-Regulation
  • Dihydrotestosterone
  • Liver Cancer
  • Washington
  • Steroids
  • Neoplasm Metastasis
  • Membrane Proteins
  • Aldo-Keto Reductases
  • Single Nucleotide Polymorphism
  • Prostate Cancer
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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

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

Latest Publications: AKR1C2 (cancer-related)

Benenemissi IH, Sifi K, Sahli LK, et al.
Angiotensin-converting enzyme insertion/deletion gene polymorphisms and the risk of glioma in an Algerian population.
Pan Afr Med J. 2019; 32:197 [PubMed] Free Access to Full Article Related Publications
Introduction: Just recently, it has been established that the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism is linked to the pathogenesis and to the evolution of human cancers. Therefore, the present study was concerned with the investigation of an eventual association between glioma and I/D polymorphism of the ACE gene.
Methods: The expression of ACE gene was detected by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis in 36 Algerian patients with glioma and 195 healthy controls.
Results: In glioma cases, allelic frequencies and genotypes distribution of the ACE I/D polymorphism were different from controls cases. ACE DD genotype were highly presented in glioma cases (63.9%) than controls (33.8%) and conferred 3.64-fold risk for predisposition in glioma cases (vs ID genotype, p<0.001). Recessive model (ACE II + ID genotypes vs DD) was associated with a 72% reduced risk of glioma (OR = 0.28, 95% CI: 0.13-0.60, p <0.001). Per copy D allele frequency was found higher in glioma cases (79.2%) than in controls (63.3 %), OR = 2.20, 95% CI: 1.20 - 4.03, p = 0.009.
Conclusion: The obtained data showed that the presence of the D allele might be a risk factor for the development of glioma. Further studies considering different ethnic groups with large samples are required to confirm this finding.

Wu MH, Hung YW, Gong CL, et al.
Contribution of Caspase-8 Genotypes to Colorectal Cancer Risk in Taiwan.
Anticancer Res. 2019; 39(6):2791-2797 [PubMed] Related Publications
BACKGROUND/AIM: The aim of this study was to examine the role of caspase-8 rs3834129 polymorphism on colorectal cancer (CRC) risk in Taiwanese CRC patients and healthy controls.
MATERIALS AND METHODS: The caspase-8 rs3834129 (-652 6N insertion/deletion) polymorphic genotypes were analyzed in 362 patients with CRC and the same number of age- and gender-matched healthy subjects. The interaction of caspase-8 rs3834129 genotypes with personal behaviors and clinicopathological features were also examined.
RESULTS: The percentage of variants ID and DD for caspase-8 rs3834129 genotype were 37.6 and 5.8% in CRC group and 39.0 and 6.6% in the control group, respectively (p for trend=0.7987). The allelic frequency distribution analysis showed that caspase-8 rs3834129 D allele conferred a non-significant lower susceptibility for CRC compared with I allele (OR=0.92, 95%CI=0.74-1.20, p=0.5063). There was no obvious link between caspase-8 rs3834129 genotype and CRC risk among ever-smokers, non-smokers, non-alcohol drinkers or alcohol drinkers. No statistically significant correlation was observed between caspase-8 rs3834129 genotypic distribution and age, gender, tumor size, location or metastasis status.
CONCLUSION: Overall, caspase-8 rs3834129 genotypes may not serve as predictors for CRC risk or prognosis.

Yoon H, Kim M, Jang K, et al.
p27 transcriptionally coregulates cJun to drive programs of tumor progression.
Proc Natl Acad Sci U S A. 2019; 116(14):7005-7014 [PubMed] Free Access to Full Article Related Publications
p27 shifts from CDK inhibitor to oncogene when phosphorylated by PI3K effector kinases. Here, we show that p27 is a cJun coregulator, whose assembly and chromatin association is governed by p27 phosphorylation. In breast and bladder cancer cells with high p27pT157pT198 or expressing a CDK-binding defective p27pT157pT198 phosphomimetic (p27CK-DD), cJun is activated and interacts with p27, and p27/cJun complexes localize to the nucleus. p27/cJun up-regulates

Wang R, Qin HM, Qin L, et al.
Genetic association of promoter in GRP78 gene with nasopharyngeal carcinoma in a Chinese population.
Int J Clin Oncol. 2019; 24(4):359-365 [PubMed] Related Publications
BACKGROUND: Emerging evidences were accumulated to support the view that GRP78 might be associated with multiple types of cancer. Given these, the aim of this study is to investigate the relationship between single nucleotide polymorphisms (SNPs) of GRP78 gene promoter and nasopharyngeal carcinoma (NPC).
METHODS: Three SNPs (rs3216733, rs17840761 and rs17840762) in GRR78 promoter were estimated in 422 NPC patients and 452 controls. Genotyping was performed using SNaPshot SNP. Serum GRP78 level was performed by enzyme-linked immunosorbent assay (ELISA). Data were analyzed by SPSS 17.0 software.
RESULTS: Significant association between rs3216733 polymorphism and NPC was observed (Cd vs. dd: OR = 0.57, 95% CI 0.43-0.76, P < 0.001; CC vs. dd: OR = 0.62, 95% CI 0.39-0.98, P = 0.043; Cd/CC vs. dd: OR = 0.58, 95% CI 0.44-0.76, P < 0.001; C vs. d OR = 0.70, 95% CI 0.57-0.86, P = 0.001). Additionally, we further found that expression were down-regulated in serum of patients with NPC carrying rs3216733 CC genotype when compared to that of dd genotype (P < 0.001).
CONCLUSION: The observations suggest that rs3216733 polymorphism in the GRP78 gene promoter may correlate with NPC susceptibility.

Berrandou T, Mulot C, Cordina-Duverger E, et al.
Association of breast cancer risk with polymorphisms in genes involved in the metabolism of xenobiotics and interaction with tobacco smoking: A gene-set analysis.
Int J Cancer. 2019; 144(8):1896-1908 [PubMed] Related Publications
Single nucleotide polymorphisms (SNPs) in genes involved in xenobiotics metabolism (XM) are suspected to play a role in breast cancer risk. However, previous findings based on a SNP by SNP approach need to be replicated taking into account the combined effects of multiple SNPs. We used a gene-set analysis method to study the association between breast cancer risk and genetic variation in XM genes (seen as a set of SNPs) and in the XM pathway (seen as a set of genes). We also studied the interaction between variants in XM genes and tobacco smoking. The analysis was conducted in a case-control study of 1,125 cases and 1,172 controls. Using a dedicated chip, genotyping data of 585 SNPs in 68 XM genes were available. Genetic variation in the whole XM pathway was significantly associated with premenopausal breast cancer risk (p = 0.008). This association was mainly driven by genetic variation in NAT2, CYP2C18, CYP2C19, AKR1C2 and ALDH1A3. The association between the XM gene pathway and breast cancer was observed among current and previous smokers, but not among never smokers (p = 0.013 for interaction between XM genes and tobacco smoking status). The association with breast cancer risk indicates that XM genes variants may play a role in breast carcinogenesis through their detoxification function of environmental pollutants, such as those contained in tobacco smoke.

Nikpey P, Nazari T, Khalili S, Ebrahimi A
The role of epidermal growth factor receptor (EGFR) common gene mutations in Iranian women with uterine fibroids.
Eur J Obstet Gynecol Reprod Biol. 2018; 229:103-107 [PubMed] Related Publications
OBJECTIVE: Uterine myomas are benign uterine tumors that originate from smooth muscle cells of the myometrium. This common complication can be associated with irreversible complications, including infertility and malignancy. Better understanding of the genetic characteristics of myoma may effect on treatment. Epidermal growth factor receptor gene (EGFR) is one of the most important genes that has the major role in the pathogenesis of myoma, cell growth, differentiation, proliferation and mutagenesis. The aim of this study was to investigate EGFR common gene mutations in Iranian women with uterine fibroids.
METHODS: In this case-control study, Common EGFR gene mutations in exons 21 and exons 19 of 100 women with uterine leiomyoma as cases and 100 healthy women as controls were studied. To investigate deletion mutations of exon 19 (rs121913438) and point mutations of exon 21 (rs121434568), Tetra ARMS/PCR, ARMS and conventional PCR methods were used respectively and the results were analyzed using χ 2 test. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression with control for age.
RESULT: Our results showed significant difference in genotypes frequency of (TT, TG, GG) for exon 21 and (WW, WD, DD) of exon 19 among cases and controls (P-Value = 5.672e-20) and (P-Value = 3.242e-15). There was a significant relationship between [G] allele and risk uterine myoma (P-Value = 3.018e-36) and the presence of [G] allele increased the chance of developing the disease OR = 0.004, 95% CI 0.001-0.013. The result also showed significant relationship between [D] allele and risk of uterine myoma (P-Value = 1.324e-15). In addition, presence of [D] allele, increased the chance of developing the disease (OR = 0.008, 95% C.I. = 0.002-0.033).
CONCLUSION: The results indicated a significant correlation between mutations in exon 19 (rs121913438) and exon 21(rs121434568) of EGFR gene and susceptibility of myoma in the study population.

Canter RJ, Murphy WJ
A possible new pathway in natural killer cell activation also reveals the difficulty in determining human NK cell function in cancer.
J Immunother Cancer. 2018; 6(1):79 [PubMed] Free Access to Full Article Related Publications
Immunotherapy is rapidly becoming the fourth arm of cancer treatment, and breakthrough successes have been observed in multiple malignancies. However, despite the potential for impressive anti-tumor effects, on average, only 25% of patients respond, and barriers clearly remain. Hence, uncovering innovative ways to apply immunotherapy and overcome immune resistance remains an unmet need in immuno-oncology. Natural killer (NK) cells are an attractive candidate for extending the promise of immunotherapy, although success to date has been largely limited to hematological cancers. An important study has identified novel ways in which NK cells sense and respond to tumors, and these findings may impact clinical translation of NK cells in cancer immunotherapy. Using the activating receptor NKp44, NK cells were shown to bind platelet-derived growth factor DD (PDGF-DD) which was secreted by tumors. Using transgenic mice, NKp44 binding of tumor-expressed PDGF-DD was able to limit tumor growth, and expression of natural cytotoxicity receptor-associated gene signatures (of which NKp44 is a member) was correlated to clinical outcomes. This study highlights the potential for effector-target interactions to impact immune homeostasis in previously unrecognized ways, while at the same time, underscoring the complexities inherent in pre-clinical/ translational experimental design which may confound clinical application of these interesting results.

Dean M, Rauscher EA
Men's and Women's Approaches to Disclosure About BRCA-Related Cancer Risks and Family Planning Decision-Making.
Qual Health Res. 2018; 28(14):2155-2168 [PubMed] Related Publications
Little is known about how men and women who test positive for a BRCA gene mutation or have a strong family history of carrying a BRCA mutation manage disclosures about their BRCA-related cancer risks and family planning decision-making. By conducting interviews with 25 men and 20 women, this study investigated men's and women's approaches to disclosing their BRCA-related cancer risks and family planning decision-making. Guided by the Disclosure Decision-Making Model (DD-MM), this study demonstrates that men and women assess both information and the recipients of disclosures when making disclosure decisions. Theoretical implications for the DD-MM are discussed along with practical implications for hereditary cancer risk and family planning.

Wang ZY, Li HY, Jiang ZP, Zhou TB
Relationship between angiotensin-converting enzyme insertion/deletion gene polymorphism and prostate cancer susceptibility.
J Cancer Res Ther. 2018; 14(Supplement):S375-S380 [PubMed] Related Publications
Background and Objective: Investigations on the relationship between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and prostate cancer risk are conflicting. This meta-analysis was conducted to assess the relationship between ACE I/D gene polymorphism and prostate cancer risk.
Materials and Methods: Reports were identified from PubMed, Cochrane Library, and China Biological Medicine (CBM)-disc (CBM database) on December 30, 2014, and eligible studies were recruited.
Results: ACE I/D gene polymorphism was not associated with prostate cancer risk for overall populations in this meta-analysis (D allele: Odds ratio [OR] =1.56, 95% confidence interval [95% CI]: 1.00-2.46, P = 0.05; DD genotype: OR = 1.74, 95% CI: 0.95-3.20, P = 0.07; II genotype: OR = 0.67, 95% CI: 0.39-1.15, P = 0.15). Furthermore, the association of ACE I/D gene polymorphism with colorectal cancer risk was not found for the Caucasians. Interestingly, ACE I/D gene polymorphism was associated with prostate cancer risk for the Asian population and Latino population.
Conclusions: There was an association between ACE I/D gene polymorphism and prostate cancer risk for the Asians and Latino population in this meta-analysis. However, more investigations should be performed to confirm this relationship.

Fang D, Gan H, Cheng L, et al.
H3.3K27M mutant proteins reprogram epigenome by sequestering the PRC2 complex to poised enhancers.
Elife. 2018; 7 [PubMed] Free Access to Full Article Related Publications
Expression of histone H3.3K27M mutant proteins in human diffuse intrinsic pontine glioma (DIPG) results in a global reduction of tri-methylation of H3K27 (H3K27me3), and paradoxically, H3K27me3 peaks remain at hundreds of genomic loci, a dichotomous change that lacks mechanistic insights. Here, we show that the PRC2 complex is sequestered at poised enhancers, but not at active promoters with high levels of H3.3K27M proteins, thereby contributing to the global reduction of H3K27me3. Moreover, the levels of H3.3K27M proteins are low at the retained H3K27me3 peaks and consequently having minimal effects on the PRC2 activity at these loci. H3K27me3-mediated silencing at specific tumor suppressor genes, including Wilms Tumor 1, promotes proliferation of DIPG cells. These results support a model in which the PRC2 complex is redistributed to poised enhancers in H3.3K27M mutant cells and contributes to tumorigenesis in part by locally enhancing H3K27me3, and hence silencing of tumor suppressor genes.

Sakashita S, Shiba-Ishii A, Murata Y, et al.
Case report of three EGFR TKI naïve lung adenocarcinoma containing double EGFR mutations (L858R/T790M or Exon 19 Deletion/T790M); Comparing genetic information and histology.
Pathol Res Pract. 2018; 214(8):1224-1230 [PubMed] Related Publications
EGFR T790M mutation is a crucial gene alteration causing EGFR TKI resistance. However, the implication of T790M mutation is still unknown for the stepwise progression of EGFR TKI naïve lung adenocarcinoma. In this study, we studied site-related EGFR T790M mutation analysis in EGFR TKI naïve lung adenocarcinomas harboring double EGFR mutation (L858R and T790M or Exon 19 deletion (Del.19) and T790M) by droplet digital (dd) PCR method. We examined three resected lung adenocarcinoma cases harboring EGFR double mutation including T790M. These cases didn't receive EGFR TKI treatment. We divided formalin-fixed and paraffin embedded (FFPE) unstained slide tissues into 11-18 areas in each tumor and extracted DNAs from each area separately. The DNAs were analyzed by ddPCR. T790M mutation ratio (T790M/L858R or T790M/Del.19) were calculated. For three cases, we also performed EGFR FISH for analyzing EGFR copy number.In Case 2 and 3, T790M mutation ratio were 100% and 30% homogeneously and showed increased EGFR copy number also homogeneously. However, in case 1, it was different between invasive and non-invasive areas. EGFR copy number was also heterogeneous and showed increasing only in invasive area. We indicated a peculiar case harboring T790M heterogeneity and only invasive area had T790M mutation even though the case was not treated by EGFR TKI. It suggests that T790M is possibly significant not only for EGFR TKI resistance but also the progression in lung adenocarcinoma.

Wang WJ, Zheng CF, Liu Z, et al.
Droplet digital PCR for BCR/ABL(P210) detection of chronic myeloid leukemia: A high sensitive method of the minimal residual disease and disease progression.
Eur J Haematol. 2018; 101(3):291-296 [PubMed] Related Publications
OBJECTIVE: This study intended to establish a droplet digital PCR (dd-PCR) for monitoring minimal residual disease (MRD) in patients with BCR/ABL (P210)-positive chronic myeloid leukemia (CML), thereby achieving deep-level monitoring of tumor load and determining the efficacy for guided clinically individualized treatment.
METHODS: Using dd-PCR and RT-qPCR, two cell suspensions were obtained from K562 cells and normal peripheral blood mononuclear cells by gradient dilution and were measured at the cellular level. At peripheral blood (PB) level, 61 cases with CML-chronic phase (CML-CP) were obtained after tyrosine kinase inhibitor (TKI) treatment and regular follow-ups. By RT-qPCR, BCR/ABL (P210) fusion gene was undetectable in PB after three successive analyses, which were performed once every 3 months. At the same time, dd-PCR was performed simultaneously with the last equal amount of cDNA. Ten CML patients with MR4.5 were followed up by the two methods.
RESULTS: At the cellular level, consistency of results of dd-PCR and RT-qPCR reached R
CONCLUSION: In contrast with RT-qPCR, dd-PCR is more sensitive, thus enabling accurate conversion of dd-PCR results into internationally standard RT-qPCR results by conversion equation, to achieve a deeper molecular biology-based stratification of BCR/ABL(P210) MRD. It has some reference value to monitor disease progression in clinic.

Beird HC, Wu CC, Ingram DR, et al.
Genomic profiling of dedifferentiated liposarcoma compared to matched well-differentiated liposarcoma reveals higher genomic complexity and a common origin.
Cold Spring Harb Mol Case Stud. 2018; 4(2) [PubMed] Free Access to Full Article Related Publications
Well-differentiated (WD) liposarcoma is a low-grade mesenchymal tumor with features of mature adipocytes and high propensity for local recurrence. Often, WD patients present with or later progress to a higher-grade nonlipogenic form known as dedifferentiated (DD) liposarcoma. These DD tumors behave more aggressively and can metastasize. Both WD and DD liposarcomas harbor neochromosomes formed from amplifications and rearrangements of Chr 12q that encode oncogenes (

Basoglu H, Goncu B, Akbas F
Magnetic nanoparticle-mediated gene therapy to induce Fas apoptosis pathway in breast cancer.
Cancer Gene Ther. 2018; 25(5-6):141-147 [PubMed] Related Publications
CD95 (Fas) is a complex integral protein that can be expressed in many cells. It induces apoptosis when interacted with its ligand CD95L (FasL). However, cancer cells are resistant to CD95-induced apoptosis because of the changes in death domain (DD) of CD95 (procaspase-8 and c-Flip). In this study, magnetic nanoparticles and lipid-based gene transfection methods were performed to provide active Fas expression in breast cancer cells. Plasmid DNA (pDNA), which can express both human Fas and GFP, was transfected to MCF-7 breast cancer cells. Expression of c-FLIP and caspase-8 and effect of monoclonal antibody FasL for apoptosis stimulation were investigated. Also transfection success of methods and effects on surface protein were compared. Western blot results indicated that MCF-7 cells do not express caspase-8 but express large amount of c-FLIP

Lee KT, Gopalan V, Islam F, et al.
GAEC1 mutations and copy number aberration is associated with biological aggressiveness of colorectal cancer.
Eur J Cell Biol. 2018; 97(3):230-241 [PubMed] Related Publications
GAEC1 (gene amplified in oesophageal cancer 1) is a transforming oncogene with tumorigenic potential observed in both oesophageal squamous cell carcinoma and colorectal cancer. Nonetheless, there has been a lack of study done on this gene to understand how this gene exert its oncogenic properties in cancer. This study aims to identify novel mutation sites in GAEC1. To do so, seventy-nine matched colorectal cancers were tested for GAEC1 mutation via Sanger sequencing. The mutations noted were investigated for the correlations with the clinicopathological parameters of the patients with the cancer. Additionally, GAEC1 copy number aberration (CNA), mRNA and protein expression were determined with the use of droplet digital (dd) polymerase chain reaction (PCR), real-time PCR and Western blot (confirmed with immunofluorescence analysis). GAEC1 mutation was noted in 8.8% (n = 7/79) of the cancer tissues including one missense mutation, four loss of heterozygosity (LOH) and two substitutions. These mutations were significantly associated with cancer perforation (p = 0.021). GAEC1 mutation is frequently associated with increased GAEC1 protein expression. Nevertheless, GAEC1 mRNA and protein are only weakly associated. Taken together, GAEC1 mutation affects GAEC1 expression and is associated with poorer clinical outcomes. This further strengthens the role of GAEC1 as an oncogene.

Bortolozzi R, Bresolin S, Rampazzo E, et al.
AKR1C enzymes sustain therapy resistance in paediatric T-ALL.
Br J Cancer. 2018; 118(7):985-994 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Despite chemotherapy intensification, a subgroup of high-risk paediatric T-cell acute lymphoblastic leukemia (T-ALL) patients still experience treatment failure. In this context, we hypothesised that therapy resistance in T-ALL might involve aldo-keto reductase 1C (AKR1C) enzymes as previously reported for solid tumors.
METHODS: Expression of NRF2-AKR1C signaling components has been analysed in paediatric T-ALL samples endowed with different treatment outcomes as well as in patient-derived xenografts of T-ALL. The effects of AKR1C enzyme modulation has been investigated in T-ALL cell lines and primary cultures by combining AKR1C inhibition, overexpression, and gene silencing approaches.
RESULTS: We show that T-ALL cells overexpress AKR1C1-3 enzymes in therapy-resistant patients. We report that AKR1C1-3 enzymes play a role in the response to vincristine (VCR) treatment, also ex vivo in patient-derived xenografts. Moreover, we demonstrate that the modulation of AKR1C1-3 levels is sufficient to sensitise T-ALL cells to VCR. Finally, we show that T-ALL chemotherapeutics induce overactivation of AKR1C enzymes independent of therapy resistance, thus establishing a potential resistance loop during T-ALL combination treatment.
CONCLUSIONS: Here, we demonstrate that expression and activity of AKR1C enzymes correlate with response to chemotherapeutics in T-ALL, posing AKR1C1-3 as potential targets for combination treatments during T-ALL therapy.

Pilsworth JA, Cochrane DR, Xia Z, et al.
TERT promoter mutation in adult granulosa cell tumor of the ovary.
Mod Pathol. 2018; 31(7):1107-1115 [PubMed] Related Publications
The telomerase reverse transcriptase (TERT) gene is highly expressed in stem cells and silenced upon differentiation. Cancer cells can attain immortality by activating TERT to maintain telomere length and telomerase activity, which is a crucial step of tumorigenesis. Two somatic mutations in the TERT promoter (C228T; C250T) have been identified as gain-of-function mutations that promote transcriptional activation of TERT in multiple cancers, such as melanoma and glioblastoma. A recent study investigating TERT promoter mutations in ovarian carcinomas found C228T and C250T mutations in 15.9% of clear cell carcinomas. However, it is unknown whether these mutations are frequent in other ovarian cancer subtypes, in particular, sex cord-stromal tumors including adult granulosa cell tumors. We performed whole-genome sequencing on ten adult granulosa cell tumors with matched normal blood and identified a TERT C228T promoter mutation in 50% of tumors. We found that adult granulosa cell tumors with mutated TERT promoter have increased expression of TERT mRNA and exhibited significantly longer telomeres compared to those with wild-type TERT promoter. Extension cohort analysis using allelic discrimination revealed the TERT C228T mutation in 51 of 229 primary adult granulosa cell tumors (22%), 24 of 58 recurrent adult granulosa cell tumors (41%), and 1 of 22 other sex cord-stromal tumors (5%). There was a significant difference in overall survival between patients with TERT C228T promoter mutation in the primary tumors and those without it (p = 0.00253, log-rank test). In seven adult granulosa cell tumors, we found the TERT C228T mutation present in recurrent tumors and absent in the corresponding primary tumor. Our data suggest that TERT C228T promoter mutations may have an important role in progression of adult granulosa cell tumors.

Roskoski R
The role of small molecule platelet-derived growth factor receptor (PDGFR) inhibitors in the treatment of neoplastic disorders.
Pharmacol Res. 2018; 129:65-83 [PubMed] Related Publications
Platelet-derived growth factor (PDGF) was discovered as a serum-derived component necessary for the growth of smooth muscle cells, fibroblasts, and glial cells. The PDGF family is a product of four gene products and consists of five dimeric isoforms: PDGF-AA, PDGF-BB, PDGF-CC, PDGF-DD, and the PDGF-AB heterodimer. This growth factor family plays an essential role in embryonic development and in wound healing in the adult. These growth factors mediate their effects by binding to and activating their receptor protein-tyrosine kinases, which are encoded by two genes: PDGFRA and PDGFRB. The functional receptors consist of the PDGFRα/α and PDGFRβ/β homodimers and the PDGFRα/β heterodimer. Although PDGF signaling is most closely associated with mesenchymal cells, PDGFs and PDGF receptors are widely expressed in the mammalian central nervous system. The PDGF receptors contain an extracellular domain that is made up of five immunoglobulin-like domains (Ig-d1/2/3/4/5), a transmembrane segment, a juxtamembrane segment, a protein-tyrosine kinase domain that contains an insert of about 100 amino acid residues, and a carboxyterminal tail. Although uncommon, activating mutations in the genes for PDGF or PDGF receptors have been documented in various neoplasms including dermatofibrosarcoma protuberans (DFSP) and gastrointestinal stromal tumors (GIST). In most neoplastic diseases, PDGF expression and action appear to involve the tumor stroma. Moreover, this family is pro-angiogenic. More than ten PDGFRα/β multikinase antagonists have been approved by the FDA for the treatment of several neoplastic disorders and interstitial pulmonary fibrosis (www.brimr.org/PKI/PKIs.htm). Type I protein kinase inhibitors interact with the active enzyme form with DFG-D of the proximal activation segment directed inward toward the active site (DFG-D

Barrow AD, Edeling MA, Trifonov V, et al.
Natural Killer Cells Control Tumor Growth by Sensing a Growth Factor.
Cell. 2018; 172(3):534-548.e19 [PubMed] Free Access to Full Article Related Publications
Many tumors produce platelet-derived growth factor (PDGF)-DD, which promotes cellular proliferation, epithelial-mesenchymal transition, stromal reaction, and angiogenesis through autocrine and paracrine PDGFRβ signaling. By screening a secretome library, we found that the human immunoreceptor NKp44, encoded by NCR2 and expressed on natural killer (NK) cells and innate lymphoid cells, recognizes PDGF-DD. PDGF-DD engagement of NKp44 triggered NK cell secretion of interferon gamma (IFN)-γ and tumor necrosis factor alpha (TNF-α) that induced tumor cell growth arrest. A distinctive transcriptional signature of PDGF-DD-induced cytokines and the downregulation of tumor cell-cycle genes correlated with NCR2 expression and greater survival in glioblastoma. NKp44 expression in mouse NK cells controlled the dissemination of tumors expressing PDGF-DD more effectively than control mice, an effect enhanced by blockade of the inhibitory receptor CD96 or CpG-oligonucleotide treatment. Thus, while cancer cell production of PDGF-DD supports tumor growth and stromal reaction, it concomitantly activates innate immune responses to tumor expansion.

Popławski P, Wiśniewski JR, Rijntjes E, et al.
Restoration of type 1 iodothyronine deiodinase expression in renal cancer cells downregulates oncoproteins and affects key metabolic pathways as well as anti-oxidative system.
PLoS One. 2017; 12(12):e0190179 [PubMed] Free Access to Full Article Related Publications
Type 1 iodothyronine deiodinase (DIO1) contributes to deiodination of 3,5,3',5'-tetraiodo-L-thyronine (thyroxine, T4) yielding of 3,5,3'-triiodothyronine (T3), a powerful regulator of cell differentiation, proliferation, and metabolism. Our previous work showed that loss of DIO1 enhances proliferation and migration of renal cancer cells. However, the global effects of DIO1 expression in various tissues affected by cancer remain unknown. Here, the effects of stable DIO1 re-expression were analyzed on the proteome of renal cancer cells, followed by quantitative real-time PCR validation in two renal cancer-derived cell lines. DIO1-induced changes in intracellular concentrations of thyroid hormones were quantified by L-MS/MS and correlations between expression of DIO1 and potential target genes were determined in tissue samples from renal cancer patients. Stable re-expression of DIO1, resulted in 26 downregulated proteins while 59 proteins were overexpressed in renal cancer cells. The 'downregulated' group consisted mainly of oncoproteins (e.g. STAT3, ANPEP, TGFBI, TGM2) that promote proliferation, migration and invasion. Furthermore, DIO1 re-expression enhanced concentrations of two subunits of thyroid hormone transporter (SLC7A5, SLC3A2), enzymes of key pathways of cellular energy metabolism (e.g. TKT, NAMPT, IDH2), sex steroid metabolism and anti-oxidative response (AKR1C2, AKR1B10). DIO1 expression resulted in elevated intracellular concentration of T4. Expression of DIO1-affected genes strongly correlated with DIO1 transcript levels in tissue samples from renal cancer patients as well as with their poor survival. This first study addressing effects of deiodinase re-expression on proteome of cancer cells demonstrates that induced DIO1 re-expression in renal cancer robustly downregulates oncoproteins, affects key metabolic pathways, and triggers proteins involved in anti-oxidative protection. This data supports the notion that suppressed DIO1 expression and changes in local availability of thyroid hormones might favor a shift from a differentiated to a more proliferation-prone state of cancer tissues and cell lines.

Sheng X, Parmentier JH, Tucci J, et al.
Adipocytes Sequester and Metabolize the Chemotherapeutic Daunorubicin.
Mol Cancer Res. 2017; 15(12):1704-1713 [PubMed] Free Access to Full Article Related Publications
Obesity is associated with poorer outcome for many cancers. Previously, we observed that adipocytes protect acute lymphoblastic leukemia (ALL) cells from the anthracycline, daunorubicin. In this study, it is determined whether adipocytes clear daunorubicin from the tumor microenvironment (TME). Intracellular daunorubicin concentrations were evaluated using fluorescence. Daunorubicin and its largely inactive metabolite, daunorubicinol, were analytically measured in media, cells, and tissues using liquid chromatography/mass spectrometry (LC/MS). Expression of daunorubicin-metabolizing enzymes, aldo-keto reductases (AKR1A1, AKR1B1, AKR1C1, AKR1C2, AKR1C3, and AKR7A2) and carbonyl reductases (CBR1, CBR3), in human adipose tissue, were queried using public databases and directly measured by quantitative PCR (qPCR) and immunoblot. Adipose tissue AKR activity was measured by colorimetric assay. Adipocytes absorbed and efficiently metabolized daunorubicin to daunorubicinol, reducing its antileukemia effect in the local microenvironment. Murine studies confirmed adipose tissue conversion of daunorubicin to daunorubicinol

Zheng X, Liu G, Cui G, et al.
Angiotensin-Converting Enzyme Gene Deletion Polymorphism is Associated with Lymph Node Metastasis in Colorectal Cancer Patients in a Chinese Population.
Med Sci Monit. 2017; 23:4926-4931 [PubMed] Free Access to Full Article Related Publications
BACKGROUND The purpose of this study was to assess the effect of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism on the risk of lymph node metastasis (LNM) in colorectal cancer (CRC) patients. MATERIAL AND METHODS We enrolled 146 CRC patients and 106 healthy controls in this study. ACE gene I/D polymorphism was genotyped by polymerase chain reaction (PCR). Hardy-Weinberg equilibrium (HWE) was used to assess the goodness of fit of the genotypes. χ² test was used to calculate the differences of genotype and allele distributions. Odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs) were used to analyze the association between ACE I/D polymorphism and LNM in CRC patients. RESULTS Insertion/deletion (ID) and deletion/deletion (DD) genotypes were frequently observed in CRC patients, but only DD genotype and D allele were related to the susceptibility of CRC (P=0.038, OR=2.158, 95%CI=1.039-4.480; P=0.026, OR=1.501, 95%CI=1.048-2.150). DD genotype and D allele also increased the risk of LNM in CRC patients (P=0.028, OR=2.844, 95%CI=1.107-7.038; P=0.026, OR=1.692, 95%CI=1.063-2.693). CONCLUSIONS DD genotype and D allele of ACE gene I/D polymorphism might increase the risk of LNM in CRC patients.

Pandith AA, Qasim I, Zahoor W, et al.
ACE I/D sequence variants but not MTHFR C677T, is strongly linked to malignant glioma risk and its variant DD genotype may act as a promising predictive biomarker for overall survival of glioma patients.
Gene. 2018; 639:62-68 [PubMed] Related Publications
OBJECTIVE: ACE I/D and MTHFR C677T gene polymorphisms can be seen as candidate genes for glioma on the basis of their biological functions and their involvement in different cancers. The aim of this study was to analyze potential association and overall survival between MTHFR C677T and ACE I/D polymorphism in glioma patients in our population.
MATERIALS AND METHODS: We tested genotype distribution of 112 glioma patients against 141 cancer-free controls from the same region. Kaplan-Meier survival analysis was performed to evaluate overall survival of patients for both genes.
RESULTS: No significant differences were found among MTHFR C677T wild type C and variant genotypes CT/TT with glioma patients. In ACE, the distribution of variant ID and DD was found to be significantly higher in glioma cases as compared to controls (p<0.0001). ACE DD genotypes were highly presented in glioma cases 26.8% versus 10.6% in controls (p<0.0001) and conferred 5-fold risk for predisposition in glioma cases. Per copy D allele frequency was found higher in cases than in controls (0.54 versus 0.25: p<0.0001). Interestingly we found a significant overall survival (with log rank p<0.01) in patients who presented with ACE DD genotypes had the least estimated overall survival of 13.4months in comparison to 21. 7 and 17.6months for ACE II and I/D genotypes respectively.
CONCLUSION: We conclude ACE I/D polymorphism plays a vital role in predisposition of higher risk for glioma. We also suggest that ACE DD genotypes may act as an important predictive biomarker for overall survival of glioma patients.

Ng M, Thakkar D, Southam L, et al.
A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional Variants Implicated in Fibrosis.
Am J Hum Genet. 2017; 101(3):417-427 [PubMed] Free Access to Full Article Related Publications
Individuals with Dupuytren disease (DD) are commonly seen by physicians and surgeons across multiple specialties. It is an increasingly common and disabling fibroproliferative disorder of the palmar fascia, which leads to flexion contractures of the digits, and is associated with other tissue-specific fibroses. DD affects between 5% and 25% of people of European descent and is the most common inherited disease of connective tissue. We undertook the largest GWAS to date in individuals with a surgically validated diagnosis of DD from the UK, with replication in British, Dutch, and German individuals. We validated association at all nine previously described signals and discovered 17 additional variants with p ≤ 5 × 10

Alyamani M, Li Z, Berk M, et al.
Steroidogenic Metabolism of Galeterone Reveals a Diversity of Biochemical Activities.
Cell Chem Biol. 2017; 24(7):825-832.e6 [PubMed] Free Access to Full Article Related Publications
Galeterone is a steroidal CYP17A1 inhibitor, androgen receptor (AR) antagonist, and AR degrader, under evaluation in a phase III clinical trial for castration-resistant prostate cancer (CRPC). The A/B steroid ring (Δ

Ouyang X, Ye XL, Wei HB
BRM promoter insertion polymorphisms increase the risk of cancer: A meta-analysis.
Gene. 2017; 626:420-425 [PubMed] Related Publications
INTRODUCTION: Many studies have suggested that the BRM promoter insertion polymorphisms might be associated with susceptibility to many different types of cancer. However, previous studies reported contradictory results. This current meta-analysis was performed to address this issue.
EVIDENCE ACQUISITION: A comprehensive search was conducted in multiple databases, including PubMed, Embase and China National Knowledge Infrastructure (CNKI). We collected relevant articles to explore the association between the BRM insertion polymorphisms and susceptibility of cancers.
EVIDENCE SYNTHESIS: For the BRM-741 polymorphism, a total of 2901 cases and 3667 controls from 6 studies were included. For the BRM-1321 polymorphism, a total of 2899 cases and 3769 controls from 6 studies were included. Overall, a significant difference was observed in BRM-741 (OR 0.81; 95%CI 0.68, 0.96; P=0.02) and BRM-1321 (OR 0.76; 95%CI 0.66, 0.88; P<0.01) for allele frequency (D versus I). In the subgroup analysis, for the BRM-741, a significant difference was observed in Asian (OR 0.88; 95%CI 0.78, 0.99; P=0.03) for D versus I. Similarly, for the BRM-1321, a significant difference was observed in Asian (OR 0.43; 95%CI 0.32, 0.58; P<0.001) and Caucasian (OR 0.74; 95%CI 0.62, 0.88; P<0.001) for DD versus II.
CONCLUSIONS: BRM-741 and BRM-1321 insertion polymorphisms are associated with susceptibility to cancer. Further studies are warranted to verify the clinical utility of BRM promoter insertion polymorphisms in human tumors.

Bisogno LS, Keene JD
Analysis of post-transcriptional regulation during cancer progression using a donor-derived isogenic model of tumorigenesis.
Methods. 2017; 126:193-200 [PubMed] Free Access to Full Article Related Publications
Post-transcriptional regulation of gene expression by RNA binding proteins (RBPs) and non-coding RNAs plays an important role in global gene expression. Many post-transcriptional regulators are misexpressed and misregulated in cancers, resulting in altered programs of protein biosynthesis that can drive tumor progression. While comparative studies of several RBPs and microRNAs expressed in various cancer types have been reported, a model system that can be used to quantify RBP regulation and functional outcomes during the initiation and early stages of tumorigenesis is lacking. It was previously demonstrated that oncogenic transformation of normal human cells can be induced by expressing hTERT, p53

Delahaye LJMJ, Drukker CA, Dreezen C, et al.
A breast cancer gene signature for indolent disease.
Breast Cancer Res Treat. 2017; 164(2):461-466 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Early-stage hormone-receptor positive breast cancer is treated with endocrine therapy and the recommended duration of these treatments has increased over time. While endocrine therapy is considered less of a burden to patients compared to chemotherapy, long-term adherence may be low due to potential adverse side effects as well as compliance fatigue. It is of high clinical utility to identify subgroups of breast cancer patients who may have excellent long-term survival without or with limited duration of endocrine therapy to aid in personalizing endocrine treatment.
METHODS: We describe a new ultralow risk threshold for the 70-gene signature (MammaPrint) that identifies a group of breast cancer patients with excellent 20 year, long-term survival prognosis. Tumors of these patients are referred to as "indolent breast cancer." We used patient series on which we previously established and assessed the 70-gene signature high-low risk threshold.
RESULTS: In an independent validation cohort, we show that patients with indolent breast cancer had 100% breast cancer-specific survival at 15 years of follow-up.
CONCLUSIONS: Our data indicate that patients with indolent disease may be candidates for limited treatment with adjuvant endocrine therapy based on their very low risk of distant recurrences or death of breast cancer.

Shiiba M, Yamagami H, Yamamoto A, et al.
Mefenamic acid enhances anticancer drug sensitivity via inhibition of aldo-keto reductase 1C enzyme activity.
Oncol Rep. 2017; 37(4):2025-2032 [PubMed] Related Publications
Resistance to anticancer medications often leads to poor outcomes. The present study explored an effective approach for enhancing chemotherapy targeted against human cancer cells. Real-time quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed overexpression of members of aldo-keto reductase (AKR) 1C family, AKR1C1, AKR1C2, AKR1C3, and AKR1C4, in cisplatin, cis-diamminedichloroplatinum (II) (CDDP)-resistant human cancer cell lines, HeLa (cervical cancer cells) and Sa3 (oral squamous cell carcinoma cells). The genes were downregulated using small-interfering RNA (siRNA) transfection, and the sensitivity to CDDP or 5-fluorouracil (5-FU) was investigated. When the genes were knocked down, sensitivity to CDDP and 5-FU was restored. Furthermore, we found that administration of mefenamic acid, a widely used non-steroidal anti-inflammatory drug (NSAID) and a known inhibitor of AKR1Cs, enhanced sensitivity to CDDP and 5-FU. The present study suggests that AKR1C family is closely associated with drug resistance to CDDP and 5-FU, and mefenamic acid enhances their sensitivity through its inhibitory activity in drug-resistant human cancer cells. Thus, the use of mefenamic acid to control biological function of AKR1C may lead to effective clinical outcomes by overcoming anticancer drug resistance.

Hata T, Dal Molin M, Hong SM, et al.
Predicting the Grade of Dysplasia of Pancreatic Cystic Neoplasms Using Cyst Fluid DNA Methylation Markers.
Clin Cancer Res. 2017; 23(14):3935-3944 [PubMed] Free Access to Full Article Related Publications

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