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:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:aldo-keto reductase family 1 member C2
Source:NCBIAccessed: 14 March, 2017


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 (1992-2017)
Graph generated 14 March 2017 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.

  • 20-Hydroxysteroid Dehydrogenases
  • AKR1C2
  • Breast Cancer
  • Stomach Cancer
  • Gene Expression Profiling
  • Apoptosis
  • Case-Control Studies
  • Young Adult
  • Androgen Receptors
  • Antineoplastic Agents
  • 3-Hydroxysteroid Dehydrogenases
  • Adenocarcinoma
  • Cell Proliferation
  • Drug Resistance
  • Chromosome 10
  • RNA Interference
  • Esophageal Cancer
  • ras Proteins
  • Neoplasm Metastasis
  • Oligonucleotide Array Sequence Analysis
  • Steroids
  • Hydroxyprostaglandin Dehydrogenases
  • Tumor Suppressor Proteins
  • Washington
  • Messenger RNA
  • Down-Regulation
  • Hydroxysteroid Dehydrogenases
  • Prostate Cancer
  • Dihydrotestosterone
  • Disease Progression
  • Signal Transduction
  • Liver Cancer
  • siRNA
  • Membrane Proteins
  • Up-Regulation
  • Receptors, Progesterone
  • Single Nucleotide Polymorphism
  • Testosterone
  • Steroid Isomerases
  • Cancer Gene Expression Regulation
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase
Tag cloud generated 14 March, 2017 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)

Carotenuto F, Albertini MC, Coletti D, et al.
How Diet Intervention via Modulation of DNA Damage Response through MicroRNAs May Have an Effect on Cancer Prevention and Aging, an in Silico Study.
Int J Mol Sci. 2016; 17(5) [PubMed] Free Access to Full Article Related Publications
The DNA damage response (DDR) is a molecular mechanism that cells have evolved to sense DNA damage (DD) to promote DNA repair, or to lead to apoptosis, or cellular senescence if the damage is too extensive. Recent evidence indicates that microRNAs (miRs) play a critical role in the regulation of DDR. Dietary bioactive compounds through miRs may affect activity of numerous genes. Among the most studied bioactive compounds modulating expression of miRs are epi-gallocatechin-3-gallate, curcumin, resveratrol and n3-polyunsaturated fatty acids. To compare the impact of these dietary compounds on DD/DDR network modulation, we performed a literature search and an in silico analysis by the DIANA-mirPathv3 software. The in silico analysis allowed us to identify pathways shared by different miRs involved in DD/DDR vis-à-vis the specific compounds. The results demonstrate that certain miRs (e.g., -146, -21) play a central role in the interplay among DD/DDR and the bioactive compounds. Furthermore, some specific pathways, such as "fatty acids biosynthesis/metabolism", "extracellular matrix-receptor interaction" and "signaling regulating the pluripotency of stem cells", appear to be targeted by most miRs affected by the studied compounds. Since DD/DDR and these pathways are strongly related to aging and carcinogenesis, the present in silico results of our study suggest that monitoring the induction of specific miRs may provide the means to assess the antiaging and chemopreventive properties of particular dietary compounds.

Grasso C, Trevisan M, Fiano V, et al.
Performance of Different Analytical Software Packages in Quantification of DNA Methylation by Pyrosequencing.
PLoS One. 2016; 11(3):e0150483 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Pyrosequencing has emerged as an alternative method of nucleic acid sequencing, well suited for many applications which aim to characterize single nucleotide polymorphisms, mutations, microbial types and CpG methylation in the target DNA. The commercially available pyrosequencing systems can harbor two different types of software which allow analysis in AQ or CpG mode, respectively, both widely employed for DNA methylation analysis.
OBJECTIVE: Aim of the study was to assess the performance for DNA methylation analysis at CpG sites of the two pyrosequencing software which allow analysis in AQ or CpG mode, respectively. Despite CpG mode having been specifically generated for CpG methylation quantification, many investigations on this topic have been carried out with AQ mode. As proof of equivalent performance of the two software for this type of analysis is not available, the focus of this paper was to evaluate if the two modes currently used for CpG methylation assessment by pyrosequencing may give overlapping results.
METHODS: We compared the performance of the two software in quantifying DNA methylation in the promoter of selected genes (GSTP1, MGMT, LINE-1) by testing two case series which include DNA from paraffin embedded prostate cancer tissues (PC study, N = 36) and DNA from blood fractions of healthy people (DD study, N = 28), respectively.
RESULTS: We found discrepancy in the two pyrosequencing software-based quality assignment of DNA methylation assays. Compared to the software for analysis in the AQ mode, less permissive criteria are supported by the Pyro Q-CpG software, which enables analysis in CpG mode. CpG mode warns the operators about potential unsatisfactory performance of the assay and ensures a more accurate quantitative evaluation of DNA methylation at CpG sites.
CONCLUSION: The implementation of CpG mode is strongly advisable in order to improve the reliability of the methylation analysis results achievable by pyrosequencing.

Saita C, Goto R, Aruga T, et al.
Invasive papillary carcinoma treated with neoadjuvant endocrine therapy in which pathological complete response was achieved.
BMC Res Notes. 2016; 9:46 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Invasive papillary carcinoma is a rare type of invasive ductal carcinoma. Neoadjuvant endocrine therapy is now considered as an optional therapy for postmenopausal women with hormone receptor-positive breast cancers, including invasive papillary carcinoma.
CASE PRESENTATION: We discuss the case of an 83-year-old postmenopausal Japanese female with hormone receptor-positive invasive papillary carcinoma who started treatment with an aromatase inhibitor and achieved pathological complete response after 12 months of endocrine treatment.
CONCLUSION: Appropriate drugs and durations of neoadjuvant endocrine treatment have yet to be established. Continuing therapy with an aromatase inhibitor until the best clinical response is achieved may represent one of the best strategies in neoadjuvant endocrine therapy.

Zhang A, Zhang J, Plymate S, Mostaghel EA
Classical and Non-Classical Roles for Pre-Receptor Control of DHT Metabolism in Prostate Cancer Progression.
Horm Cancer. 2016; 7(2):104-13 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Androgens play an important role in prostate cancer (PCa) development and progression. Accordingly, androgen deprivation therapy remains the front-line treatment for locally recurrent or advanced PCa, but patients eventually relapse with the lethal form of the disease termed castration resistant PCa (CRPC). Importantly, castration does not eliminate androgens from the prostate tumor microenvironment which is characterized by elevated tissue androgens that are well within the range capable of activating the androgen receptor (AR). In this mini-review, we discuss emerging data that suggest a role for the enzymes mediating pre-receptor control of dihydrotestosterone (DHT) metabolism, including AKR1C2, HSD17B6, HSD17B10, and the UGT family members UGT2B15 and UGT2B17, in controlling intratumoral androgen levels, and thereby influencing PCa progression. We review the expression of steroidogenic enzymes involved in this pathway in primary PCa and CRPC, the activity and regulation of these enzymes in PCa experimental models, and the impact of genetic variation in genes mediating pre-receptor DHT metabolism on PCa risk. Finally, we discuss recent data that suggests several of these enzymes may also play an unrecognized role in CRPC progression separate from their role in androgen inactivation.

de Groot S, Charehbili A, van Laarhoven HW, et al.
Insulin-like growth factor 1 receptor expression and IGF1R 3129G > T polymorphism are associated with response to neoadjuvant chemotherapy in breast cancer patients: results from the NEOZOTAC trial (BOOG 2010-01).
Breast Cancer Res. 2016; 18(1):3 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: The insulin-like growth factor 1 (IGF-1) pathway is involved in cell growth and proliferation and is associated with tumorigenesis and therapy resistance. This study aims to elucidate whether variation in the IGF-1 pathway is predictive for pathologic response in early HER2 negative breast cancer (BC) patients, taking part in the phase III NEOZOTAC trial, randomizing between 6 cycles of neoadjuvant TAC chemotherapy with or without zoledronic acid.
METHODS: Formalin-fixed paraffin-embedded tissue samples of pre-chemotherapy biopsies and operation specimens were collected for analysis of IGF-1 receptor (IGF-1R) expression (n = 216) and for analysis of 8 candidate single nucleotide polymorphisms (SNPs) in genes of the IGF-1 pathway (n = 184) using OpenArray® RealTime PCR. Associations with patient and tumor characteristics and chemotherapy response according to Miller and Payne pathologic response were performed using chi-square and regression analysis.
RESULTS: During chemotherapy, a significant number of tumors (47.2 %) showed a decrease in IGF-1R expression, while in a small number of tumors an upregulation was seen (15.1 %). IGF-1R expression before treatment was not associated with pathological response, however, absence of IGF-1R expression after treatment was associated with a better response in multivariate analysis (P = 0.006) and patients with a decrease in expression during treatment showed a better response to chemotherapy as well (P = 0.020). Moreover, the variant T allele of 3129G > T in IGF1R (rs2016347) was associated with a better pathological response in multivariate analysis (P = 0.032).
CONCLUSIONS: Absent or diminished expression of IGF-1R after neoadjuvant chemotherapy was associated with a better pathological response. Additionally, we found a SNP (rs2016347) in IGF1R as a potential predictive marker for chemotherapy efficacy in BC patients treated with TAC.
TRIAL REGISTRATION: ClinicalTrials.gov NCT01099436 . Registered April 6, 2010.

Wang J, Yang S, Guo FH, et al.
Quantitative assessment of the association between the angiotensin-converting enzyme gene insertion/deletion polymorphism and digestive system cancer risk.
Genet Mol Res. 2015; 14(4):14291-9 [PubMed] Related Publications
The angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been reported to be associated with digestive system cancer; however, the results from previous studies have been conflicting. The present study aimed to investigate the association between the ACE I/D polymorphism and the risk of digestive system cancer using a meta-analysis of previously published studies. Databases were systematically searched to identify relevant studies published prior to December 2014. We estimated the pooled OR with its 95%CI to assess the association. The meta-analysis consisted of thirteen case-control studies that included 2557 patients and 4356 healthy controls. Meta-analysis results based on all the studies showed no significant association between the ACE I/D polymorphism and the risk of digestive system cancer (DD vs II: OR = 0.85, 95%CI = 0.59-1.24; DI vs II: OR = 0.94, 95%CI = 0.78-1.15; dominant model: OR = 0.96, 95%CI = 0.81- 1.15; recessive model: OR = 1.06, 95%CI = 0.76-1.48). Subgroup analyses by race and cancer type did not detect an association between the ACE I/D polymorphism and digestive system cancer risk. However, when the analyses were restricted to smaller studies (N < 500 patients), the summary OR of DI vs II was 0.80 (95%CI = 0.66-0.97). Our analyses detected a possibility of publication bias with a misestimate of the true association by smaller studies. Overall, meta-analysis results suggest the ACE I/D polymorphism might not be associated with susceptibility to digestive system cancer. Further large and well-designed studies are needed to confirm these conclusions.

Kitamura T, Watanabe-Okochi N, Enomoto Y, et al.
Novel working hypothesis for pathogenesis of hematological malignancies: combination of mutations-induced cellular phenotypes determines the disease (cMIP-DD).
J Biochem. 2016; 159(1):17-25 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Recent progress in high-speed sequencing technology has revealed that tumors harbor novel mutations in a variety of genes including those for molecules involved in epigenetics and splicing, some of which were not categorized to previously thought malignancy-related genes. However, despite thorough identification of mutations in solid tumors and hematological malignancies, how these mutations induce cell transformation still remains elusive. In addition, each tumor usually contains multiple mutations or sometimes consists of multiple clones, which makes functional analysis difficult. Fifteen years ago, it was proposed that combination of two types of mutations induce acute leukemia; Class I mutations induce cell growth or inhibit apoptosis while class II mutations block differentiation, co-operating in inducing acute leukemia. This notion has been proven using a variety of mouse models, however most of recently found mutations are not typical class I/II mutations. Although some novel mutations have been found to functionally work as class I or II mutation in leukemogenesis, the classical class I/II theory seems to be too simple to explain the whole story. We here overview the molecular basis of hematological malignancies based on clinical and experimental results, and propose a new working hypothesis for leukemogenesis.

Wang Y, Chen C, Dong F, et al.
NK cells play a significant role in immunosurveillance at the early stage of MLL-AF9 acute myeloid leukemia via CD226/CD155 interactions.
Sci China Life Sci. 2015; 58(12):1288-98 [PubMed] Related Publications
Acute myeloid leukemia (AML) is an aggressive hematological malignancy, and the mechanism underlying immune system involvement in leukemia development is unclear. In the present study, we utilized a myeloid/lymphoid or mixed-lineage leukemia; translocated to, 3 (MLLT3/MLL-AF9)-induced AML mouse model with or without exposure to irradiation. We found that the leukemia cells could survive and expand in hosts with intact immune systems, whereas leukemia progression was accelerated in mice with impaired immune systems. Moreover, the leukemia cells escaped from host immunosurveillance via editing their immunogenicity, including the up-regulation of an inhibitory antigen (i.e., CD47) and the down-regulation of active antigens (i.e., CD86, CD54, retinoic acid early transcript (RAE), histocompatibility 2, D region locus b (H2-Db) and H2-Dd). Natural killer (NK) cells were activated in the early phase of AML progression, whereas T cells were stimulated in the late phase. Furthermore, NK cell depletion showed that NK cells were necessary for the elimination of leukemia cells in our AML mouse model. Notably, CD155/CD226 primarily mediated the interaction between NK cells and leukemia cells and contributed to the antitumor effects of NK cells during the early phase of AML. Clinical data from patients with diverse hematological malignancies showed that CD155 expression was decreased in hematological malignancies. Taken together, our results demonstrate that NK cells play a pivotal role in immunosurveillance against leukemia cells during the early stage of AML primarily through the CD226/CD155 interaction; however, NK cells are not sufficient to eliminate leukemia cells.

Martinez E, Silvy F, Fina F, et al.
Rs488087 single nucleotide polymorphism as predictive risk factor for pancreatic cancers.
Oncotarget. 2015; 6(37):39855-64 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Pancreatic cancer (PC) is a devastating disease progressing asymptomatically until death within months after diagnosis. Defining at-risk populations should promote its earlier diagnosis and hence also avoid its development. Considering the known involvement in pancreatic disease of exon 11 of the bile salt-dependent lipase (BSDL) gene that encodes variable number of tandem repeat (VNTR) sequences, we hypothesized upon the existence of a genetic link between predisposition to PC and mutations in VNTR loci. To test this, BSDL VNTR were amplified by touchdown-PCR performed on genomic DNA extracted from cancer tissue or blood samples from a French patient cohort and amplicons were Sanger sequenced. A robust method using probes for droplet digital (dd)-PCR was designed to discriminate the C/C major from C/T or T/T minor genotypes. We report that the c.1719C > T transition (SNP rs488087) present in BSDL VNTR may be a useful marker for defining a population at risk of developing PC (occurrence: 63.90% in the PC versus 27.30% in the control group). The odds ratio of 4.7 for the T allele was larger than those already determined for other SNPs suspected to be predictive of PC. Further studies on tumor pancreatic tissue suggested that a germline T allele may favor Kras G12R/G12D somatic mutations which represent negative prognostic factors associated with reduced survival. We propose that the detection of the T allele in rs488087 SNP should lead to an in-depth follow-up of patients in whom an association with other potential risk factors of pancreatic cancer may be present.

Matsumoto A, Jinno H, Ando T, et al.
Biological markers of invasive breast cancer.
Jpn J Clin Oncol. 2016; 46(2):99-105 [PubMed] Related Publications
Biological markers for breast cancer are biomolecules that result from cancer-related processes and are associated with particular clinical outcomes; they thus help predict responses to therapy. In recent years, gene expression profiling has made the molecular classification of breast cancer possible. Classification of breast cancer by immunohistochemical expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 and Ki-67 is standard practice for clinical decision-making. Assessments of hormone receptor expression and human epidermal growth factor receptor 2 overexpression help estimate benefits from targeted therapies and have greatly improved prognoses for women with these breast cancer types. Although Ki-67 positivity is associated with an adverse outcome, its clear identification is an aid to optimal disease management. Standardization of testing methodology to minimize inter-laboratory measurement variations is a remaining issue. Multi-gene assays provide prognostic information and identify those most likely to benefit from systemic chemotherapy. Incorporating molecular profiles with conventional pathological classification would be more precise, and could enhance the clinical development of personalized therapy in breast cancer.

Li C, Wu X, Zhang W, et al.
AEG-1 Promotes Metastasis Through Downstream AKR1C2 and NF1 in Liver Cancer.
Oncol Res. 2014; 22(4):203-11 [PubMed] Related Publications
Liver cancer is one of the most lethal cancers, but our knowledge of the molecular mechanism underlying this process remains insufficient. Through deep sequencing and expression regulation analysis in liver cancer cells, we identified two novel factors, AKR1C2 (positive factor) and NF1 (negative factor), as the AEG-1 downstream players in the process of metastasis in liver cancer. They were experimentally validated to have the capacities of regulating cell migration, cell invasion, cell proliferation, and EMT. Further clinic expression and animal model evidence confirmed their functions. Together, our findings provide a new insight into the pharmaceutical and therapeutic use of AEG-1 and downstream AKR1C2 and NF1.

Hugen N, Simmer F, Mekenkamp LJ, et al.
Reduced rate of copy number aberrations in mucinous colorectal carcinoma.
Oncotarget. 2015; 6(28):25715-25 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Mucinous carcinoma (MC) is found in 10%-15% of colorectal cancer (CRC) patients. It differs from the common adenocarcinoma (AC) in histopathological appearance and clinical behavior.
METHODS: Genome-wide DNA copy number and survival data from MC and AC primary CRC samples from patients from two phase III trials (CAIRO and CAIRO2) was compared. Chromosomal copy number data from The Cancer Genome Atlas (TCGA) was used for validation. Altogether, 470 ACs were compared to 57 MCs.
RESULTS: MC showed a reduced amount of copy number aberrations (CNAs) compared with AC for the CAIRO/CAIRO2 cohort, with a median amount of CNAs that was 1.5-fold lower (P = 0.002). Data from TCGA also showed a reduced amount of CNAs for MC. MC samples in both cohorts displayed less gain at chromosome 20q and less loss of chromosome 18p. A high rate of chromosomal instability was a strong negative prognostic marker for survival in MC patients from the CAIRO cohorts (hazard ratio 15.60, 95% CI 3.24-75.05).
CONCLUSIONS: Results from this study indicate that the distinct MC phenotype is accompanied by a different genetic basis when compared with AC and show a strong association between the rate of chromosomal instability and survival in MC patients.

Li C, Wu X, Zhang W, et al.
High-Content Functional Screening of AEG-1 and AKR1C2 for the Promotion of Metastasis in Liver Cancer.
J Biomol Screen. 2016; 21(1):101-7 [PubMed] Related Publications
Liver cancer is one of the most lethal cancer types in humans, but our understanding of the molecular mechanisms underlying this process remains insufficient. Here, we conducted high-content screening of the potential genes involved in liver cancer metastasis, which we selected from the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database, based on the SAMcell method and RNA interference technology. We identified two powerful genes in the liver cancer metastasis process, AEG-1 and AKR1C2, both of which proved to be positive regulators in promoting metastasis in liver cancer. Further clinical results verified their roles in liver cancer. In summary, these findings could provide new insight into the liver cancer mechanism and potentially therapeutic novel targets for liver cancer therapies in the future.

Pabalan N, Jarjanazi H, Ozcelik H
Associations of the Insertion/Deletion Polymorphism in the ACE Gene and Risk of Gastric Cancer: A Meta-Analysis.
J Gastrointest Cancer. 2015; 46(4):370-9 [PubMed] Related Publications
BACKGROUND: Reported associations of ACE polymorphisms with gastric cancer have been inconsistent, prompting a meta-analysis of 12 published case-control studies where we estimated risk (odds ratio [OR]).
METHODS: We searched MEDLINE through PubMed and EMBASE for suitable articles that had case-control design with gastric cancer as outcome. In this meta-analysis, our overall findings were subjected to modifier analyses (outlier and sensitivity treatments). We also performed subgroup analysis based on ethnicity (German and Japanese) and histological subtype (intestinal and diffuse).
RESULTS: Significance of the protective effects among homozygote carriers of the II genotype (OR 0.54-0.63, P = 0.01-0.02) disappeared with outlier analysis (OR 0.81-0.88, P = 0.12-0.14). Among DD homozygotes, this treatment altered the direction of association from weak protection (OR 0.95-0.96, P = 0.79-0.82) to increased risk (OR 1.13-1.19, P = 0.14-0.16). No significant associations were observed among ID genotype carriers (OR 0.91-0.94, P = 0.69-0.72). Japanese pooled effects varied across the genotype comparisons (OR 0.93-1.06, P = 0.54-0.72). Sensitivity treatment demonstrated robustness of the II genotype, but not the other two, both in overall and subgroup analyses. Histological subtype analysis yielded protection from intestinal cancer across the comparisons (OR 0.38-0.71, P = 0.15-0.50) but variable results for the diffuse type (OR 0.59-1.32, P = 0.19-0.92).
CONCLUSION: In summary, carriers of the ACE II genotype appear to be protected from gastric cancer, regardless of ethnicity or tumor type.

Kooi IE, Mol BM, Moll AC, et al.
Loss of photoreceptorness and gain of genomic alterations in retinoblastoma reveal tumor progression.
EBioMedicine. 2015; 2(7):660-70 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Retinoblastoma is a pediatric eye cancer associated with RB1 loss or MYCN amplification (RB1 (+/+) MYCN(A) ). There are controversies concerning the existence of molecular subtypes within RB1(-/-) retinoblastoma. To test whether these molecular subtypes exist, we performed molecular profiling.
METHODS: Genome-wide mRNA expression profiling was performed on 76 primary human retinoblastomas. Expression profiling was complemented by genome-wide DNA profiling and clinical, histopathological, and ex vivo drug sensitivity data.
FINDINGS: RNA and DNA profiling identified major variability between retinoblastomas. While gene expression differences between RB1 (+/+) MYCN(A) and RB1(-/-) tumors seemed more dichotomous, differences within the RB1(-/-) tumors were gradual. Tumors with high expression of a photoreceptor gene signature were highly differentiated, smaller in volume and diagnosed at younger age compared with tumors with low photoreceptor signature expression. Tumors with lower photoreceptor expression showed increased expression of genes involved in M-phase and mRNA and ribosome synthesis and increased frequencies of somatic copy number alterations.
INTERPRETATION: Molecular, clinical and histopathological differences between RB1(-/-) tumors are best explained by tumor progression, reflected by a gradual loss of differentiation and photoreceptor expression signature. Since copy number alterations were more frequent in tumors with less photoreceptorness, genomic alterations might be drivers of tumor progression.
RESEARCH IN CONTEXT: Retinoblastoma is an ocular childhood cancer commonly caused by mutations in the RB1 gene. In order to determine optimal treatment, tumor subtyping is considered critically important. However, except for very rare retinoblastomas without an RB1 mutation, there are controversies as to whether subtypes of retinoblastoma do exist. Our study shows that retinoblastomas are highly diverse but rather than reflecting distinct tumor types with a different etiology, our data suggests that this diversity is a result of tumor progression driven by cumulative genetic alterations. Therefore, retinoblastomas should not be categorized in distinct subtypes, but be described according to their stage of progression.

Pander J, van Huis-Tanja L, Böhringer S, et al.
Genome Wide Association Study for Predictors of Progression Free Survival in Patients on Capecitabine, Oxaliplatin, Bevacizumab and Cetuximab in First-Line Therapy of Metastatic Colorectal Cancer.
PLoS One. 2015; 10(7):e0131091 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
PURPOSE: Despite expanding options for systemic treatment, survival for metastatic colorectal cancer (mCRC) remains limited and individual response is difficult to predict. In search of pre-treatment predictors, pharmacogenetic research has mainly used a candidate gene approach. Genome wide association (GWA) studies offer the benefit of simultaneously analyzing a large number of SNPs, in both known and still unidentified functional regions. Using a GWA approach, we searched for genetic markers affecting progression free survival (PFS) in mCRC patients treated with first-line capecitabine, oxaliplatin and bevacizumab (CAPOX-B), with or without cetuximab.
PATIENTS AND METHODS: 755 patients were included in the CAIRO2-trial, a multicenter phase III trial, randomizing between first-line treatment with CAPOX-B versus CAPOX-B plus cetuximab. Germline DNA and complete clinical information was available from 553 patients and genome wide genotyping was performed, using Illumina's OmniExpress beadchip arrays, with 647,550 markers passing all quality checks. Another 2,202,473 markers were imputated by using HapMap2. Association with PFS was analysed using a Cox proportional hazards model.
RESULTS: One marker, rs885036, associated significantly with PFS (P = 2.17x10(-8)) showing opposite effects on PFS depending on treatment arm. The minor allele was associated with increased PFS in patients receiving cetuximab. A cluster of markers located on chromosome 8 associated with PFS, irrespective of treatment arm (P-values of 2.30x10(-7) to 1.04x10(-6)).
CONCLUSION: This is the first GWA study to find SNPs affecting PFS in mCRC patients treated with CAPOX-B, either with or without cetuximab. Rs885036 is a potential predictive marker for cetuximab efficacy. These markers need to be validated in independent treatment cohorts.

Zhang M, Xiong H, Fang L, et al.
Meta-Analysis of the Association between H63D and C282Y Polymorphisms in HFE and Cancer Risk.
Asian Pac J Cancer Prev. 2015; 16(11):4633-9 [PubMed] Related Publications
BACKGROUND: Previous studies suggested that the H63D and C282Y polymorphisms in the HFE genes were susceptible to many cancer types, nevertheless, the present results were inconclusive. Thus, the present study was aimed to evaluate the association between the HFE polymorphisms (H63D and C282Y) and cancer risk via meta-analysis.
MATERIALS AND METHODS: We retrieved PubMed, Google Scholar, Embase and Web of Science databases for all eligible studies up to April 1, 2015. All the statistical analysis was conducted by STATA 12.0.
RESULTS: Finally, a total of 20 publications including 24 case-control studies, comprising 6,524 cases and 31,080 controls for HFE-C282Y polymorphism and 19 publications including 21 case control studies, comprising 5,648 cases and 14,257 controls for HFE-H63D polymorphism were enrolled in our analysis. An increased risk for overall cancer risk was identified in HFE-H63D polymorphism under allele contrast (D vs H: OR=1.153; 95%CI=1.031- 1.289, Pheterogeneity=0.002), homozygotes vs wide type (DD vs HH: OR=1.449; 95%CI=1.182-1.777, Pheterogeneity=0.391), dominant model (DD+HD vs HH: OR=1.145; 95%CI=1.007-1.301, Pheterogeneity=0.002) and recessive model (DD vs HD+HH: OR=1.416 ; 95%CI=1.156-1.735, Pheterogeneity=0.549), as well as HFE- C282Y under homozygotes vs wide type (YY vs CC: OR=1.428, 95%CI=1.017-2.006, Pheterogeneity=0.220). In addition, in the stratified analysis by cancer type, an increased risk was identified in hepatocellular carcinoma and breast cancer in C282Y polymorphism, as well as pancreatic cancer in H63D polymorphism, whereas a decreased risk of colorectal cancer was identified in C282Y polymorphism.
CONCLUSIONS: Present study suggested that H63D and C282Y polymorphisms associated with an increased risk of overall cancer. Nevertheless, well- designed study with large sample size will be continued on this issue of interest.

Hashemi M, Yousefi J, Hashemi SM, et al.
Association between Programmed Cell Death 6 Interacting Protein Insertion/Deletion Polymorphism and the Risk of Breast Cancer in a Sample of Iranian Population.
Dis Markers. 2015; 2015:854621 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
It has been suggested that genetic factors contribute to patients' vulnerability to breast cancer (BC). The programmed cell death 6 interacting protein (PDCD6IP) encodes for a protein that is known to bind to the products of the PDCD6 gene, which is involved in the apoptosis pathway. The aim of this case-control study is to investigate the relationship between the PDCD6IP 15 bp insertion/deletion (I/D) polymorphism (rs28381975) and BC risk in an Iranian population. A total of 491 females, including 266 BC patients and 225 control subjects without cancer, were enrolled into the study. Our findings revealed that the PDCD6IP 15 bp I/D polymorphism decreased the risk of BC in codominant (OR = 0.44, 95% CI = 0.31-0.65, p < 0.0001, I/D versus DD; OR = 0.39, 95% CI = 0.17-0.88, p = 0.030, I/I versus DD) and dominant (OR = 0.44, 95% CI = 0.30-0.63, p < 0.0001, D/I + I/I versus D/D) tested inheritance models. Also, the PDCD6IP I allele significantly decreased the risk of BC (OR = 0.59, 95% CI = 0.45-0.78, p < 0.001) compared to the D allele.

Satish L, Palmer B, Liu F, et al.
Developing an animal model of Dupuytren's disease by orthotopic transplantation of human fibroblasts into athymic rat.
BMC Musculoskelet Disord. 2015; 16:138 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Dupuytren's disease (DD) is a slow, progressive fibroproliferative disorder affecting the palms of the hands. The disease is characterized by the formation of collagen rich- cords which gradually shorten by the action of myofibroblasts resulting in finger contractures. It is a disease that is confined to humans, and a major limiting factor in investigating this disorder has been the lack of a faithful animal model that can recapitulate its distinct biology. The aim of this study was to develop such a model by determining if Dupuytren's disease (DD)- and control carpal tunnel (CT)-derived fibroblasts could survive in the forepaw of the nude rats and continue to exhibit the distinct characteristics they display in in vitro cultures.
METHODS: 1x10(7) fluorescently labeled DD- and CT-derived fibroblasts were transplanted into the left and right forepaws of nude rats respectively. Cells were tracked at regular intervals for a period of two months by quantifying emitted fluorescent signal using an IVIS imaging system. After a period of 62 days rat forepaw connective tissues were harvested for histology and total RNA was isolated. Human-specific probes were used to perform real time RT-PCR assays to examine the expression patterns of gene products associated with fibrosis in DD. Rat forepaw skin was also harvested to serve as an internal control.
RESULTS: Both CT- and DD-derived fibroblasts survived for a period of 62 days, but DD-derived cells showed a significantly greater level of persistent fluorescent signal at the end of this time than did CT-derived cells. mRNA expression levels of α-smooth muscle actin (α-SMA), type I- and type III- collagens were all significantly elevated in the forepaw receiving DD cord-derived fibroblasts in comparison to CT-derived fibroblasts. Masson's trichrome stain confirmed increased collagen deposition in the forepaw that was injected with DD cord-derived fibroblasts.
CONCLUSIONS: For the first time we describe an animal model for Dupuytren's disease at the orthotopic anatomical location. We further show that gene expression differences between control (CT) and diseased (DD) derived fibroblasts persist when these cells are transplanted to the forepaw of the nude rat. These preliminary findings indicate that, with further refinements, this animal model holds promise as a baseline for investigating novel therapeutic regimens to determine an effective strategy in treating DD.

Yan J, Kong LY, Hu J, et al.
FGL2 as a Multimodality Regulator of Tumor-Mediated Immune Suppression and Therapeutic Target in Gliomas.
J Natl Cancer Inst. 2015; 107(8) [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Fibrinogen-like protein 2 (FGL2) may promote glioblastoma multiforme (GBM) cancer development by inducing multiple immune-suppression mechanisms.
METHODS: The biological significance of FGL2 expression was assessed using the The Cancer Genome Atlast (TCGA) glioma database and tumor lysates analysis. The therapeutic effects of an anti-Fgl2 antibody and the role of immune suppression regulation by Fgl2 were determined in immune-competent, NOD-scid IL2Rgammanull (NSG), and FcɣRIIB-/- mice (n = 3-18 per group). Data were analyzed with two-way analysis of variance, log-rank survival analysis, and Pearson correlation. All statistical tests were two-sided.
RESULTS: In low-grade gliomas, 72.5% of patients maintained two copies of the FGL2 gene, whereas 83.8% of GBM patients had gene amplification or copy gain. Patients with high levels of FGL2 mRNA in glioma tissues had a lower overall survival (P = .009). Protein levels of FGL2 in GBM lysates were higher relative to low-grade glioma lysates (11.48±5.75ng/mg vs 3.96±1.01ng/mg, P = .003). In GL261 mice treated with an anti-FGL2 antibody, median survival was 27 days compared with only 17 days for mice treated with an isotype control antibody (P = .01). The anti-FGL2 antibody treatment reduced CD39(+) Tregs, M2 macrophages, programmed cell death protein 1 (PD-1), and myeloid-derived suppressor cells (MDSCs). FGL2-induced increases in M2, CD39, and PD-1 were ablated in FcɣRIIB-/- mice.
CONCLUSIONS: FGL2 augments glioma immunosuppression by increasing the expression levels of PD-1 and CD39, expanding the frequency of tumor-supportive M2 macrophages via the FcγRIIB pathway, and enhancing the number of MDSCs and CD39(+) regulatory T cells. Collectively, these results show that FGL2 functions as a key immune-suppressive modulator and has potential as an immunotherapeutic target for treating GBM.

Gorukmez O, Sag ŞO, Gorukmez Ö, et al.
Association of the ACE I/D gene polymorphisms with JAK2V617F-positive polycythemia vera and essential thrombocythemia.
Genet Test Mol Biomarkers. 2015; 19(6):303-8 [PubMed] Related Publications
The renin-angiotensin system contributes to cell growth, proliferation, and differentiation in the bone marrow. We investigated the role of the ACE I/D gene polymorphism in 108 polycythemia vera (PV) and essential thrombocytosis (ET) patients who were positive for the JAK2V617F mutation, with a thrombosis group (TG) of 95 patients who had a history of vascular events, but did not have a history of myeloproliferative neoplasms and compared these to a healthy control group (CG) of 72 subjects. In the patients, II genotype and I allele frequency (p=0.009, odds ratio [OR]=9.716, 95% confidence interval [CI]=1.242-76.00, p=0.004, OR=2.019, 95% CI=1.243-3.280, respectively) were found to be higher than those in the controls. The DD genotype (p=0.021, OR=0.491, 95% CI=0.268-0.899) and D allele (p=0.004, OR=0.495, 95% CI=0.305-0.805) were found to be correlated with a decreased risk of a myeloproliferative neoplasm. These findings support the hypothesis that the ACE II genotype and I allele may be related to increased risk of ET and PV. Conversely, the DD genotype and D allele may be related to decreased risk of ET and PV. The results also indicated that the ACE I/D gene polymorphism was independent of thrombosis formation.

Venderbosch S, van Lent-van Vliet S, de Haan AF, et al.
EMAST is associated with a poor prognosis in microsatellite instable metastatic colorectal cancer.
PLoS One. 2015; 10(4):e0124538 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
PURPOSE: To determine the frequency and prognostic value of elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) in metastatic colorectal cancer (mCRC) patients in relation to microsatellite instability (MSI) status and MSH3 protein expression.
MATERIAL AND METHODS: The frequency of EMAST was evaluated in mCRC patients with MSI tumors and microsatellite stable (MSS) tumors. A literature overview was performed to compare the frequency of EMAST in our study with existing data. Immunohistochemistry for MSH3 was compared with EMAST status. Outcome was studied in terms of overall survival (OS) of mCRC patients with MSI and MSS tumors.
RESULTS: EMAST was evaluated in 89 patients with MSI tumors (including 39 patients with Lynch syndrome) and 94 patients with MSS tumors. EMAST was observed in 45.9% (84 out of 183) of patients, with an increased frequency in MSI tumors (79.8% versus 13.8%, p < 0.001). We found no correlation between EMAST and MSH3 protein expression. There was no effect of EMAST on prognosis in patients with MSS tumors, but patients with MSI / non-EMAST tumors had a significantly better prognosis than patients with MSI / EMAST tumors (OS: HR 3.22, 95% CI 1.25-8.30).
CONCLUSION: Frequency of EMAST was increased in mCRC patients with MSI tumors, compared to MSS tumors. Our data suggest that the presence of EMAST correlates with worse OS in these patients. There was no effect of EMAST on the prognosis of patients with MSS tumors. A limitation of our study is the small number of patients in our subgroup analysis.

Kim H, Bhattacharya A, Qi L
Endoplasmic reticulum quality control in cancer: Friend or foe.
Semin Cancer Biol. 2015; 33:25-33 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Quality control systems in the endoplasmic reticulum (ER) mediated by unfolded protein response (UPR) and endoplasmic reticulum associated degradation (ERAD) ensure cellular function and organismal survival. Recent studies have suggested that ER quality-control systems in cancer cells may serve as a double-edged sword that aids progression as well as prevention of tumor growth in a context-dependent manner. Here we review recent advances in our understanding of the complex relationship between ER proteostasis and cancer pathology, with a focus on the two most conserved ER quality-control mechanisms--the IRE1α-XBP1 pathway of the UPR and SEL1L-HRD1 complex of the ERAD.

Mandal RK, Akhter N, Irshad M, et al.
Association of the PTEN IVS4 (rs3830675) gene polymorphism with reduced risk of cancer: evidence from a meta-analysis.
Asian Pac J Cancer Prev. 2015; 16(3):897-902 [PubMed] Related Publications
PTEN (phosphatase and tensin homologue), as a tumor suppressor gene, plays a significant role in regulating cell growth, proliferation, and apoptosis. Results from published studies for association between the PTEN IVS4 I/D (rs3830675) polymorphism and cancer risk are inconsistent and inconclusive. We therefore conducted a meta-analysis to evaluate the potential association between PTEN IVS4 I/D polymorphism and risk of cancer in detail. We searched PubMed (Medline) and EMBASE web databases to cover all relevant studies published until December 2013. The meta-analysis was carried out and pooled odds ratios (ORs) and 95% confidence intervals (95%CIs) were used to appraise the strength of association. A total of 1,993 confirmed cancer cases and 3,200 controls were included from six eligible case-control studies. Results from overall pooled analysis suggested a significant effect of the PTEN IVS4 I/D polymorphism and cancer risk in all genetic models, i.e., allele (I vs D: OR=0.743, 95%CI=0.648 to 0.852, p=0.001), homozygous (II vs DD: OR=0.673, 95%CI=0.555 to 0.816, p=0.001), heterozygous (ID vs DD: OR=0.641, 95%CI=0.489 to 0.840, p=0.001), dominant (II+ID vs DD: OR=0.626, 95%CI=0.489 to 0.802, p=0.001) and recessive (II vs DD+ID: OR=0.749, 95%CI=0.631 to 0.889, p=0.001). Significant publication bias was detected during the analysis. The present meta-analysis suggests that the PTEN IVS4 I/D polymorphism is significantly associated with reduced risk of cancer. However, future larger studies with other groups of populations are warranted to clarify this association.

Zhao D, Besser AH, Wander SA, et al.
Cytoplasmic p27 promotes epithelial-mesenchymal transition and tumor metastasis via STAT3-mediated Twist1 upregulation.
Oncogene. 2015; 34(43):5447-59 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
p27 restrains normal cell growth, but PI3K-dependent C-terminal phosphorylation of p27 at threonine 157 (T157) and T198 promotes cancer cell invasion. Here, we describe an oncogenic feedforward loop in which p27pT157pT198 binds Janus kinase 2 (JAK2) promoting STAT3 (signal transducer and activator of transcription 3) recruitment and activation. STAT3 induces TWIST1 to drive a p27-dependent epithelial-mesenchymal transition (EMT) and further activates AKT contributing to acquisition and maintenance of metastatic potential. p27 knockdown in highly metastatic PI3K-activated cells reduces STAT3 binding to the TWIST1 promoter, TWIST1 promoter activity and TWIST1 expression, reverts EMT and impairs metastasis, whereas activated STAT3 rescues p27 knockdown. Cell cycle-defective phosphomimetic p27T157DT198D (p27CK-DD) activates STAT3 to induce a TWIST1-dependent EMT in human mammary epithelial cells and increases breast and bladder cancer invasion and metastasis. Data support a mechanism in which PI3K-deregulated p27 binds JAK2, to drive STAT3 activation and EMT through STAT3-mediated TWIST1 induction. Furthermore, STAT3, once activated, feeds forward to further activate AKT.

Emami N, Saadat I, Omidvari S
Susceptibility to Colorectal Cancer and Two Genetic Polymorphisms of XRCC4.
Pathol Oncol Res. 2015; 21(4):881-5 [PubMed] Related Publications
The X-ray complementing group 4 (XRCC4, OMIM: 194363) plays a key role in non-homologous end-joining DNA repair pathway in mammalian cells. This pathway is believed to help maintain genomic stability. In the present study, it is hypothesized that genetic polymorphisms in the NHEJ repair XRCC4 gene may be associated with an increased risk in developing colorectal cancer (CRC). We genotyped two polymorphisms of XRCC4, G-1394T (rs6869366) and intron 3 insertion/deletion (I/D; rs28360071) in 200 colorectal cancer patients as well as 256 healthy individuals, and evaluated their association with CRC. We found that in G-1394T polymorphism, neither the TG nor the GG genotypes (versus the TT genotype) were associated with the risk of developing CRC. The results of our study indicate that in comparison with the II genotype, ID and DD genotypes had no significant association with the risk of developing CRC. Subjects with TT genotype and positive family history in colorectal cancer were found to be at a much lower risk of developing CRC in comparison with the reference group (OR = 0.31, 95%CI: 0.11-0.85, P =  .023). It should be noted that participants having at least one G allele (TG+GG genotypes) were at a significantly higher risk to develop the disease compared with the reference group (OR = 9.10, 95%CI: 2.00-41.3, P = 0.004). In relation to I/D polymorphism, among participants, those with positive family history, either with ID (OR =  .78, 95%CI: 2.26-10.0, P < 0.001) or DD genotypes (OR = 5.73, 95%CI: 1.99-16.4, P = 0.001) had a significantly association with the disease. Among participants with a positive family history in CRC, the haplotype GD dramatically increased the risk of developing CRC (OR = 10.2, 95%CI: 2.28-46, P = 0.002). The results of this study indicate that G-1394T and I/D polymorphisms of XRCC4 among individuals with positive family history for colorectal cancer substantially increase the risk factor for developing colorectal cancers.

Mego M, Karaba M, Minarik G, et al.
Relationship between circulating tumor cells, blood coagulation, and urokinase-plasminogen-activator system in early breast cancer patients.
Breast J. 2015 Mar-Apr; 21(2):155-60 [PubMed] Related Publications
Cancer is a risk factor for venous thromboembolism (VTE) and plasma d-dimer (DD) and tissue factor (TF) are established VTE associated markers. Circulating tumor cells (CTCs) are associated with the risk of VTE in metastatic breast cancer. This study aimed to correlate CTCs, blood coagulation and the urokinase plasminogen activator (uPA) system in primary breast cancer (PBC) patients. This prospective study included 116 PBC patients treated by primary surgery. CTCs were detected by quantitative RT-PCR assay for expression of epithelial (CK19) or epithelial-mesenchymal transition (EMT) genes (TWIST1, SNAIL1, SLUG, ZEB1, FOXC2). Plasma DD, TF, uPA system proteins were detected by enzyme-linked immunosorbent assays, while expressions of uPA system in surgical specimens were evaluated by immunohistochemistry. CTCs were detected in 27.6% patients. Patients with CTCs had a significantly higher mean plasma DD (ng/mL) than those of patients without CTCs (632.4 versus 365.4, p = 0.000004). There was no association between plasma TF and CTCs. Epithelial CTCs exhibit higher expression of uPA system genes compared to EMT_CTCs. Patients with CTCs had higher plasma uPA proteins than those of patients without CTCs; there was no correlation between tissue expression of uPA system, CTCs, DD or TF levels. In multivariate analysis CTCs and patients age were independent factors associated with plasma DD. We found association between plasma DD and CTCs indicating a potential role for activation of the coagulation cascade in the early metastatic process. CTCs could be directly involved in coagulation activation or increased CTCs could be marker of aggressive disease and increased VTE risk.

Meng G, Li Y, Lv Y, et al.
Preliminary screening of differentially expressed genes involved in methyl-CpG-binding protein 2 gene-mediated proliferation in human osteosarcoma cells.
Tumour Biol. 2015; 36(4):3009-15 [PubMed] Related Publications
Methyl-CpG-binding protein 2 (MeCP2) is essential in human brain development and has been linked to several cancer types and neuro-developmental disorders. This study aims to screen the MeCP2 related differentially expressed genes and discover the therapeutic targets for osteosarcoma. CCK8 assay was used to detect the proliferation and SaOS2 and U2OS cells. Apoptosis of cells was detected by flow cytometry analysis that monitored Annexin V-APC/7-DD binding and 7-ADD uptake simultaneously. Denaturing formaldehyde agarose gel electrophoresis was employed to examine the quality of total RNA 18S and 28S units. Gene chip technique was utilized to discover the differentially expressed genes correlated with MeCP2 gene. Differential gene screening criteria were used to screen the changed genes. The gene up-regulation or down-regulation more than 1.5 times was regarded as significant differential expression genes. The CCK8 results indicated that the cell proliferation of MeCP2 silencing cells (LV-MeCP2-RNAi) was significantly decreased compared to non-silenced cells (LV-MeCP2-RNAi-CN) (P < 0.05). MeCP2 silencing could also induce significant apoptosis compared to non-silenced cells (P < 0.05); 107 expression changed genes were screened from a total of 49,395 transcripts. Among the total 107 transcripts, 34 transcripts were up-regulated and 73 transcripts were down-regulated. There were five significant differentially expressed genes, including IGFBP4, HOXC8, LMO4, MDK, and CTGF, which correlated with the MeCP2 gene. The methylation frequency of CpG in IGFBP4 gene could achieve 55%. In conclusion, the differentially expressed IGFBP4, HOXC8, LMO4, MDK, and CTGF genes may be involved in MeCP2 gene-mediated proliferation and apoptosis in osteosarcoma cells.

Japp AS, Gessi M, Messing-Jünger M, et al.
High-resolution genomic analysis does not qualify atypical plexus papilloma as a separate entity among choroid plexus tumors.
J Neuropathol Exp Neurol. 2015; 74(2):110-20 [PubMed] Related Publications
Choroid plexus tumors are rare neoplasms that mainly affect children. They include papillomas, atypical papillomas, and carcinomas. Detailed genetic studies are rare, and information about their molecular pathogenesis is limited. Molecular inversion probe analysis is a hybridization-based method that represents a reliable tool for the analysis of highly fragmented formalin-fixed paraffin-embedded tissue-derived DNA. Here, analysis of 62 cases showed frequent hyperdiploidy in papillomas and atypical papillomas that appeared very similar in their cytogenetic profiles. In contrast, carcinomas showed mainly losses of chromosomes. Besides recurrent focal chromosomal gains common to all choroid plexus tumors, including chromosome 14q21-q22 (harboring OTX2), chromosome 7q22 (LAMB1), and chromosome 9q21.12 (TRPM3), Genomic Identification of Significant Targets in Cancer analysis uncovered focal alterations specific for papillomas and atypical papillomas (e.g. 7p21.3 [ARL4A]) and for carcinomas (16p13.3 [RBFOX1] and 6p21 [POLH, GTPBP2, RSPH9, and VEGFA]). Additional RNA expression profiling and gene set enrichment analysis revealed greater expression of cell cycle-related genes in atypical papillomas in comparison with that in papillomas. These findings suggest that atypical papillomas represent an immature variant of papillomas characterized by increased proliferative activity, whereas carcinomas seem to represent a genetically distinct tumor group.

Goud AL, Wuyts W, Bessems J, et al.
Intraosseous atypical chondroid tumor or chondrosarcoma grade 1 in patients with multiple osteochondromas.
J Bone Joint Surg Am. 2015; 97(1):24-31 [PubMed] Related Publications
BACKGROUND: The autosomal dominant condition multiple osteochondromas, formerly called multiple hereditary exostoses, is associated with a risk of malignant progression of osteochondroma into secondary peripheral chondrosarcoma. Most patients with multiple osteochondromas have exostosin-1 or exostosin-2 gene mutations. To our knowledge, it has not been previously reported that patients may also harbor intraosseous (central) chondroid neoplasms, enchondromas, or atypical chondroid tumors or central chondrosarcomas. The combination of osteochondroma and enchondromas also exists in patients with metachondromatosis, a disorder associated with a protein tyrosine phosphatase non-receptor type 11 gene mutation. This study aims to establish any correlation between multiple osteochondromas and intraosseous cartilaginous neoplasms.
METHODS: We retrospectively reviewed all histologically proven intraosseous atypical chondroid tumors or chondrosarcomas in our prospective nationwide Dutch tertiary referral multiple osteochondromas database. Demographic, clinical, radiographic, histological, and genetic data were recorded. The institutional medical ethics review board approved the study.
RESULTS: From 195 adult patients, seven (3.6%) were identified with intraosseous atypical chondroid tumor or chondrosarcoma World Health Organization grade 1 and had a mean age of forty-two years; five of these patients were male. In all cases, radiographic and genetic findings were consistent with multiple osteochondromas, not metachondromatosis; three patients had an exostosin-1 mutation, four patients had an exostosin-2 mutation, and no patients had a protein tyrosine phosphatase, non-receptor type 11 mutation. Six patients underwent successful operative treatment without complications or recurrences after a mean follow-up duration of forty-eight months (range, twelve to 144 months). One patient was scheduled for surgery after biopsy and histologic confirmation. Of the seven patients, five (71%) also developed a peripheral chondrosarcoma in a known osteochondroma during the study period.
CONCLUSIONS: Apart from osteochondromas or peripheral chondrosarcomas, multiple osteochondromas are also associated with intraosseous chondroid neoplasms, potentially resulting in central chondrosarcoma. Therefore, intraosseous lesions should not automatically be regarded as innocuous in this patient population.

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