Gene Summary

Gene:IGF2R; insulin-like growth factor 2 receptor
Aliases: MPR1, MPRI, CD222, CIMPR, M6P-R
Summary:This gene encodes a receptor for both insulin-like growth factor 2 and mannose 6-phosphate, although the binding sites for either are located on different segments of the receptor. This receptor functions in the intracellular trafficking of lysosomal enzymes, the activation of transforming growth factor beta, and the degradation of insulin-like growth factor 2. While the related mouse gene shows exclusive expression from the maternal allele, imprinting of the human gene appears to be polymorphic, with only a minority of individuals showing expression from the maternal allele. [provided by RefSeq, Apr 2013]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:cation-independent mannose-6-phosphate receptor
Source:NCBIAccessed: 27 February, 2015


What does this gene/protein do?
Show (18)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 28 February 2015 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.

  • Statistics as Topic
  • Species Specificity
  • Breast Cancer
  • Mutation
  • Tumor Stem Cell Assay
  • Survival Rate
  • Precancerous Conditions
  • Protein-Serine-Threonine Kinases
  • Trans-Activators
  • Loss of Heterozygosity
  • Transforming Growth Factor beta
  • Microsatellite Repeats
  • Receptors, Colony-Stimulating Factor
  • Transforming Growth Factor beta Receptors
  • Genetic Predisposition
  • Messenger RNA
  • Single Nucleotide Polymorphism
  • Liver Cancer
  • Structure-Activity Relationship
  • Neoplasm Proteins
  • IGF2R
  • Hepatocellular Carcinoma
  • DNA-Binding Proteins
  • Cancer Gene Expression Regulation
  • Tamoxifen
  • IGF1R
  • BCL2 protein
  • Proto-Oncogene Proteins
  • Chromosome 6
  • TNF
  • Skin Cancer
  • Sulfites
  • G-Protein-Coupled Receptors
  • Base Sequence
  • Wilms Tumour
  • Sodium Dodecyl Sulfate
  • IGF2
  • Polymerase Chain Reaction
  • Transcription
  • Tumor Suppressor Gene
  • Cancer DNA
Tag cloud generated 27 February, 2015 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: IGF2R (cancer-related)

Rashad NM, El-Shal AS, Abd Elbary EH, et al.
Impact of insulin-like growth factor 2, insulin-like growth factor receptor 2, insulin receptor substrate 2 genes polymorphisms on susceptibility and clinicopathological features of hepatocellular carcinoma.
Cytokine. 2014; 68(1):50-8 [PubMed] Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death worldwide. Insulin-like growth factor-2 (IGF-2) is an important autocrine and paracrine growth factor which may induce cell proliferation and inhibit cell apoptosis leading to the transformation of normal cells into malignant cells. This study aimed to evaluate the possible roles of IGF-2, insulin-like growth factor-2 receptor (IGF-2R), and insulin receptor substrate (IRS)-2 genes polymorphisms in susceptibility and clinicopathological features of HCC in Egyptian population.
MATERIALS AND METHODS: Four hundred and twenty-six HCC patients and 334 controls were enrolled in the study. Polymorphisms of IGF-2+3580, IGF-2+3123, IGF-2R 1619, and IRS-2 1057 gene were detected using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Serum IGF-2 were determined using ELISA.
RESULTS: Serum IGF-2 levels were significantly lower in HCC patients than in healthy controls. IGF-2+3580 AA genotype, IGF-2+3123 GG genotype or G allele, IRS-2 1057 DD genotype and D allele were significantly associated with HCC risk. The combination of IGF-2+3580 AA homozygosity and IGF-2R 1619 GG homozygosity presented a significant protective effect against HCC (OR=0.16,95% CI=0. 08-0.34, P=0. 005). Serum IGF-2 concentrations were significantly increased in HCC patients with the IGF-2+3580 AA genotype. We also observed that increased alpha-fetoprotein (AFP), Child-Pugh grade, tumor size, and number of malignant lesions were accompanied by a significant increase of serum IGF-2 mean values of in HCC patients.
CONCLUSION: IGF-2, IGF-2R, and IRS-2 genes polymorphisms and their combinations are associated with risk of HCC.

Ochs-Balcom HM, Vaughn CB, Nie J, et al.
Racial differences in the association of insulin-like growth factor pathway and colorectal adenoma risk.
Cancer Causes Control. 2014; 25(2):161-70 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Insulin resistance is believed to play an important role in the link between energy imbalance and colon carcinogenesis. Emerging evidence suggests that there are substantial racial differences in genetic and anthropometric influences on insulin-like growth factors (IGFs); however, few studies have examined racial differences in the associations of IGFs and colorectal adenoma, precursor lesions of colon cancer.
METHODS: We examined the association of circulating levels of IGF-1, IGFBP-3 and IGFBP-1, and SNPs in the IGF-1 receptor (IGF1R), IGF-2 receptor (IGF2R), and insulin receptor genes with risk of adenomas in a sample of 410 incident adenoma cases and 1,070 controls from the Case Transdisciplinary Research on Energetics and Cancer (TREC) Colon Adenomas Study.
RESULTS: Caucasians have higher IGF-1 levels compared to African Americans; mean IGF-1 levels are 119.0 ng/ml (SD = 40.7) and 109.8 ng/ml (SD = 40.8), respectively, among cases (p = 0.02). Mean IGF-1 levels are also higher in Caucasian controls (122.9 ng/ml, SD = 41.2) versus African American controls (106.9, SD = 41.2), p = 0.001. We observed similar differences in IGFBP3 levels by race. Logistic regression models revealed a statistically significant association of IGF-1 with colorectal adenoma in African Americans only, with adjusted odds ratios (ORs) of 1.68 (95 % CI 1.06-2.68) and 1.68 (95 % CI 1.05-2.71), respectively, for the second and third tertiles as compared to the first tertile. One SNP (rs496601) in IGF1R was associated with adenomas in Caucasians only; the per allele adjusted OR is 0.73 (95 % CI 0.57-0.93). Similarly, one IGF2R SNP (rs3777404) was statistically significant in Caucasians; adjusted per allele OR is 1.53 (95 % CI 1.10-2.14).
CONCLUSION: Our results suggest racial differences in the associations of IGF pathway biomarkers and inherited genetic variance in the IGF pathway with risk of adenomas that warrant further study.

Kubisch R, Fröhlich T, Arnold GJ, et al.
V-ATPase inhibition by archazolid leads to lysosomal dysfunction resulting in impaired cathepsin B activation in vivo.
Int J Cancer. 2014; 134(10):2478-88 [PubMed] Related Publications
The myxobacterial agent archazolid inhibits the vacuolar proton pump V-ATPase. V-ATPases are ubiquitously expressed ATP-dependent proton pumps, which are known to regulate the pH in endomembrane systems and thus play a crucial role in endo- and exocytotic processes of the cell. As cancer cells depend on a highly active secretion of proteolytic proteins in order to invade tissue and form metastases, inhibition of V-ATPase is proposed to affect the secretion profile of cancer cells and thus potentially abrogate their metastatic properties. Archazolid is a novel V-ATPase inhibitor. Here, we show that the secretion pattern of archazolid treated cancer cells includes various prometastatic lysosomal proteins like cathepsin A, B, C, D and Z. In particular, archazolid induced the secretion of the proforms of cathepsin B and D. Archazolid treatment abrogates the cathepsin B maturation process leading to reduced intracellular mature cathepsin B protein abundance and finally decreased cathepsin B activity, by inhibiting mannose-6-phoshate receptor-dependent trafficking. Importantly, in vivo reduced cathepsin B protein as well as a decreased proteolytic cathepsin B activity was detected in tumor tissue of archazolid-treated mice. Our results show that inhibition of V-ATPase by archazolid reduces the activity of prometastatic proteases like cathepsin B in vitro and in vivo.

Caixeiro NJ, Martin JL, Scott CD
Silencing the mannose 6-phosphate/IGF-II receptor differentially affects tumorigenic properties of normal breast epithelial cells.
Int J Cancer. 2013; 133(11):2542-50 [PubMed] Related Publications
Although loss of the mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF-IIR) in breast cancer is believed to play a role in tumorigenesis, it has not been demonstrated that M6P/IGF-IIR loss is sufficient to confer a malignant phenotype in an untransformed cell. We investigated the impact of M6P/IGF-IIR silencing using phenotypically normal (MCF-10A) and oncogenically transformed (MCF-10T, the c-Ha-ras transformed derivative of MCF-10A) human breast epithelial cell lines as model systems. In both cell lines, silencing of M6P/IGF-IIR increased cell proliferation and motility, with the effects being more pronounced in MCF-10A cells. Although anchorage-independent growth was increased by M6P/IGF-IIR silencing in MCF-10T cells, MCF-10A cells did not acquire the ability to grow in soft agar. Conversely, reduced M6P/IGF-IIR expression increased the invasive potential of MCF-10A cells, but did not enhance the already high rate of invasion of MCF-10T cells. M6P/IGF-IIR silencing had no effect on basal or IGF-II-stimulated IGF-I receptor (IGF-IR) or AKT phosphorylation in either cell line, but both were abrogated by IGF-IR kinase inhibition, which also reduced the stimulatory effect of M6P/IGF-IIR silencing on proliferation under basal and IGF-II-stimulated conditions in both cell lines. However, cell motility was neither stimulated by IGF-II nor reduced by IGF-IR inhibition, suggesting that potentiation of specific tumorigenic features in response to M6P/IGF-IIR silencing involves IGF-II- dependent and -independent mechanisms. Collectively, these data suggest that M6P/IGF-IIR silencing alone is insufficient to confer a tumorigenic phenotype, but can enhance tumorigenicity in an already transformed cell.

Shiraha H, Yamamoto K, Namba M
Human hepatocyte carcinogenesis (review).
Int J Oncol. 2013; 42(4):1133-8 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma is the third most frequent cause of cancer-related death worldwide; and its incidence rate is increasing. Clinical and molecular medical analyses have revealed substantial information on hepatocarcinogenesis. Hepatocarcinogenesis is a stepwise process during which multiple genes are altered. Genetic changes and their biological consequences in human HCC can be divided into at least 4 groups: i) tumor suppressor genes (p53, retinoblastoma, phosphatase tensin homolog and runt-related transcription factor 3), ii) oncogenes (myc, K-ras, BRAF), iii) reactivation of developmental pathways (Wnt, hedgehog), and iv) growth factors and their receptors (transforming growth factor-α, insulin-like growth factor-2 receptor). An experimental model of human hepatocarcinogenesis such as in vitro neoplastic transformation of human hepatocytes has not been successfully achieved yet, but several immortalized human hepatocyte cell lines have been established. These immortalized human hepatocytes will become useful tools for the elucidation of hepatocarcinogenesis, especially for the initial step of multistep hepatocarcinogenesis.

Mountzios G, Kostopoulos I, Kotoula V, et al.
Insulin-like growth factor 1 receptor (IGF1R) expression and survival in operable squamous-cell laryngeal cancer.
PLoS One. 2013; 8(1):e54048 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Prognosis of patients with operable laryngeal cancer is highly variable and therefore potent prognostic biomarkers are warranted. The insulin-like growth factor receptor (IGFR) signaling pathway plays a critical role in laryngeal carcinogenesis and progression.
PATIENTS AND METHODS: We identified all patients with localized TNM stage I-III laryngeal cancer managed with potentially curative surgery between 1985 and 2008. Immunohistochemical (IHC) expression of IGF1R-alpha, IGF1R-beta and IGF2R was evaluated using the immunoreactive score (IRS) and mRNA levels of important effectors of the IGFR pathway were assessed, including IGF1R, IGF-binding protein 3 (IGFBP3), suppressor of cytokine signaling 2 (SOCS2) and members of the MAP-kinase (MAP2K1, MAPK9) and phosphatidyl-inositol-3 kinase (PIK3CA, PIK3R1) families. Cox-regression models were applied to assess the predictive value of biomarkers on disease-free survival (DFS) and overall survival (OS).
RESULTS: Among 289 eligible patients, 95.2% were current or ex smokers, 75.4% were alcohol abusers, 15.6% had node-positive disease and 32.2% had received post-operative irradiation. After a median follow-up of 74.5 months, median DFS was 94.5 months and median OS was 106.3 months. Using the median IRS as the pre-defined cut-off, patients whose tumors had increased IGF1R-alpha cytoplasm or membrane expression experienced marginally shorter DFS and significantly shorter OS compared to those whose tumors had low IGF1R-alpha expression (91.1 vs 106.2 months, p = 0.0538 and 100.3 vs 118.6 months, p = 0.0157, respectively). Increased mRNA levels of MAPK9 were associated with prolonged DFS (p = 0.0655) and OS (p = 0.0344). In multivariate analysis, IGF1R-alpha overexpression was associated with a 46.6% increase in the probability for relapse (p = 0.0374). Independent predictors for poor OS included node-positive disease (HR = 2.569, p<0.0001), subglottic/transglottic localization (HR = 1.756, p = 0.0438) and IGF1R-alpha protein overexpression (HR = 1.475, p = 0.0504).
CONCLUSION: IGF1R-alpha protein overexpression may serve as an independent predictor of relapse and survival in operable laryngeal cancer. Prospective evaluation of the IGF1R-alpha prognostic utility is warranted.

van Dorp W, van den Heuvel-Eibrink MM, Stolk L, et al.
Genetic variation may modify ovarian reserve in female childhood cancer survivors.
Hum Reprod. 2013; 28(4):1069-76 [PubMed] Related Publications
STUDY QUESTION: Are genetic polymorphisms, previously identified as being associated with age at menopause in the healthy population, associated with ovarian reserve and predicted age at menopause in adult long-term survivors of childhood cancer?
SUMMARY ANSWER: The CT genotype of rs1172822 in the BRSK1 gene is associated with lower serum anti-Müllerian hormone (AMH) levels and a younger predicted age at menopause in adult survivors of childhood cancer.
WHAT IS KNOWN ALREADY: Gonadotoxicity is a well-known late side effect of chemotherapy and radiotherapy in adult survivors of childhood cancer. In the healthy population, several genetic polymorphisms are associated with age at natural menopause. Currently, data on the impact of previously identified variants in gene loci associated with ovarian reserve in adult long-term survivors of childhood cancer are lacking.
STUDY DESIGN, SIZE, DURATION: We performed a pilot study in a single-centre cohort of adult female Caucasian childhood cancer survivors (n = 176).
PARTICIPANTS/MATERIALS, SETTING, METHODS: We determined serum AMH levels (a marker of ovarian reserve) in adult survivors of childhood cancer (n = 176) and studied single nucleotide polymorphisms (SNPs) previously reported to be associated with age at natural menopause: BRSK1 (rs1172822), ARHGEF7 (rs7333181), MCM8 (rs236114), PCSK1 (rs271924), IGF2R (rs9457827) and TNF (rs909253). Association analysis was performed using the additive genetic model. Linear regression was conducted to assess the effect of significant polymorphisms in two previously published menopause prediction models.
MAIN RESULTS AND THE ROLE OF CHANCE: The CT genotype of rs1172822 in the BRSK1 (BR serine/threonine kinase 1) gene was negatively associated with serum AMH levels in our cohort (odds ratio: 3.15, 95% confidence interval: 1.35-7.32, P = 0.008) and significantly associated with the predicted age at menopause (P = 0.04). The other five SNPs were not associated with serum AMH levels.
LIMITATIONS, REASONS FOR CAUTION: This is a pilot study showing preliminary data which must be confirmed. To confirm our findings and enlarge the project, a nationwide genome-wide association (GWA) project on the ovarian reserve in female survivors of childhood cancer should be performed, including a replication cohort.
WIDER IMPLICATIONS OF THE FINDINGS: Our findings support the hypothesis that previously identified genetic polymorphisms associated with age at menopause in healthy women may have an effect on the onset of menopause in female survivors of childhood cancer. Our study highlights a new aspect of the influences on the ovarian reserve after childhood cancer, which should be investigated further in a nationwide GWA study. Eventually, this information can help us to improve counselling on fertility preservation prior to cancer treatment based on genetic factors in individual patients.
STUDY FUNDING AND CONFLICT OF INTEREST: W.D. is supported by the Paediatric Oncology Centre Society for Research (KOCR), Rotterdam, The Netherlands. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Genovum, Merck-Serono, Organon, Schering Plough and Serono. All other authors have nothing to disclose.

Probst OC, Karayel E, Schida N, et al.
The mannose 6-phosphate-binding sites of M6P/IGF2R determine its capacity to suppress matrix invasion by squamous cell carcinoma cells.
Biochem J. 2013; 451(1):91-9 [PubMed] Free Access to Full Article Related Publications
The M6P (mannose 6-phosphate)/IGF2R (insulin-like growth factor II receptor) interacts with a variety of factors that impinge on tumour invasion and metastasis. It has been shown that expression of wild-type M6P/IGF2R reduces the tumorigenic and invasive properties of receptor-deficient SCC-VII squamous cell carcinoma cells. We have now used mutant forms of M6P/IGF2R to assess the relevance of the different ligand-binding sites of the receptor for its biological activities in this cellular system. The results of the present study demonstrate that M6P/IGF2R does not require a functional binding site for insulin-like growth factor II for inhibition of anchorage-independent growth and matrix invasion by SCC-VII cells. In contrast, the simultaneous mutation of both M6P-binding sites is sufficient to impair all cellular functions of the receptor tested. These findings highlight that the interaction between M6P/IGF2R and M6P-modified ligands is not only important for intracellular accumulation of lysosomal enzymes and formation of dense lysosomes, but is also crucial for the ability of the receptor to suppress SCC-VII growth and invasion. The present study also shows that some of the biological activities of M6P/IGF2R in SCC-VII cells strongly depend on a functional M6P-binding site within domain 3, thus providing further evidence for the non-redundant cellular functions of the individual carbohydrate-binding domains of the receptor.

Haouzi D, Assou S, Monzo C, et al.
Altered gene expression profile in cumulus cells of mature MII oocytes from patients with polycystic ovary syndrome.
Hum Reprod. 2012; 27(12):3523-30 [PubMed] Related Publications
STUDY QUESTION: Oocyte developmental competence is altered in patients with polycystic ovary syndrome (PCOS); is gene expression in cumulus cells (CCs) from mature metaphase II oocytes of patients with PCOS altered as well?
SUMMARY ANSWER: Compared with CCs from non-PCOS patients, the gene expression profile of CCs isolated from mature oocytes of patients with PCOS present alterations that could explain the abnormal folliculogenesis and reduced oocyte competence in such patients.
WHAT IS KNOWN ALREADY: Abnormal mRNA expression of several members of the insulin-like growth factor (IGF) family in CCs from PCOS patients was previously reported. Moreover, the whole transcriptome has been investigated in cultured CCs from PCOS patients.
STUDY DESIGN, SIZE AND DURATION: This retrospective study included six PCOS patients diagnosed following the Rotterdam Criteria and six non-PCOS patients who all underwent ICSI for male infertility in the assisted reproduction technique (ART) Department of Montpellier University Hospital, between 2009 and 2011.
PARTICIPANTS/MATERIALS, SETTING AND METHODS: CCs from PCOS and non-PCOS patients who underwent controlled ovarian stimulation (COS) were isolated mechanically before ICSI. Gene expression profiles were analysed using the microarray technology and the Significance Analysis of Microarray was applied to compare the expression profiles of CCs from PCOS and non-PCOS patients.
MAIN RESULTS: The gene expression profile of CCs from patients with PCOS was significantly different from that of CCs from non-PCOS patients. Specifically, CCs from women with PCOS were characterized by abnormal expression of many growth factors, including members of the epidermal growth factor-like (EGFR, EREG and AREG) and IGF-like families (IGF1R, IGF2R, IGF2BP2 and IGFBP2), that are known to play a role in oocyte competence. In addition, mRNA transcripts of factors involved in steroid metabolism, such as CYP11A1, CYP1B1, CYP19A1 and CYP2B7P1, were deregulated in PCOS CCs, and this could explain the abnormal steroidogenesis observed in these women. Functional annotation of the differentially expressed genes suggests that defects in the transforming growth factor β and estrogen receptors signalling cascades may contribute to the reduced oocyte developmental competence in patients with PCOS.
LIMITATIONS AND REASONS FOR CAUTION: Owing to the strict selection criteria (similar age, weight and reasons for ART), this study included a small sample size (six cases and six controls), and thus, further investigations using a large cohort of patients are needed to confirm these results.
WIDER IMPLICATIONS OF THE FINDINGS: This study opens a new perspective for understanding the pathogenesis of PCOS.
STUDY FUNDING/COMPETING INTERESTS: This work was partially supported by a grant from the Ferring Pharmaceutical. The authors of the study have no competing interests to report.

Kaur S, Archer KJ, Devi MG, et al.
Differential gene expression in granulosa cells from polycystic ovary syndrome patients with and without insulin resistance: identification of susceptibility gene sets through network analysis.
J Clin Endocrinol Metab. 2012; 97(10):E2016-21 [PubMed] Free Access to Full Article Related Publications
CONTEXT: Polycystic ovary syndrome (PCOS) is a heterogeneous, genetically complex, endocrine disorder of uncertain etiology in women.
OBJECTIVE: Our aim was to compare the gene expression profiles in stimulated granulosa cells of PCOS women with and without insulin resistance vs. matched controls.
RESEARCH DESIGN AND METHODS: This study included 12 normal ovulatory women (controls), 12 women with PCOS without evidence for insulin resistance (PCOS non-IR), and 16 women with insulin resistance (PCOS-IR) undergoing in vitro fertilization. Granulosa cell gene expression profiling was accomplished using Affymetrix Human Genome-U133 arrays. Differentially expressed genes were classified according to gene ontology using ingenuity pathway analysis tools. Microarray results for selected genes were confirmed by real-time quantitative PCR.
RESULTS: A total of 211 genes were differentially expressed in PCOS non-IR and PCOS-IR granulosa cells (fold change≥1.5; P≤0.001) vs. matched controls. Diabetes mellitus and inflammation genes were significantly increased in PCOS-IR patients. Real-time quantitative PCR confirmed higher expression of NCF2 (2.13-fold), TCF7L2 (1.92-fold), and SERPINA1 (5.35-fold). Increased expression of inflammation genes ITGAX (3.68-fold) and TAB2 (1.86-fold) was confirmed in PCOS non-IR. Different cardiometabolic disease genes were differentially expressed in the two groups. Decreased expression of CAV1 (-3.58-fold) in PCOS non-IR and SPARC (-1.88-fold) in PCOS-IR was confirmed. Differential expression of genes involved in TGF-β signaling (IGF2R, increased; and HAS2, decreased), and oxidative stress (TXNIP, increased) was confirmed in both groups.
CONCLUSIONS: Microarray analysis demonstrated differential expression of genes linked to diabetes mellitus, inflammation, cardiovascular diseases, and infertility in the granulosa cells of PCOS women with and without insulin resistance. Because these dysregulated genes are also involved in oxidative stress, lipid metabolism, and insulin signaling, we hypothesize that these genes may be involved in follicular growth arrest and metabolic disorders associated with the different phenotypes of PCOS.

Chokkalingam AP, Metayer C, Scelo G, et al.
Fetal growth and body size genes and risk of childhood acute lymphoblastic leukemia.
Cancer Causes Control. 2012; 23(9):1577-85 [PubMed] Free Access to Full Article Related Publications
Accumulating evidence suggests that childhood acute lymphoblastic leukemia (ALL) may be initiated in utero or early in the postnatal period. High birth weight (or rapid fetal growth) is associated with risk of ALL, but the mechanisms are not understood. In a population-based epidemiologic study of childhood ALL, we utilized a haplotype-based approach to assess the role of eight genes involved in fetal growth and body size regulation in 377 childhood ALL cases and 448 controls. We found significant haplotype associations with risk of childhood ALL for IGF1 among non-Hispanics and Hispanics together (p = 0.002), for IGF2 among Hispanics (p = 0.040), and for IGF2R among Hispanics and non-Hispanics (p = 0.051 and 0.009, respectively). No haplotype associations were observed for IGF1R or the studied genes involved in body size regulation, including LEP, LEPR, GHRL, and NPY. Our study is the first to identify an association between the genes involved in the IGF axis and risk of childhood ALL. These findings for childhood ALL emphasize the importance of fetal growth, when lymphoid progenitor cells are not yet fully differentiated and therefore more susceptible to malignant transformation. Additional studies are needed to confirm these findings and identify specific causal variants.

Kuhlmann JD, Schwarzenbach H, Wimberger P, et al.
LOH at 6q and 10q in fractionated circulating DNA of ovarian cancer patients is predictive for tumor cell spread and overall survival.
BMC Cancer. 2012; 12:325 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: We recently showed that LOH proximal to M6P/IGF2R locus (D6S1581) in primary ovarian tumors is predictive for the presence of disseminated tumor cells (DTC) in the bone marrow (BM). For therapy-monitoring, it would be highly desirable to establish a blood-based biomarker. Therefore, we quantified circulating DNA (cirDNA) in sera of 63 ovarian cancer patients before surgery and after chemotherapy, measured incidence of LOH at four cancer-relevant chromosomal loci, correlated LOH with tumor cell spread to the BM and evaluated prognostic significance of LOH.
METHODS: cirDNA was fractionated into high- and low molecular-weight fraction (HMWF, LMWF) for LOH-profiling, utilizing PCR-based fluorescence microsatellite analysis. BM aspirates were analyzed for DTC by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3.
RESULTS: cirDNA levels in the HMWF before surgery were predictive for residual tumor load (p = 0.017). After chemotherapy, we observed a significant decline of cirDNA in the LMWF (p = 0.0001) but not in the HMWF. LOH was prevalently detected in the LMWF with an overall frequency of 67%, only moderately ablating after chemotherapy (45%). Before surgery, LOH in the LMWF at marker D10S1765 and D13S218 significantly correlated with tumor grading and FIGO stage (p = 0.033, p = 0.004, respectively). In both combined fractions, LOH at D6S1581 additionally associated with overall survival (OS) (p = 0.030). Moreover, solely LOH at D10S1765 in LMWF after therapy correlated with DTC in BM after therapy (p = 0.017).
CONCLUSION: We demonstrate the applicability and necessity of DNA-fractionation prior to analyzing circulating LOH and identify LOH at D10S1765 and D6S1581 as novel blood-based biomarkers for ovarian cancer, being relevant for therapy-monitoring.

Kreiling JL, Montgomery MA, Wheeler JR, et al.
Dominant-negative effect of truncated mannose 6-phosphate/insulin-like growth factor II receptor species in cancer.
FEBS J. 2012; 279(15):2695-713 [PubMed] Free Access to Full Article Related Publications
Oligomerization of the mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) is important for optimal ligand binding and internalization. M6P/IGF2R is a tumor suppressor gene that exhibits loss of heterozygosity and is mutated in several cancers. We tested the potential dominant-negative effects of two cancer-associated mutations that truncate M6P/IGF2R in ectodomain repeats 9 and 14. Our hypothesis was that co-expression of the truncated receptors with the wild-type/endogenous full-length M6P/IGF2R would interfere with M6P/IGF2R function by heterodimer interference. Immunoprecipitation confirmed formation of heterodimeric complexes between full-length M6P/IGF2Rs and the truncated receptors, termed Rep9F and Rep14F. Remarkably, increasing expression of either Rep9F or Rep14F provoked decreased levels of full-length M6P/IGF2Rs in both cell lysates and plasma membranes, indicating a dominant-negative effect on receptor availability. Loss of full-length M6P/IGF2R was not due to increased proteasomal or lysosomal degradation, but instead arose from increased proteolytic cleavage of cell-surface M6P/IGF2Rs, resulting in ectodomain release, by a mechanism that was inhibited by metal ion chelators. These data suggest that M6P/IGF2R truncation mutants may contribute to the cancer phenotype by decreasing the availability of full-length M6P/IGF2Rs to perform tumor-suppressive functions such as binding/internalization of receptor ligands such as insulin-like growth factor II.

Takahashi Y, Mimori K, Yamamoto K, et al.
Genomic copy number of a carcinogenic single nucleotide polymorphism at 8q24 in non-risk allele colorectal cancer associated with insulin growth factor 2 receptor expression.
J Gastroenterol Hepatol. 2012; 27 Suppl 3:95-9 [PubMed] Related Publications
BACKGROUND AND AIM: The incidence of both diabetes mellitus and hyperlipidemia is increasing and they are risk factors for colorectal cancer (CRC). On the other hand, the carcinogenic significance of the single nucleotide polymorphism (SNP), rs6983267 at 8q24, in CRC has been reported. The association between the SNP genotype and genes associated with diabetes or hyperlipidemia was investigated in cases of CRC.
METHODS: In 107 cases of CRC diagnosed in eight institutes from 2003 to 2008, array-CGH and cDNA microarray was performed and the data analyzed from two groups subdivided according to SNP genotype.
RESULTS: In the array-CGH data, we selected 38 genes related to diabetes or fat metabolism, and of these 10 had a correlation coefficient between the genome copy number at 8q24 locus and that of each gene. Of the 10 genes, insulin growth factor 2 receptor (IGF2R) was the only one with an expression level significantly associated with the 8q24 genotype. IGF2R expression was significantly lower in non-risk allele than in risk allele cases (P = 0.012). There was neither a diabetes- nor a fat metabolism-related gene that was significantly associated with CRC cases with the risk allele at 8q24.
CONCLUSIONS: SNP at 8q24 makes diabetes a risk factor of CRC via IGF2R, especially in genetically non-risk allele cases. We speculate that the risk allele of 8q24 might be risky enough that diabetes is not necessary to worsen the risk for CRC.

Hartmann EM, Beà S, Navarro A, et al.
Increased tumor cell proliferation in mantle cell lymphoma is associated with elevated insulin-like growth factor 2 mRNA-binding protein 3 expression.
Mod Pathol. 2012; 25(9):1227-35 [PubMed] Related Publications
Mantle cell lymphoma is an aggressive, non-curable B-cell lymphoma, characterized by the translocation t(11;14)(q13;q32) involving CCND1 and a high number of additional genetic alterations. Chromosomal gains of 7p are frequent in mantle cell lymphoma, with insulin-like growth factor II mRNA-binding protein 3 (IGF2BP3 aka IMP3) being the most upregulated gene in this region. IGF2BP3 is a member of the IGF II mRNA-BP family, and increased IGF2BP3 expression is associated with an aggressive behavior in many malignant tumors. We here analyze selected genes related to IGF signaling in gene expression and genomic array data of 8 mantle cell lymphoma cell lines and 12 primary mantle cell lymphomas and study IGF2BP3 protein expression in 172 well-characterized primary mantle cell lymphomas by immunohistochemistry. The majority of mantle cell lymphoma cell lines and primary cases showed elevated IGF2BP3 mRNA expression and a subset also expressed the IGF1 and IGF2 receptors. On the protein level, 66 of 172 primary mantle cell lymphomas showed IGF2BP3 expression in >50% of tumor cells, and strong IGF2BP3 protein expression was highly associated with increased proliferation as measured by the Ki-67 index, but not with overall survival of mantle cell lymphoma patients. Only a subset of mantle cell lymphomas with marked IGF2BP3 expression had an underlying chromosomal gain in 7p, suggesting that additional mechanisms are involved in the upregulation of IGF2BP3 in mantle cell lymphoma. In seven paired mantle cell lymphoma samples, IGF2BP3 protein expression remained constant between primary diagnosis and relapse. Increased IGF2BP3 expression and, potentially, enhanced IGF signaling may contribute proproliferative stimuli in the evolution of mantle cell lymphoma tumor cells.

Hoyo C, Murphy SK, Schildkraut JM, et al.
IGF2R genetic variants, circulating IGF2 concentrations and colon cancer risk in African Americans and Whites.
Dis Markers. 2012; 32(2):133-41 [PubMed] Free Access to Full Article Related Publications
The Mannose 6 Phosphate/Insulin-like Growth Factor Receptor-2 (IGF2R) encodes a type-1 membrane protein that modulates availability of the potent mitogen, IGF2. We evaluated the associations between IGF2R non-synonymous genetic variants (c.5002G>A, Gly1619Arg(rs629849), and c.901C>G, Leu252Val(rs8191754)), circulating IGF2 levels, and colon cancer (CC) risk among African American and White participants enrolled in the North Carolina Colon Cancer Study (NCCCS). Generalized linear models were used to compare circulating levels of IGF2 among 298 African American and 518 White controls. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of IGF2R genetic variants and CC risk. Women homozygous for the IGF2R c.5002 G>A allele, had higher mean levels of circulating IGF2, 828 (SD=321) ng/ml compared to non-carriers, 595 (SD=217) ng/ml (p-value=0.01). This pattern was not apparent in individuals homozygous for the IGF2R c.901 C>G variant. Whites homozygous for the IGF2R c.901 C>G variant trended towards a higher risk of CC, OR=2.2 [95% CI(0.9-5.4)], whereas carrying the IGF2R c.5002 G>A variant was not associated with CC risk. Our findings support the hypothesis that being homozygous for the IGF2R c.5002 G>A modulates IGF2 circulating levels in a sex-specific manner, and while carrying the IGF2R c.901 C>G may increase cancer risk, the mechanism may not involve modulation of circulating IGF2.

Chen Y, Shao H, Li H, et al.
[Relationship of insulin-like growth factor receptor single nucleotide polymorphism (SNP) with platinum-based chemotherapy outcomes in advanced non-small cell lung cancer].
Zhongguo Fei Ai Za Zhi. 2012; 15(2):65-71 [PubMed] Related Publications
BACKGROUND AND OBJECTIVE: It has been proven that the insulin-like growth factor 1 receptor (IGF-1R) gene is an important regulator of many aspects of growth, differentiation, and development. The insulin-like growth factor 2 receptor (IGF-2R) gene is a negative mediator for carcinogenesis. The aim of this study is to investigate the relationship of IGF-1R+1013(G/A) and IGF-2R+1619(G/A) single nucleotide polymorphism (SNP) with platinum-based chemotherapy outcomes in advanced non-small cell lung cancer (NSCLC).
METHODS: A total of 132 patients with NSCLC were routinely treated with platinum-based chemotherapy, and their clinical responses were evaluated after four cycles of chemotherapy. IGF-1R+1013(G/A) and IGF-2R+1619(G/A) were genotyped using polymerase chain reaction-restrictive fragment length polymorphism. The relationship between IGF-1R+1013(G/A) and IGF-2R+1619(G/A) genotypes and the clinical benefit rate, as well as the median survival time (MST), was analyzed.
RESULTS: No significant association was found between IGF-1R+1013(G/A) and IGF-2R+1619(G/A) polymorphisms with clinical benefit (P>0.05). Further, we found that the two SNPs could not work together (P=0.975). The MST of patients with IGF-1R+1013(G/A) genotypes with A allele (GA+AA) was significantly shorter than that of GG genotype carriers (P=0.017). There was no significant difference in MST in patients with IGF-2R+1619(G/A) A allele (GA+AA) carrier and GG genotype carrier (P=0.575). The two SNPs showed a synergistic effect on MST. Patients who carried a mutant allele A of IGF-1R+1013(G/A) and a mutant allele A of IGF-2R+1619(G/A) had a MST of 12 months, which was significantly shorter than that of patients with other genotypes (P<0.05). Estimation by the Cox proportional hazards model showed that IGF-1R+1013(G/A) polymorphism is an independent prognostic factor (P=0.020), and IGF-1R+1013(G/A) polymorphism in combination with IGF-2R +1619(G/A) polymorphism is an independent prognostic factor in advanced NSCLC (P=0.025).
CONCLUSIONS: IGF-1R+1013(G/A) polymorphism alone or in combination with IGF-2R +1619(G/A) polymorphism was associated with the overall survival period in patients with advanced NSCLC after treatment with platin-based chemotherapy, which might be a prognostic factor in platin-treated patients with advanced NSCLC.

Dong X, Li Y, Tang H, et al.
Insulin-like growth factor axis gene polymorphisms modify risk of pancreatic cancer.
Cancer Epidemiol. 2012; 36(2):206-11 [PubMed] Related Publications
OBJECTIVE: Insulin-like growth factor (IGF)-axis genes plays a critical role in cancer development and progression via their impact on the RAS/MAPK/ERK and PI3K/AKT/mTOR signaling pathways. We hypothesized that IGF-axis genetic variants modify individual susceptibility to pancreatic cancer.
METHODS: We retrospectively genotyped 41 single-nucleotide polymorphisms of 10 IGF-axis genes (IGF1, IGF2, IGF1R, IGF2R, IGFBP1, IGFBP3, IGFBP5, IRS1, IRS2, and IRS4) in 706 pancreatic cancer patients and 706 cancer-free controls using Sequenom and TaqMan technology. The association between genotype and pancreatic cancer risk was evaluated using multivariate logistic regression. A P value ≤.007 at a false discovery rate of 10% was set as the significance level.
RESULTS: We observed that the IGF1 *10212C>A and Ex4+2776G>A and IGF1R IVS2-70184A>G and IVS2+46329T>C variant genotypes were significantly associated with decreased pancreatic cancer risk (odds ratio [OR] range, 0.60-0.75) and that IGFBP1 Ex4+111A>G (I253M) was significantly associated with increased pancreatic cancer risk (OR=1.46) after adjusted for other risk factors and multiple comparisons (P≤.007). IGF2R and IGFBP3 variant haplotypes were associated with increased and decreased pancreatic cancer risk, respectively (P<.001). We also observed a weak interaction of the IGF1R IVS2+46329T>C and IGF2R Ex45+11C>T (L2222L) genotypes with diabetes (P(interaction)=.05) and interaction of IGF2R and IRS1 genotypes with alcohol consumption (P(interaction)=.03 and .019, respectively) on increased pancreatic cancer risk.
CONCLUSION: These findings support our hypothesis that polymorphic variants of IGF-axis genes act alone or jointly with other risk factors to affect susceptibility to pancreatic cancer.

Kuhlmann JD, Schwarzenbach H, Otterbach F, et al.
Loss of heterozygosity proximal to the M6P/IGF2R locus is predictive for the presence of disseminated tumor cells in the bone marrow of ovarian cancer patients before and after chemotherapy.
Genes Chromosomes Cancer. 2011; 50(8):598-605 [PubMed] Related Publications
Disseminated tumor cells (DTC) in the bone marrow (BM) are present in about 35% of ovarian cancers before surgery and after chemotherapy and are associated with worse prognosis. A molecular biomarker in the primary tumor predicting tumor cell spread would be highly desirable. The purpose of the study was to investigate loss of heterozygosity (LOH) in primary ovarian tumors at four ovarian cancer-relevant chromosomal loci involved in apoptosis, platinum sensitivity, or DNA-repair, to assess the prognostic value of LOH and to correlate LOH with DTC occurrence before surgery and after chemotherapy. Primary tumor DNA of 88 patients was analyzed for LOH at four polymorphic microsatellite markers using PCR-based fluorescence microsatellite analysis. BM aspirates were analyzed for DTC by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. LOH at the entire marker set correlated with tumor grading (P = 0.0001) and histology (P = 0.004). LOH at marker D10S1765 correlated with FIGO stage (P = 0.046) and grading (P = 0.05), whereas LOH at D17S855 significantly associated with grading (P = 0.023) and histology (P = 0.012), respectively. DTC were detected in 49% of patients before surgery and in 50% of patients after chemotherapy. Interestingly, LOH proximal to D6S1581 significantly correlated with DTC presence before surgery (P = 0.05) and after chemotherapy (P = 0.022). Conclusively, our data suggest that allelic loss at D6S1581 (proximal to M6P/IGF2R locus) serves as a molecular biomarker for the presence of DTC in the BM before and after chemotherapy.

Yoon AJ, Zavras AI, Chen MK, et al.
Association between Gly1619ARG polymorphism of IGF2R domain 11 (rs629849) and advanced stage of oral cancer.
Med Oncol. 2012; 29(2):682-5 [PubMed] Related Publications
Insulin-like growth factor II receptor (IGF2R) degrades mitogen and hence is associated with tumor suppressor function. The aim of this study was to assess whether genetic variation in the mitogen-binding domain of IGF2R, Gly1619Arg, disrupts normal function of IGF2R and contributes to further progression and distant metastasis of localized oral squamous cell carcinoma (OSCC). Gly1619Arg polymorphism of IGF2R domain 11 (rs629849) was assessed in blood samples of 113 individuals with histology-confirmed OSCC, and IGF2R genotypes were correlated with the stage of tumor (localized; TMN stages I-II versus advanced; TMN stages III-IV). After controlling for demographic covariates and known risk factors for oral cancer, such as tobacco, alcohol, and areca nut use, threefold increased risk of advanced stage of OSCC was noted in those subjects who had one or two copies of the IGF2R-A-allele when compared with the GG genotype. In contrast, when compared with the carriers of the A-allele, the GG genotype demonstrated to be protective against advanced disease (adjusted odds ratios of 0.32). IGF2R genetic polymorphism may be associated with decreased function of IGF2 receptor there by contributing to the advancement and distant metastasis of localized oral cancer.

Chargari C, Boige V, Deutsch E
[New perspectives for radiosensitization in hepatocellular carcinoma: a review of mechanisms involved in liver oncogenesis].
Cancer Radiother. 2011; 15(1):32-8 [PubMed] Related Publications
New perspectives for radiosensitization in hepatocellular carcinoma (HCC) have emerged with the increasing knowledge of mechanisms involved in liver oncogenesis. As a matter of fact, some of these mechanisms have also a role in the response to ionizing radiation. We review some of the major molecular pathways involved in the oncogenesis of hepatocellular carcinoma. These include cellular proliferation pathways, repair systems, apoptosis, and angiogenesis. However, there are few preclinical data on concurrent targeted therapies and ionizing radiation in hepatocellular carcinoma models. Preliminary studies are ongoing. Their results might help to better define the potential benefit of such radiosensitizing strategies in the management of hepatocellular carcinoma.

Malaguarnera R, Frasca F, Garozzo A, et al.
Insulin receptor isoforms and insulin-like growth factor receptor in human follicular cell precursors from papillary thyroid cancer and normal thyroid.
J Clin Endocrinol Metab. 2011; 96(3):766-74 [PubMed] Related Publications
CONTEXT: Factors involved in the biology of normal and cancer stem/precursor cells from the thyroid are unknown. Thyroid cancer cells are responsive to insulin and IGF-I and IGF-II and often overexpress the insulin receptor (IR) and the IGF-I receptor (IGF-IR).
OBJECTIVE: We investigated the role of IR isoforms (IR-A and IR-B), IGF-IR, and their ligands in thyroid follicular cell precursors both normal and malignant.
DESIGN: We established cultures of follicular cell precursors as thyrospheres from three papillary thyroid cancers and the corresponding nonaffected tissues. The expression of IR, IGF-IR, and their ligands was evaluated by quantitative RT-PCR and, in one case, also by Western blot. The effects of insulin and IGFs on thyrosphere growth and self-renewal were evaluated.
RESULTS: Thyrospheres were characterized by the expression of stem cell markers and low/absent thyroid specific markers. Thyrospheres from normal tissue, but not from cancer tissue, could be induced to differentiate. Both IR isoforms, IGF-IR, IGF-I and IGF-II, were expressed at high levels in thyrospheres and markedly decreased in differentiating cells. IR-A was the predominant isoform in thyrospheres, especially from cancer, while IR-B was predominant in differentiating cells. Cancer thyrosphere growth was stimulated by insulin and IGFs.
CONCLUSIONS: Our data suggest that IR isoforms and IGF-IR play a role in the biology of follicular thyroid precursors. Cell differentiation is associated with marked changes in the expression of these receptors and cognate ligands. These data may provide insight for future differentiation therapies in thyroid cancer.

Levy C, Khaled M, Iliopoulos D, et al.
Intronic miR-211 assumes the tumor suppressive function of its host gene in melanoma.
Mol Cell. 2010; 40(5):841-9 [PubMed] Free Access to Full Article Related Publications
When it escapes early detection, malignant melanoma becomes a highly lethal and treatment-refractory cancer. Melastatin is greatly downregulated in metastatic melanomas and is widely believed to function as a melanoma tumor suppressor. Here we report that tumor suppressive activity is not mediated by melastatin but instead by a microRNA (miR-211) hosted within an intron of melastatin. Increasing expression of miR-211 but not melastatin reduced migration and invasion of malignant and highly invasive human melanomas characterized by low levels of melastatin and miR-211. An unbiased network analysis of melanoma-expressed genes filtered for their roles in metastasis identified three central node genes: IGF2R, TGFBR2, and NFAT5. Expression of these genes was reduced by miR-211, and knockdown of each gene phenocopied the effects of increased miR-211 on melanoma invasiveness. These data implicate miR-211 as a suppressor of melanoma invasion whose expression is silenced or selected against via suppression of the entire melastatin locus during human melanoma progression.

Pinheiro M, Ahlquist T, Danielsen SA, et al.
Colorectal carcinomas with microsatellite instability display a different pattern of target gene mutations according to large bowel site of origin.
BMC Cancer. 2010; 10:587 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Only a few studies have addressed the molecular pathways specifically involved in carcinogenesis of the distal colon and rectum. We aimed to identify potential differences among genetic alterations in distal colon and rectal carcinomas as compared to cancers arising elsewhere in the large bowel.
METHODS: Constitutional and tumor DNA from a test series of 37 patients with rectal and 25 patients with sigmoid carcinomas, previously analyzed for microsatellite instability (MSI), was studied for BAX, IGF2R, TGFBR2, MSH3, and MSH6 microsatellite sequence alterations, BRAF and KRAS mutations, and MLH1 promoter methylation. The findings were then compared with those of an independent validation series consisting of 36 MSI-H carcinomas with origin from each of the large bowel regions. Immunohistochemical and germline mutation analyses of the mismatch repair system were performed when appropriate.
RESULTS: In the test series, IGFR2 and BAX mutations were present in one and two out of the six distal MSI-H carcinomas, respectively, and no mutations were detected in TGFBR2, MSH3, and MSH6. We confirmed these findings in the validation series, with TGFBR2 and MSH3 microsatellite mutations occurring less frequently in MSI-H rectal and sigmoid carcinomas than in MSI-H colon carcinomas elsewhere (P = 0.00005 and P = 0.0000005, respectively, when considering all MSI-carcinomas of both series). No MLH1 promoter methylation was observed in the MSI-H rectal and sigmoid carcinomas of both series, as compared to 53% found in MSI-H carcinomas from other locations (P = 0.004). KRAS and BRAF mutational frequencies were 19% and 43% in proximal carcinomas and 25% and 17% in rectal/sigmoid carcinomas, respectively.
CONCLUSION: The mechanism and the pattern of genetic changes driving MSI-H carcinogenesis in distal colon and rectum appears to differ from that occurring elsewhere in the colon and further investigation is warranted both in patients with sporadic or hereditary disease.

Massoner P, Ladurner-Rennau M, Eder IE, Klocker H
Insulin-like growth factors and insulin control a multifunctional signalling network of significant importance in cancer.
Br J Cancer. 2010; 103(10):1479-84 [PubMed] Free Access to Full Article Related Publications
Insulin-like growth factor (IGF) and insulin (INS) proteins regulate key cellular functions through a complex interacting multi-component molecular network, known as the IGF/INS axis. We describe how dynamic and multilayer interactions give rise to the multifunctional role of the IGF/INS axis. Furthermore, we summarise the importance of the regulatory IGF/INS network in cancer, and discuss the possibilities and limitations of therapies targeting the IGF/INS axis with reference to ongoing clinical trials concerning the blockage of IGF1R in several types of cancer.

Yashiro M, Hirakawa K, Boland CR
Mutations in TGFbeta-RII and BAX mediate tumor progression in the later stages of colorectal cancer with microsatellite instability.
BMC Cancer. 2010; 10:303 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Microsatellite instability (MSI) occurs in 15% of colorectal cancers (CRC). The genetic targets for mutation in the MSI phenotype include somatic mutations in the transforming growth factor beta receptor typeII (TGFbetaRII), BAX, hMSH3 and hMSH6. It is not clear how mutations of these genes mediate tumor progression in the MSI pathway, and the temporal sequence of these mutations remains uncertain. In this study, early stage CRCs were examined for frameshift mutations in these target genes, and compared with late stage tumors and CRC cell lines.
METHODS: We investigated 6 CRC cell lines and 71 sporadic CRCs, including 61 early stage cancers and 10 late stage cancers. Mutations of repetitive mononucleotide tracts in the coding regions of TGFbetaRII, BAX, hMSH3, hMSH6, IGFIIR and Fas antigen were identified by direct sequencing.
RESULTS: Thirteen (18.3%) of 71 CRC, including 9/61 (14.7%) early stage cancers and 4/10 (40%) late stage cancers, were identified as MSI and analyzed for frameshift mutations. No mutation in the target genes was observed in any of the 9 early stage MSI CRCs. In contrast, frameshift mutations of TGFbetaRII, BAX, hMSH3 and hMSH6 were present in 3/4 late stage MSI tumors. There is a statistical association (p = 0.014) between mutation in any one gene and tumor stage.
CONCLUSIONS: TGFbetaRII, BAX, hMSH3 and hMSH6 mutations are relatively late events in the genesis of MSI CRCs. The frameshift mutations in these target genes might mediate progression from early to late stage cancer, rather than mediating the adenoma to carcinoma transition.

Xu L, Hausmann M, Dietmaier W, et al.
Expression of growth factor receptors and targeting of EGFR in cholangiocarcinoma cell lines.
BMC Cancer. 2010; 10:302 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cholangiocarcinoma (CC) is a malignant neoplasm of the bile ducts or the gallbladder. Targeting of growth factor receptors showed therapeutic potential in palliative settings for many solid tumors. The aim of this study was to determine the expression of seven growth factor receptors in CC cell lines and to assess the effect of blocking the EGFR receptor in vitro.
METHODS: Expression of EGFR (epithelial growth factor receptor), HGFR (hepatocyte growth factor receptor) IGF1R (insulin-like growth factor 1 receptor), IGF2R (insulin-like growth factor 2 receptor) and VEGFR1-3 (vascular endothelial growth factor receptor 1-3) were examined in four human CC cell lines (EGI-1, HuH28, OZ and TFK-1). The effect of the anti-EGFR-antibody cetuximab on cell growth and apoptosis was studied and cell lines were examined for KRAS mutations.
RESULTS: EGFR, HGFR and IGFR1 were present in all four cell lines tested. IGFR2 expression was confirmed in EGI-1 and TFK-1. No growth-inhibitory effect was found in EGI-1 cells after incubation with cetuximab. Cetuximab dose-dependently inhibited growth in TFK-1. Increased apoptosis was only seen in TFK-1 cells at the highest cetuximab dose tested (1 mg/ml), with no dose-response-relationship at lower concentrations. In EGI-1 a heterozygous KRAS mutation was found in codon 12 (c.35G>A; p.G12D). HuH28, OZ and TFK-1 lacked KRAS mutation.
CONCLUSION: CC cell lines express a pattern of different growth receptors in vitro. Growth factor inhibitor treatment could be affected from the KRAS genotype in CC. The expression of EGFR itself does not allow prognoses on growth inhibition by cetuximab.

Soares MR, Huber J, Rios AF, Ramos ES
Investigation of IGF2/ApaI and H19/RsaI polymorphisms in patients with cutaneous melanoma.
Growth Horm IGF Res. 2010; 20(4):295-7 [PubMed] Related Publications
OBJECTIVE: The etiology of cutaneous melanoma is complex, involving both heterogeneous genetic and environmental components. The aim of our study was to verify if single polymorphic sites within IGF2 and H19 genes and their consequent haplotypes influence risk and/or prognosis of familial melanoma.
DESIGN: Twenty one patients with clinical criteria of hereditary melanoma (early onset, presence of multiple primary melanoma, and/or one or more affected first- or second-degree relatives) and previously screened for CDKN2A mutations were genotyped by IGF2/ApaI and H19/RsaI PCR-RFLPs. Data were compared between patients and a control group (100 healthy young individuals) using Chi-square and Fisher's exact tests. We also investigated if these polymorphic sites could be microRNAs potential targets, using RegRNA software.
RESULTS: Although the IGF2 and H19 genotypes/haplotypes were not significantly associated with melanoma, two of the most severe cases (very early onset or multiple melanomas) showed to be heterozygous for both genes. We found an overlap between IGF2/ApaI and miR-615-5p, and between H19/RsaI and miR-574-3p.
CONCLUSIONS: Some studies have shown H19, and IGF2 genes (or related genes or protein, for example, IGF2R and IMP-3) differential expression in melanoma. However, no study has attempted to examine markers across this cluster in relation to melanoma until now. Since the base change may impair the pairing of microRNA and its binding site, our results suggest a new window for future studies of IGF2 and H19 genetic variability and posttranscriptional regulation. Due to the importance and based on the present results, we suggest that the genotype/haplotype analysis of IGF2 and H19 polymorphisms should be better investigated in large populations with cutaneous melanoma, attempting to tie the association with progression of the disease.

Dong X, Javle M, Hess KR, et al.
Insulin-like growth factor axis gene polymorphisms and clinical outcomes in pancreatic cancer.
Gastroenterology. 2010; 139(2):464-73, 473.e1-3 [PubMed] Free Access to Full Article Related Publications
BACKGROUND & AIMS: Insulin-like growth factor (IGF)-axis mediated signaling pathways play an important role in pancreatic cancer development and progression. We examined whether IGF-axis gene variants are associated with clinical outcomes in pancreatic cancer.
METHODS: We retrospectively genotyped 41 single-nucleotide polymorphisms from 10 IGF-axis genes in 333 patients with localized pancreatic adenocarcinoma and validated the findings in 373 patients with advanced disease. Associations between genotype and overall survival (OS) were evaluated using multivariable Cox proportional hazard regression models.
RESULTS: IGF1 *8470T>C, IGF1R IVS2+46329T>C, IGFBP3 A32G, IRS1 G972R in patients with localized disease; IGF1R IVS20-3431A>G, IGF1R T766T, IGFBP3-202A>C, IRS1 IVS1+4315C>G, IRS1 G972R in patients with advanced disease; and IGF1R T766T, IGF2R L252V, IGFBP3 -202A>C, IRS1 IVS1+4315C>G, IRS1 G972R, IRS2 IVS1+5687T>C in all patients were significantly associated with OS (PA, and an IRS2 haplotype predicted worse OS (PCONCLUSIONS: These data suggest that individual genetic variations in the IGF axis pathway may predict worse survival in patients with pancreatic cancer. This information may identify population subgroups that could benefit from IGF(1)R-targeted agents.

Kalla Singh S, Tan QW, Brito C, et al.
Insulin-like growth factors I and II receptors in the breast cancer survival disparity among African-American women.
Growth Horm IGF Res. 2010; 20(3):245-54 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: African-American (AA) women with breast cancer are more likely to have advanced disease at diagnosis, higher risk of recurrence and poorer prognosis than Caucasian (CA) women. We have recently shown higher insulin-like growth factor II (IGF-II) expression in paired breast tissue samples from AA women as compared to CA women. IGF-II is a potent mitogen that induces cell proliferation and survival signals through activation of the IGF-I and Insulin receptors (IGF-IR, IR) while IGF-II circulating levels are regulated by cellular uptake through the IGF2 receptor. We hypothesize that differential expression of the IGF1R and IGF2R among AA and CA women potentiates IGF-II mitogenic effects, thus contributing to the health disparity observed between these ethnic groups.
DESIGN: We examined IGF-IR and IGF2R mRNA, protein expression and IGF1R phosphorylation in paired breast tissue samples from AA and CA women by Real Time-PCR, Western blot analysis, immunohistochemistry and ELISA techniques.
RESULTS: Our results showed significantly increased expression of IGF1R in AA normal tissues as compared to CA normal tissues. IGF1R expression was similar between AA normal and malignant tissues, while IGF1R, IRS-1 and Shc phosphorylation was significantly higher in AA tumor samples. Significantly higher levels of IGF2R were found in CA tumor samples as compared to AA tumor samples.
CONCLUSIONS: We conclude that IGF1R and IGF2R differential expression may contribute to the increased risk of malignant transformation in young AA women and to the more aggressive breast cancer phenotype observed among AA breast cancer patients and represent, along with IGF-II, potential therapeutic targets in breast cancer.

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