Gene Summary

Gene:LRIG3; leucine rich repeats and immunoglobulin like domains 3
Aliases: LIG3
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:leucine-rich repeats and immunoglobulin-like domains protein 3
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
LRIG3 is implicated in:
- integral to membrane
Data from Gene Ontology via CGAP

Cancer Overview

Research Indicators

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

Literature Analysis

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

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: LRIG3 (cancer-related)

Hua RX, Zhuo Z, Zhu J, et al.
LIG3 gene polymorphisms and risk of gastric cancer in a Southern Chinese population.
Gene. 2019; 705:90-94 [PubMed] Related Publications
DNA ligase III (LIG3) has been implicated in the etiology of cancer. However, few studies have accessed the association of LIG3 single nucleotide polymorphisms (SNPs) with gastric cancer risk, especially in Chinese population. The current study was undertaken to investigate contribution of LIG3 gene polymorphisms to gastric cancer risk. We first applied TaqMan assay to genotype three LIG3 gene SNPs (rs1052536 C > T, rs3744356 C > T, rs4796030 A > C) in 1142 patients with gastric cancer and 1173 healthy controls. And then, we adopted unconditional multivariate logistic regression analysis to estimate the association between LIG3 SNP genotypes and gastric cancer risk. In all, no positive association was found between the three LIG3 SNPs and gastric cancer risk in single locus analysis or combined risk genotypes analysis. However, compared with participants with rs4796030 AA genotype, participants with the AC/CC had a decreased risk of developing tumors from cardia at an adjusted OR of 0.68 (95% CI = 0.48-0.96, P = 0.026). In addition, we found that participants harboring 2-3 risk genotypes were at a significantly increased risk of developing tumor from cardia (adjusted OR = 1.63, 95% CI = 1.16-2.28, P = 0.005). These results suggest that genetic variations in LIG3 gene may play a weak role in modifying the risk of gastric cancer. Future functional studies should be performed to elucidate the biological role of LIG3 polymorphisms in gastric cancer carcinogenesis.

Karlsson T, Kvarnbrink S, Holmlund C, et al.
LMO7 and LIMCH1 interact with LRIG proteins in lung cancer, with prognostic implications for early-stage disease.
Lung Cancer. 2018; 125:174-184 [PubMed] Related Publications
OBJECTIVES: The human leucine-rich repeats and immunoglobulin-like domains (LRIG) protein family comprises the integral membrane proteins LRIG1, LRIG2 and LRIG3. LRIG1 is frequently down-regulated in human cancer, and high levels of LRIG1 in tumor tissue are associated with favorable clinical outcomes in several tumor types including non-small cell lung cancer (NSCLC). Mechanistically, LRIG1 negatively regulates receptor tyrosine kinases and functions as a tumor suppressor. However, the details of the molecular mechanisms involved are poorly understood, and even less is known about the functions of LRIG2 and LRIG3. The aim of this study was to further elucidate the functions and molecular interactions of the LRIG proteins.
MATERIALS AND METHODS: A yeast two-hybrid screen was performed using a cytosolic LRIG3 peptide as bait. In transfected human cells, co-immunoprecipitation and co-localization experiments were performed. Proximity ligation assay was performed to investigate interactions between endogenously expressed proteins. Expression levels of LMO7 and LIMCH1 in normal and malignant lung tissue were investigated using qRT-PCR and through in silico analyses of public data sets. Finally, a clinical cohort comprising 355 surgically treated NSCLC cases was immunostained for LMO7.
RESULTS: In the yeast two-hybrid screen, the two paralogous proteins LMO7 and LIMCH1 were identified as interaction partners to LRIG3. LMO7 and LIMCH1 co-localized and co-immunoprecipitated with both LRIG1 and LRIG3. Endogenously expressed LMO7 was in close proximity of both LRIG1 and LRIG3. LMO7 and LIMCH1 were highly expressed in normal lung tissue and down-regulated in malignant lung tissue. LMO7 immunoreactivity was shown to be a negative prognostic factor in LRIG1 positive tumors, predicting poor patient survival.
CONCLUSION: These findings suggest that LMO7 and LIMCH1 physically interact with LRIG proteins and that expression of LMO7 is of clinical importance in NSCLC.

Chen Y, Wang Q, Wang M, Li M
Overexpressed LRIG3 gene ameliorates prostate cancer through suppression of cell invasion and migration.
Int J Biol Macromol. 2019; 124:1-9 [PubMed] Related Publications
Prostate cancer (PC) is one of the most common human malignancies, which has been steadily rising among males in many countries. The leucine-rich repeats and immunoglobulin-like domains (LRIG) genes were applied in the prognosis of different types of cancers, including PC. In that case, this study is supposed to investigate the effects of LRIG3 on PC cells. LRIG3 was overexpressed or under-expressed by the rAd and siRNA to determine the effect of LRIG3 on PC and explore the possible mechanism. The mRNA and protein levels of LRIG3 were tested by RT-qPCR and western blot analysis. Cell apoptosis, viability, migration and invasion were measured using MTT assay, flow cytometry and Transwell assay respectively. We observed that LRIG3 mRNA and protein levels were decreased in PC-3 cells. PC-3 cells treated with rAd-LRIG3 exhibited significantly increased cell apoptosis while inhibited viability, adhesion, migration and invasion. However, C4-2 cells treated with siRNA-LRIG3 showed reciprocal results. In conclusion, these data of the current study indicated that overexpressed LRIG3 gene expression might inhibit the viability, adhesion, invasion and migration and promote the apoptosis of PC cells. rAd-mediated LRIG3 may facilitate a novel aspect of the treatment of patients suffering from with PC.

Caracciolo D, Di Martino MT, Amodio N, et al.
miR-22 suppresses DNA ligase III addiction in multiple myeloma.
Leukemia. 2019; 33(2):487-498 [PubMed] Free Access to Full Article Related Publications
Multiple myeloma (MM) is a hematologic malignancy characterized by high genomic instability. Here we provide evidence that hyper-activation of DNA ligase III (LIG3) is crucial for genomic instability and survival of MM cells. LIG3 mRNA expression in MM patients correlates with shorter survival and even increases with more advanced stage of disease. Knockdown of LIG3 impairs MM cells viability in vitro and in vivo, suggesting that neoplastic plasmacells are dependent on LIG3-driven repair. To investigate the mechanisms involved in LIG3 expression, we investigated the post-transcriptional regulation. We identified miR-22-3p as effective negative regulator of LIG3 in MM. Enforced expression of miR-22 in MM cells downregulated LIG3 protein, which in turn increased DNA damage inhibiting in vitro and in vivo cell growth. Taken together, our findings demonstrate that myeloma cells are addicted to LIG3, which can be effectively inhibited by miR-22, promoting a novel axis of genome stability regulation.

Hu Y, Lin J, Fang H, et al.
Targeting the MALAT1/PARP1/LIG3 complex induces DNA damage and apoptosis in multiple myeloma.
Leukemia. 2018; 32(10):2250-2262 [PubMed] Free Access to Full Article Related Publications
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a highly conserved long non-coding RNA (lncRNA). Overexpression of MALAT1 has been demonstrated to related to poor prognosis of multiple myeloma (MM) patients. Here, we demonstrated that MALAT1 plays important roles in MM DNA repair and cell death. We found bone marrow plasma cells from patients with monoclonal gammopathy of undetermined significance (MGUS) and MM express elevated MALAT1 and involve in alternative non-homozygous end joining (A-NHEJ) pathway by binding to PARP1 and LIG3, two key components of the A-NHEJ protein complex. Degradation of the MALAT1 RNA by RNase H using antisense gapmer DNA oligos in MM cells stimulated poly-ADP-ribosylation of nuclear proteins, defected the DNA repair pathway, and further provoked apoptotic pathways. Anti-MALAT1 therapy combined with PARP1 inhibitor or proteasome inhibitor in MM cells showed a synergistic effect in vitro. Furthermore, using novel single-wall carbon nanotube (SWCNT) conjugated with anti-MALAT1 oligos, we successfully knocked-down MALAT1 RNA in cultured MM cell lines and xenograft murine models. Most importantly, anti-MALAT1 therapy induced DNA damage and cell apoptosis in vivo, indicating that MALAT1 could serve as a potential novel therapeutic target for MM treatment.

Liao YH, Ren JT, Zhang W, et al.
Polymorphisms in homologous recombination repair genes and the risk and survival of breast cancer.
J Gene Med. 2017; 19(9-10) [PubMed] Related Publications
BACKGROUND: Immunoglobulin (Ig)A antibody of Epstein-Barr virus (EBV) was found to associate with breast cancer (BC), whereas IgA positivity was related to a series of genetic markers in the genes of homologous recombination repair system (HRRs). We assessed the associations of the polymorphisms in HRR genes with the risk and survival of BC.
METHODS: A case-control study was conducted with 1551 bc cases and 1605 age-matched healthy controls between October 2008 and March 2012 in the Guangzhou Breast Cancer Study (GZBCS), China, and the case population were followed up until 31 January 2016. Five single nucleotide polymorphisms of candidate genes in HRR system were genotyped. Odds ratios (ORs) and hazards ratios (HRs) were calculated using multivariate logistic regression and Cox proportional hazards regression to estimate the risk and prognostic effect, respectively.
RESULTS: RFC1 rs6829064 (AA) was associated with an increased BC risk [OR = 1.35; 95% confidence interval (CI) = 1.06-1.73] compared to the wild genotype (GG). NRM rs1075496 (GT/TT versus GG) was associated with a worse progression-free survival (PFS) and the HR was 1.34 (95% CI = 1.01-1.78), particularly among advanced patients. LIG3 rs1052536 (CT/TT versus CC) was associated with a better PFS and the HR was 0.70 (95% CI = 0.53-0.93). However, RAD54L rs1710286 and RPA1 rs11078676 were not observed to be associated with either the risk or survival of BC.
CONCLUSIONS: The findings of the present study suggest that the polymorphisms in HRR genes were associated with BC risk (RFC1 rs6829064) and prognosis (NRM rs1075496 and LIG3 rs1052536), whereas RAD54L rs1710286 and RPA1 rs11078676 had null associations with BC.

Krupa R, Czarny P, Wigner P, et al.
The Relationship Between Single-Nucleotide Polymorphisms, the Expression of DNA Damage Response Genes, and Hepatocellular Carcinoma in a Polish Population.
DNA Cell Biol. 2017; 36(8):693-708 [PubMed] Related Publications
The molecular mechanism of hepatocellular carcinoma (HCC) is related to DNA damage caused by oxidative stress products induced by hepatitis B virus (HBV) or C (HCV) infection and exposure to environmental pollutants. Single-nucleotide polymorphisms (SNPs) of DNA damage response (DDR) genes may influence individual susceptibility to environmental risk factors and affect DNA repair efficacy, which, in turn, can influence the risk of HCC. The study evaluates a panel of 15 SNPs in 11 DDR genes (XRCC1, XRCC3, XPD, MUTYH, LIG1, LIG3, hOGG1, PARP1, NFIL1, FEN1, and APEX1) in 65 HCC patients, 50 HBV- and 50 HCV-infected non-cancerous patients, and 50 healthy controls. It also estimates the mRNA expression of nine DDR genes in cancerous and adjacent healthy liver tissues. Two of the investigated polymorphisms (rs1052133 and rs13181) were associated with HCC risk. For all investigated genes, the level of mRNA was significantly lower in HCC cancer tissue than in non-cancerous liver tissue. Seven of the investigated polymorphisms were statistically related to gene expression in cancer tissues. The disruption of DDR genes may be responsible for hepatocellular transformation in HCV-infected patients.

Roskoski R
ROS1 protein-tyrosine kinase inhibitors in the treatment of ROS1 fusion protein-driven non-small cell lung cancers.
Pharmacol Res. 2017; 121:202-212 [PubMed] Related Publications
ROS1 protein-tyrosine kinase fusion proteins are expressed in 1-2% of non-small cell lung cancers. The ROS1 fusion partners include CD74, CCDC6, EZR, FIG, KDELR2, LRIG3, MSN, SDC4, SLC34A2, TMEM106B, TMP3, and TPD52L1. Physiological ROS1 is closely related to the ALK, LTK, and insulin receptor protein-tyrosine kinases. ROS1 is a so-called orphan receptor because the identity of its activating ligand, if any, is unknown. The receptor is expressed during development, but little is expressed in adults and its physiological function is unknown. The human ROS1 gene encodes 2347 amino acid residues and ROS1 is the largest protein-tyrosine kinase receptor protein. Unlike the ALK fusion proteins that are activated by the dimerization induced by their amino-terminal portions, the amino-terminal domains of several of its fusion proteins including CD74 apparently lack the ability to induce dimerization so that the mechanism of constitutive protein kinase activation is unknown. Downstream signaling from the ROS1 fusion protein leads to the activation of the Ras/Raf/MEK/ERK1/2 cell proliferation module, the phosphatidyl inositol 3-kinase cell survival pathway, and the Vav3 cell migration pathway. Moreover, several of the ROS1 fusion proteins are implicated in the pathogenesis of a very small proportion of other cancers including glioblastoma, angiosarcoma, and cholangiocarcinoma as well as ovarian, gastric, and colorectal carcinomas. The occurrence of oncogenic ROS1 fusion proteins, particularly in non-small cell lung cancer, has fostered considerable interest in the development of ROS1 inhibitors. Although the percentage of lung cancers driven by ROS1 fusion proteins is low, owing to the large number of new cases of non-small cell lung cancer per year, the number of new cases of ROS1-positive lung cancers is significant and ranges from 2000 to 4000 per year in the United States and 10,000-15,000 worldwide. Crizotinib was the first inhibitor approved by the US Food and Drug Administration for the treatment of ROS1-positive non-small cell lung cancer in 2016. Other drugs that are in clinical trials for the treatment of these lung cancers include ceritinib, cabozantinib, entrectinib, and lorlatinib. Crizotinib forms a complex within the front cleft between the small and large lobes of an active ROS1 protein-kinase domain and it is classified as type I inhibitor.

Zhu L, Sturgis EM, Lu Z, et al.
Association between miRNA-binding site polymorphisms in double-strand break repair genes and risk of recurrence in patients with squamous cell carcinomas of the non-oropharynx.
Carcinogenesis. 2017; 38(4):432-438 [PubMed] Free Access to Full Article Related Publications
Genetic polymorphisms at miRNA-binding sites may affect miRNA-mediated gene regulation. Thus, miRNA-binding site polymorphisms in double-strand break (DSB) repair genes may affect DNA repair capacity, which in turn could affect cancer prognosis. To determine whether miRNA-binding site polymorphisms in DSB repair genes are associated with the risk of recurrence of squamous cell carcinoma of the non-oropharynx (SCCNOP), we used a log-rank test and multivariable Cox models to evaluate the associations between miRNA-binding site polymorphisms in DSB repair genes and SCCNOP recurrence. Compared with patients without common homozygous genotypes, patients with the variant genotypes of ATM rs227091, LIG3 rs4796030, and RAD51 rs7180135 had significantly better disease-free survival (DFS) (log-rank P = 0.046, 0.002, and 0.041, respectively) and lower risk of disease recurrence [HR (95% CI) = 0.7 (0.6-0.9), 0.6 (0.5-0.9), and 0.7 (0.6-0.9), respectively]. Furthermore, patients with the variant genotypes of these 3 polymorphisms had significantly lower recurrence risk than those without common homozygous genotypes did [HR = 0.3 (95% CI = 0.2-0.7)]. Among patients who received chemoradiation, those with the individual or combined variant genotypes of the three polymorphisms had a significantly lower risk of disease recurrence than those with the individual or combined common homozygous genotypes did. The individual or combined variant genotypes of the ATM rs227091, LIG3 rs4796030, and RAD51 rs7180135 polymorphisms significantly modify the risk of SCCNOP recurrence, particularly for patients treated with chemoradiation. Future prospective studies with larger sample sizes are warranted to validate these findings to enable more effective personalized treatment for SCCNOP patients.

Malik U, Javed A
LRIGs: A Prognostically Significant Family with Emerging Therapeutic Competence against Cancers.
Curr Cancer Drug Targets. 2017; 17(1):3-16 [PubMed] Related Publications
The human leucine-rich repeats and immunoglobulin like domains (LRIG) are evolutionary conserved family of single-pass transmembrane proteins. LRIG gene family includes three members, LRIG1 (formerly LIG1), LRIG2 and LRIG3, all of which are differentially expressed in human tissues and have long been proposed to be tumor suppressors. However, recently accumulated evidence on LRIG protein expression in human cancer appears to be inconsistent with this belief, as LRIG proteins have been found to be upregulated in certain tumors. Moreover, LRIG3 has been shown to act in an opposite manner to LRIG1 and LRIG1, in turn, has been shown to attenuate LRIG3 activity by its proteolytic degradation. These remarkable observations underline and reveal the previously unappreciated complexity of LRIG family dynamics. In the current review, the role of LRIG proteins in various human cancers is summarized and their differential regulation and expression is brought to light in order to understand how these proteins are involved in the genesis and progression of human cancers. Moreover, this is the first compilation that highlights the therapeutic potential of LRIG1 and suggests the same to be undertaken for LRIG2 and LRIG3. By virtue of their potential in prognosis of several cancer types, as well as their role as probable therapeutic proteins or in enhancing the receptiveness of the cancer cells to anti-tumor agents, it is strongly proposed that LRIG analysis should be undertaken and consequently be employed as a part of potential cancer treatment strategies.

Kabzinski J, Mucha B, Cuchra M, et al.
Efficiency of Base Excision Repair of Oxidative DNA Damage and Its Impact on the Risk of Colorectal Cancer in the Polish Population.
Oxid Med Cell Longev. 2016; 2016:3125989 [PubMed] Free Access to Full Article Related Publications
DNA oxidative lesions are widely considered as a potential risk factor for colorectal cancer development. The aim of this work was to determine the role of the efficiency of base excision repair, both in lymphocytes and in epithelial tissue, in patients with CRC and healthy subjects. SNPs were identified within genes responsible for steps following glycosylase action in BER, and patients and healthy subjects were genotyped. A radioisotopic BER assay was used for assessing repair efficiency and TaqMan for genotyping. Decreased BER activity was observed in lymphocyte extract from CRC patients and in cancer tissue extract, compared to healthy subjects. In addition, polymorphisms of EXO1, LIG3, and PolB may modulate the risk of colorectal cancer by decreasing (PolB) or increasing (LIG3 and EXO1) the chance of malignant transformation.

Singh PK, Mistry KN
A computational approach to determine susceptibility to cancer by evaluating the deleterious effect of nsSNP in XRCC1 gene on binding interaction of XRCC1 protein with ligase III.
Gene. 2016; 576(1 Pt 1):141-9 [PubMed] Related Publications
Several reports suggest that non-synonymous single nucleotide polymorphisms affect the function of XRCC1 which impairs DNA repair capacity and thus increases risk to diseases like cancer. In our study, we predicted the most damaging nsSNPs using a computational approach and analysed its functional impact on the XRCC1 and LIG3 interaction. SNP rs2307166 was predicted to be deleterious using eight software programs: SIFT, PolyPhen, PANTHER, PhD-SNP, nsSNPAnalyzer, SNPS&GO, SNAP and I-Mutant. Protein structural analysis was performed using Swiss PDB viewer, and PyMOL. Xenoview was used for molecular dynamic simulation and energy minimisation. Finally, PatchDock and FireDock were used to analyse the interactions of XRCC1 and LIG3. By comparing the results we found that the mutant protein has less binding energy and the interacting amino acids than native protein. In silico analysis predicted rs2307166 to be more damaging than three other extensively studied SNPs. Identification of this SNP will help in determining the susceptibility of the individual to cancer, their prognosis and further treatment.

Muvarak N, Kelley S, Robert C, et al.
c-MYC Generates Repair Errors via Increased Transcription of Alternative-NHEJ Factors, LIG3 and PARP1, in Tyrosine Kinase-Activated Leukemias.
Mol Cancer Res. 2015; 13(4):699-712 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: Leukemias expressing the constitutively activated tyrosine kinases (TK) BCR-ABL1 and FLT3/ITD activate signaling pathways that increase genomic instability through generation of reactive oxygen species (ROS), DNA double-strand breaks (DSB), and error-prone repair. The nonhomologous end-joining (NHEJ) pathway is a major pathway for DSB repair and is highly aberrant in TK-activated leukemias; an alternative form of NHEJ (ALT-NHEJ) predominates, evidenced by increased expression of DNA ligase IIIα (LIG3) and PARP1, increased frequency of large genomic deletions, and repair using DNA sequence microhomologies. This study, for the first time, demonstrates that the TK target c-MYC plays a role in transcriptional activation and subsequent expression of LIG3 and PARP1 and contributes to the increased error-prone repair observed in TK-activated leukemias. c-MYC negatively regulates microRNAs miR-150 and miR-22, which demonstrate an inverse correlation with LIG3 and PARP1 expression in primary and cultured leukemia cells and chronic myelogenous leukemia human patient samples. Notably, inhibition of c-MYC and overexpression of miR-150 and -22 decreases ALT-NHEJ activity. Thus, BCR-ABL1 or FLT3/ITD induces c-MYC expression, leading to genomic instability via augmented expression of ALT-NHEJ repair factors that generate repair errors.
IMPLICATIONS: In the context of TK-activated leukemias, c-MYC contributes to aberrant DNA repair through downstream targets LIG3 and PARP1, which represent viable and attractive therapeutic targets.

Guo D, Yang H, Guo Y, et al.
LRIG3 modulates proliferation, apoptosis and invasion of glioblastoma cells as a potent tumor suppressor.
J Neurol Sci. 2015; 350(1-2):61-8 [PubMed] Related Publications
Leucine-rich repeats and immunoglobulin-like domains (LRIG) 3 gene is mapped to chromosome 12q13.2, a region that is frequently deleted in a subset of glioblastoma multiforme (GBM). It has been reported that perinuclear LRIG3 staining correlated with low WHO grade of glioma and better survival of the patients. However, the relationship between LRIG3 and glioma is not very clear. The purpose of this study is to demonstrate the impacts of LRIG3 on biological characteristics of glioma and its possible mechanisms. We found that transduction of LRIG3 into glioblastoma cells inhibited cell growth in vitro and in vivo, promoted cell apoptosis, and restrained cell invasion and migration. Further studies demonstrated that LRIG3 negatively regulated the epidermal growth factor receptor (EGFR) signaling pathway. Inhibition of EGFR could reduce the effects of LRIG3 knockdown on cell proliferation and EGFR signaling pathway. In conclusion, LRIG3 functions as a tumor suppressor by attenuating EGFR signaling pathway and the restoration of LRIG3 may offer therapeutic potential against malignant gliomas.

Newman EA, Lu F, Bashllari D, et al.
Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma.
Mol Cancer Res. 2015; 13(3):470-82 [PubMed] Related Publications
UNLABELLED: In neuroblastoma, MYCN genomic amplification and segmental chromosomal alterations including 1p or 11q loss of heterozygocity and/or 17q gain are associated with progression and poor clinical outcome. Segmental alterations are the strongest predictor of relapse and result from unbalanced translocations attributable to erroneous repair of chromosomal breaks. Although sequence analysis of affected genomic regions suggests that these errors arise by nonhomologous end-joining (NHEJ) of DNA double-strand breaks (DSB), abnormalities in NHEJ have not been implicated in neuroblastoma pathogenesis. On this basis, the hypothesis that an error-prone mechanism of NHEJ is critical for neuroblastoma cell survival was tested. Plasmid-based DSB repair assays demonstrated efficient NHEJ activity in human neuroblastoma cells with repair products that were error-prone relative to nontransformed cells. Neuroblastoma cells derived from tumorigenic neuroblastic phenotypes had differential DNA repair protein expression patterns compared with nontumorigenic cells. Tumorigenic neuroblastoma cells were deficient in DNA ligase IV (Lig4) and Artemis (DCLRE1C), mediators of canonical NHEJ. Conversely, enzymes required for an error-prone alternative NHEJ pathway (alt-NHEJ), DNA Ligase IIIα (Lig3), DNA Ligase I (Lig1), and PARP1 protein were upregulated. Inhibition of Lig3 and Lig1 led to DSB accumulation and cell death, linking alt-NHEJ to cell survival in neuroblastoma. Neuroblastoma cells demonstrated sensitivity to PARP1 inhibition (PARPi) that paralleled PARP1 expression. In a dataset of human neuroblastoma patient tumors, overexpression of genes encoding alt-NHEJ proteins associated with poor survival.
IMPLICATIONS: These findings provide an insight into DNA repair fidelity in neuroblastoma and identify components of the alt-NHEJ pathway as promising therapeutic targets.

De Langhe S, Mulliez T, Veldeman L, et al.
Factors modifying the risk for developing acute skin toxicity after whole-breast intensity modulated radiotherapy.
BMC Cancer. 2014; 14:711 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: After breast-conserving radiation therapy most patients experience acute skin toxicity to some degree. This may impair patients' quality of life, cause pain and discomfort. In this study, we investigated treatment and patient-related factors, including genetic polymorphisms, that can modify the risk for severe radiation-induced skin toxicity in breast cancer patients.
METHODS: We studied 377 patients treated at Ghent University Hospital and at ST.-Elisabeth Clinic and Maternity in Namur, with adjuvant intensity modulated radiotherapy (IMRT) after breast-conserving surgery for breast cancer. Women were treated in a prone or supine position with normofractionated (25 × 2 Gy) or hypofractionated (15 × 2.67 Gy) IMRT alone or in combination with other adjuvant therapies. Patient- and treatment-related factors and genetic markers in regulatory regions of radioresponsive genes and in LIG3, MLH1 and XRCC3 genes were considered as variables. Acute dermatitis was scored using the CTCAEv3.0 scoring system. Desquamation was scored separately on a 3-point scale (0-none, 1-dry, 2-moist).
RESULTS: Two-hundred and twenty patients (58%) developed G2+ dermatitis whereas moist desquamation occurred in 56 patients (15%). Normofractionation (both p < 0.001), high body mass index (BMI) (p = 0.003 and p < 0.001), bra cup size ≥ D (p = 0.001 and p = 0.043) and concurrent hormone therapy (p = 0.001 and p = 0.037) were significantly associated with occurrence of acute dermatitis and moist desquamation, respectively. Additional factors associated with an increased risk of acute dermatitis were the genetic variation in MLH1 rs1800734 (p=0.008), smoking during RT (p = 0.010) and supine IMRT (p = 0.004). Patients receiving trastuzumab showed decreased risk of acute dermatitis (p < 0.001).
CONCLUSIONS: The normofractionation schedule, supine IMRT, concomitant hormone treatment and patient related factors (high BMI, large breast, smoking during treatment and the genetic variation in MLH1 rs1800734) were associated with increased acute skin toxicity in patients receiving radiation therapy after breast-conserving surgery. Trastuzumab seemed to be protective.

Lindquist D, Kvarnbrink S, Henriksson R, Hedman H
LRIG and cancer prognosis.
Acta Oncol. 2014; 53(9):1135-42 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Optimal treatment decisions for cancer patients require reliable prognostic and predictive information. However, this information is inadequate in many cases. Several recent studies suggest that the leucine-rich repeats and immunoglobulin-like domains (LRIG) genes, transcripts, and proteins have prognostic implications in various cancer types.
MATERIAL AND METHODS: Relevant literature was identified on PubMed using the key words lrig1, lrig2, and lrig3. LRIG mRNA expression in cancer versus normal tissues was investigated using the Oncomine database.
RESULTS: The three human LRIG genes, LRIG1, LRIG2, and LRIG3, encode single-pass transmembrane proteins. LRIG1 is a negative regulator of growth factor signaling that has been shown to function as a tumor suppressor in vitro and in vivo in mice. The functions of LRIG2 and LRIG3 are less well defined. LRIG gene and protein expression are commonly dysregulated in human cancer. In early stage breast cancer, LRIG1 copy number was recently shown to predict early and late relapse in addition to overall survival; in nasopharyngeal carcinoma, loss of LRIG1 is also associated with poor survival. LRIG gene and protein expression have prognostic value in breast cancer, uterine cervical cancer, head-and-neck cancer, glioma, non-small cell lung cancer, prostate cancer, and cutaneous squamous cell carcinoma. In general, expression of LRIG1 and LRIG3 is associated with good survival, whereas expression of LRIG2 is associated with poor survival. Additionally, LRIG1 regulates cellular sensitivity to anti-cancer drugs, which indicates a possible role as a predictive marker.
CONCLUSIONS: LRIG gene statuses and mRNA and protein expression are clinically relevant prognostic indicators in several types of human cancer. We propose that LRIG analyses could become important when making informed and individualized clinical decisions regarding the management of cancer patients.

Lindström AK, Hellberg D
Immunohistochemical LRIG3 expression in cervical intraepithelial neoplasia and invasive squamous cell cervical cancer: association with expression of tumor markers, hormones, high-risk HPV-infection, smoking and patient outcome.
Eur J Histochem. 2014; 58(2):2227 [PubMed] Free Access to Full Article Related Publications
The novel biomarker LRIG3 is a member of the LRIG family (LRIG1-3). While LRIG1 has been associated with favorable prognosis and LRIG2 with poor prognosis in invasive cervical cancer, little is known about the role of LRIG3. The aim of this study was to investigate the expression of LRIG3 in invasive cancer and cervical intraepithelial neoplasia (CIN) for possible correlation with other tumor markers, to hormones and smoking, as a diagnostic adjunct in CIN, and prognostic value in invasive cancer. Cervical biopsies from 129 patients with invasive squamous cell carcinoma and 170 biopsies showing low grade and high grade CIN, or normal epithelium were stained for LRIG3 and 17 additional tumor markers. Among other variables the following were included: smoking habits, hormonal contraceptive use, serum progesterone, serum estradiol, high-risk HPV-infection, menopausal status and ten-year survival. In CIN, high expression of the tumor suppressors retinoblastoma protein, p53, and p16, and E-cadherin (cell-cell interaction), or low expression of CK10, correlated to LRIG3 expression. In addition, progestogenic contraceptive use correlated to high expression of LRIG3. In invasive cancer there was a correlation between expression of the major tumor promoter c-myc and high LRIG3 expression. High LRIG3 expression correlated significantly to presence of high-risk HPV infection in patients with normal epithelium and CIN. There was no correlation between LRIG3 expression and 10-year survival in patients with invasive cell cervical cancer. LRIG3 expression is associated with a number of molecular events in CIN. Expression also correlates to hormonal contraceptive use. The results on expression of other tumor markers suggest that LRIG3 is influenced by or influences a pattern of tumor markers in cancer and precancerous cells. Further studies are needed to elucidate if LRIG3 expression might be clinically useful.

Khrunin AV, Khokhrin DV, Moisseev AA, et al.
Pharmacogenomic assessment of cisplatin-based chemotherapy outcomes in ovarian cancer.
Pharmacogenomics. 2014; 15(3):329-37 [PubMed] Related Publications
AIM: Cisplatin and its analogs are potent antitumor agents. However, their use is restricted by significant variability in tumor response and toxicity. There is a great need to identify genetic markers to predict the most important adverse events and patient outcomes.
MATERIALS & METHODS: We have evaluated the association between polymorphisms in 106 genes involved mainly in xenobiotic metabolism, DNA repair, the cell cycle and apoptosis, and outcomes in 104 ovarian cancer patients receiving cisplatin-cyclophosphamide chemotherapy. Arrayed primer extension technology was used to genotype 228 SNPs.
RESULTS: Ten SNPs in nine genes were found to be associated with one or more of the assessed clinical end points. SNPs in TPMT and NQO1 were significantly associated with progression-free survival. Polymorphisms in ERCC5, RAD52, MUTYH and LIG3 correlated with the occurrence of severe neutropenia. SNPs in NAT2 and EPHX1 were associated with anemia and nephrotoxicity, respectively. A SNP in ADH1C was correlated with complete tumor response.
CONCLUSION: The results obtained suggest that SNPs in different genes involved in drug metabolism can be important in identifying patients at risk for nonresponse to or toxicity from cisplatin-based treatment.

Rondahl V, Holmlund C, Karlsson T, et al.
Lrig2-deficient mice are protected against PDGFB-induced glioma.
PLoS One. 2013; 8(9):e73635 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins constitute an integral membrane protein family that has three members: LRIG1, LRIG2, and LRIG3. LRIG1 negatively regulates growth factor signaling, but little is known regarding the functions of LRIG2 and LRIG3. In oligodendroglial brain tumors, high expression of LRIG2 correlates with poor patient survival. Lrig1 and Lrig3 knockout mice are viable, but there have been no reports on Lrig2-deficient mice to date.
METHODOLOGY/PRINCIPAL FINDINGS: Lrig2-deficient mice were generated by the ablation of Lrig2 exon 12 (Lrig2E12). The Lrig2E12-/- mice showed a transiently reduced growth rate and an increased spontaneous mortality rate; 20-25% of these mice died before 130 days of age, with the majority of the deaths occurring before 50 days. Ntv-a transgenic mice with different Lrig2 genotypes were transduced by intracranial injection with platelet-derived growth factor (PDGF) B-encoding replication-competent avian retrovirus (RCAS)-producing DF-1 cells. All injected Lrig2E12+/+ mice developed Lrig2 expressing oligodendroglial brain tumors of lower grade (82%) or glioblastoma-like tumors of higher grade (18%). Lrig2E12-/- mice, in contrast, only developed lower grade tumors (77%) or had no detectable tumors (23%). Lrig2E12-/- mouse embryonic fibroblasts (MEF) showed altered induction-kinetics of immediate-early genes Fos and Egr2 in response to PDGF-BB stimulation. However, Lrig2E12-/- MEFs showed no changes in Pdgfrα or Pdgfrβ levels or in levels of PDGF-BB-induced phosphorylation of Pdgfrα, Pdgfrβ, Akt, or extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). Overexpression of LRIG1, but not of LRIG2, downregulated PDGFRα levels in HEK-293T cells.
CONCLUSIONS: The phenotype of Lrig2E12-/- mice showed that Lrig2 was a promoter of PDGFB-induced glioma, and Lrig2 appeared to have important molecular and developmental functions that were distinct from those of Lrig1 and Lrig3.

Corral R, Lewinger JP, Joshi AD, et al.
Genetic variation in the base excision repair pathway, environmental risk factors, and colorectal adenoma risk.
PLoS One. 2013; 8(8):e71211 [PubMed] Free Access to Full Article Related Publications
Cigarette smoking, high alcohol intake, and low dietary folate levels are risk factors for colorectal adenomas. Oxidative damage caused by these three factors can be repaired through the base excision repair pathway (BER). We hypothesized that genetic variation in BER might modify colorectal adenoma risk. In a sigmoidoscopy-based study, we examined associations between 182 haplotype tagging SNPs in 14 BER genes, and colorectal adenoma risk, and examined their potential role as modifiers of the effect cigarette smoking, alcohol intake, and dietary folate levels. Among all individuals, no statistically significant associations between BER SNPs and adenoma risk persisted after correction for multiple comparisons. However, among Asian-Pacific Islanders we observed two SNPs in FEN1 and one in NTHL1, and among African-Americans one SNP in APEX1 that were associated with colorectal adenoma risk. Significant associations were also observed between SNPs in the NEIL2 gene and rectal adenoma risk. Three SNPS modified the effect of smoking (MUTYH interaction p = 0.002; OGG1 interaction p = 0.013); FEN1 interaction p = 0.013)), one SNP in LIG3 modified the effect of alcohol consumption (interaction p = 0.024) and two SNPs in LIG3 modified the effect of dietary folate (interaction p = 0.001 and p = 0.08) on colorectal adenoma risk. These findings support a role for genetic variants in the BER pathway as potential modifiers of colorectal adenoma risk. Our findings strengthen the role of oxidative damage induced by key lifestyle and dietary risk factors in colorectal adenoma formation.

Wang Y, Poulin EJ, Coffey RJ
LRIG1 is a triple threat: ERBB negative regulator, intestinal stem cell marker and tumour suppressor.
Br J Cancer. 2013; 108(9):1765-70 [PubMed] Free Access to Full Article Related Publications
In baseball parlance, a triple threat is a person who can run, hit and throw with aplomb. Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a cell surface protein that antagonises ERBB receptor signalling by downregulating receptor levels. Over 10 years ago, Hedman et al postulated that LRIG1 might be a tumour suppressor. Recently, Powell et al provided in vivo evidence substantiating that claim by demonstrating that Lrig1 loss in mice leads to spontaneously arising, highly penetrant intestinal adenomas. Interestingly, Lrig1 also marks stem cells in the gut, suggesting a potential role for Lrig1 in maintaining intestinal epithelial homeostasis. In this review, we will discuss the ability of LRIG1 to act as a triple threat: pan-ERBB negative regulator, intestinal stem cell marker and tumour suppressor. We will summarise studies of LRIG1 expression in human cancers and discuss possible related roles for LRIG2 and LRIG3.

Muller S, Lindquist D, Kanter L, et al.
Expression of LRIG1 and LRIG3 correlates with human papillomavirus status and patient survival in cervical adenocarcinoma.
Int J Oncol. 2013; 42(1):247-52 [PubMed] Related Publications
The incidence of cervical adenocarcinoma, which accounts for 10-20% of all cervical cancers, has increased continuously in developed countries during the last two decades, unlike squamous cell cervical carcinoma. This increasing trend, noted particularly among women under the age of 40 years, has occurred despite extensive cytological Pap smear screening. A deeper understanding of the etiology of cervical adenocarcinoma, better preventive measures and reliable prognostic markers are urgently needed. The human leucine-rich repeats and immunoglobulin-like domains (LRIG) gene family includes: LRIG1, LRIG2 and LRIG3. LRIG expression has proven to be of prognostic value in different types of human cancers, including breast cancer, early stage invasive squamous cervical cancer, cutaneous squamous cell carcinoma, oligodendroglioma and astrocytoma. LRIG1 functions as a tumor suppressor, while less is known about the functions of LRIG2 and LRIG3. This study evaluated the expression of the three LRIG proteins in tumor specimens from 86 women with pure cervical adenocarcinoma by immunohistochemistry. Possible correlations between LRIG expression and known prognostic factors, including human papillomavirus (HPV) status, FIGO stage and histology were investigated. Patient survival data were collected retrospectively and the possible prognostic value of LRIG protein expression was investigated. High staining intensity of LRIG1 and high fraction of LRIG3-positive cells were significantly associated with patient survival, and positive correlations were found between LRIG1 and LRIG3 staining intensity and HPV status. Thus, the LRIG proteins may be important determinants of cervical adenocarcinoma progression and their diagnostic and prognostic potential should be studied further.

Røe OD, Szulkin A, Anderssen E, et al.
Molecular resistance fingerprint of pemetrexed and platinum in a long-term survivor of mesothelioma.
PLoS One. 2012; 7(8):e40521 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Pemetrexed, a multi-folate inhibitor combined with a platinum compound is the first-line treatment of malignant mesothelioma, but median survival is still one year. Intrinsic and acquired resistance to pemetrexed is common, but its biological basis is obscure. Here we report for the first time a genome-wide profile of acquired resistance in the tumour from an exceptional case with advanced pleural mesothelioma and almost six years survival after 39 cycles of second-line pemetrexed/carboplatin treatment.
METHODOLOGY AND PRINCIPAL FINDINGS: Genome-wide analysis with Illumina BeadChip Kit of 25,000 genes was performed on mRNA from pre-treatment and post-resistance biopsies from this individual as well on case and control samples from our previously published study (in total 17 samples). Cell specific expression of proteins encoded by selected genes were analysed by immunohistochemistry. Serial serum levels of CA125, CYFRA21-1 and SMRP levels were examined. TS protein, the main target of pemetrexed was overexpressed. Proteins and genes related to DNA damage response, elongation and telomere extension and repair related directly and indirectly to platinum resistance were overexpressed, as the CHK1 protein and the genes CHEK2, LIG3, POLD1, POLA2, FANCD2, PRPF19, RECQ5 respectively, the last two not previously described in mesothelioma. We observed a down-regulation of leukocyte transendothelial migration and cell adhesion molecules pathways. Silencing of NT5C in two mesothelioma cell lines did not sensitize the cells to Pemetrexed. Proposed resistance markers are TS, KRT7/ CK7, TYMP/ thymidine phosphorylase and down-regulated SPARCL1 and CDKN1B. Moreover, comparison of the primary expression of the sensitive versus a primary resistant case showed multi-fold overexpressed DNA repair, cell cycle, cytokinesis, and spindle formation in the latter. Serum CA125 and SMRP reflected the clinical and radiological course and tumour burden.
CONCLUSIONS: Genome-wide microarray of mesothelioma pre- and post-resistance biopsies indicated a novel resistance signature to pemetrexed/carboplatin that deserve validation in a larger cohort.

Santonocito C, Scapaticci M, Penitente R, et al.
Polymorphisms in base excision DNA repair genes and association with melanoma risk in a pilot study on Central-South Italian population.
Clin Chim Acta. 2012; 413(19-20):1519-24 [PubMed] Related Publications
Base excision repair plays a key role in the removing of DNA damage from exposure to endogenous and exogenous carcinogens. The BER pathway removes alterations of a single oxidized, reduced or methylated base. Recently some studies have explored the association between risk for cutaneous melanoma and non-synonymous single-nucleotide polymorphisms (nsSNPs) in DNA-repair genes, although with contradictory results. We hypothesized that common nsSNPs of BER genes, specifically ADPRT rs1136410, XRCC1 rs25487, rs25489, rs1799782, APEX1 rs1130409, OGG1 rs1052133, LIG3 rs3136025 and MUTYH rs3219466, may contribute to risk of melanoma. The aim of this study is to investigate whether or not a correlation between these nsSNPs and melanoma risk and/or aggressiveness is present. 167 melanoma patients and 186 healthy control subjects were analysed. By multivariate statistical analysis no association was found between nsSNP and melanoma aggressiveness, while only the two XRCC1 (rs25487 and rs25489) nsSNPs showed a strong correlation (p<0.001) with melanoma risk. To our knowledge this is the first study reporting an association between BER nsSNPs and melanoma risk in Central-South Italian individuals. Our findings, if confirmed in larger population studies, will allow the inclusion of these XRCC1 nsSNPs in a screening panel for those individuals at higher risk for melanoma.

Yang H, Mao F, Zhang H, et al.
Effect of over-expressed LRIG3 on cell cycle and survival of glioma cells.
J Huazhong Univ Sci Technolog Med Sci. 2011; 31(5):667 [PubMed] Related Publications
This study examined the effects of over-expression of leucine-rich repeats and immunoglobulin-like domains 3 (LRIG3) on the cell cycle and survival of human glioma cell line U87 and U251 and explored the possible mechanisms. The LRIG3 gene was transduced into U87 and U251 cells respectively by using lentivirus and the transduced cells were selected by puromycin. The changes in LRIG3 mRNA and protein levels were measured by RT-PCR and Western blotting. The apoptosis rate was detected by Annexin V-FITC/PI double labeling and the cell cycle was flow cytometrically analyzed. Compared with control cells, LRIG3 mRNA expression in U251 and U87 cells transduced with pLVX-DsRed-LRIG3-Monomer-N1 were increased by 77.6% and 129.7%, and LRIG3 protein expression was raised by 141.3% and 322.7%, respectively. Cell cycle analysis showed that LRIG3 over-expression increased the percentage of cells at G(0)/G(1) phase (P<0.01). Over-expressed LRIG3 could significantly promote the apoptosis of U87 and U251 cells (P<0.05). These findings suggest that the over-expression of LRIG3 could arrest the cell cycle in G(0)/G(1) phase, and promote apoptosis of U87 and U251 cells.

Murray RJ, Tanteles GA, Mills J, et al.
Association between single nucleotide polymorphisms in the DNA repair gene LIG3 and acute adverse skin reactions following radiotherapy.
Radiother Oncol. 2011; 99(2):231-4 [PubMed] Related Publications
Many genes have been associated with radiotherapy toxicity, but most have only been found in a single study. Using our cohort of 480 breast cancer patients, we provide replicated evidence that a polymorphism near the LIG3 gene is associated with acute skin toxicity following radiotherapy.

Yuan X, Bao S, Yang W, Ye Z
Effect of silencing LRIG3 gene on the proliferation and apoptosis of bladder cancer T24 cells.
J Huazhong Univ Sci Technolog Med Sci. 2011; 31(2):220 [PubMed] Related Publications
This study examined the effect of silencing LRIG3 expression on the proliferation and apoptosis of bladder cancer T24 cells and explored the role of LRIG3 in the tumorigenesis of bladder cancer. Bladder cancer T24 cells were routinely cultured and pSilencer plasmids were employed to construct LRIG3 eukaryotic expression vector of LRIG3-siRNA, i.e., pSilencer-LRIG3-siRNA. After confirmation, the vector was transfected into HEK293 cells to make a replication-deficient adenovirus, pAd-LRIG3-siRNA, which was then introduced into bladder cancer T24 cells. RT-PCR, Western-blotting were performed to detect the levels of LRIG3 mRNA and proteins. Cells number was determined by using MTT test. Hoechst33258 staining, transmission microscopy, flow cytometery were conducted to examine the cell apoptosis. Three groups included a blank control group, a negative control group (containing non-interfering plasmids) and a pAd-LRIG3-siRNA group. Our results showed that the recombinant pAd-LRIG3-siRNA was successfully transfected into the bladder cancer T24 cells. The siRNA formed by the transcription of the recombinant plasmids resulted in significantly reduced expressions of LRIG3 gene and protein and significantly decreased cell proliferation and growth in the pAd-LRIG3-siRNA group as compared with the control group (P<0.01). The siRNA also caused apoptotic changes of some cells, with the apoptosis rate being (17.69±0.75)%, which was significantly different from that of the control group (P<0.01). It was concluded that recombinant pAd-LRIG3-siRNA plasmids could effectively decrease the expression of LRIG3 mRNA and proteins and, to some extent, inhibit the proliferation and promote the apoptosis of bladder cancer T24 cells. Silencing LRIG3 gene might be a novel alternative for the treatment of bladder cancer.

Ostroff RM, Bigbee WL, Franklin W, et al.
Unlocking biomarker discovery: large scale application of aptamer proteomic technology for early detection of lung cancer.
PLoS One. 2010; 5(12):e15003 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Lung cancer is the leading cause of cancer deaths worldwide. New diagnostics are needed to detect early stage lung cancer because it may be cured with surgery. However, most cases are diagnosed too late for curative surgery. Here we present a comprehensive clinical biomarker study of lung cancer and the first large-scale clinical application of a new aptamer-based proteomic technology to discover blood protein biomarkers in disease.
METHODOLOGY/PRINCIPAL FINDINGS: We conducted a multi-center case-control study in archived serum samples from 1,326 subjects from four independent studies of non-small cell lung cancer (NSCLC) in long-term tobacco-exposed populations. Sera were collected and processed under uniform protocols. Case sera were collected from 291 patients within 8 weeks of the first biopsy-proven lung cancer and prior to tumor removal by surgery. Control sera were collected from 1,035 asymptomatic study participants with ≥ 10 pack-years of cigarette smoking. We measured 813 proteins in each sample with a new aptamer-based proteomic technology, identified 44 candidate biomarkers, and developed a 12-protein panel (cadherin-1, CD30 ligand, endostatin, HSP90α, LRIG3, MIP-4, pleiotrophin, PRKCI, RGM-C, SCF-sR, sL-selectin, and YES) that discriminates NSCLC from controls with 91% sensitivity and 84% specificity in cross-validated training and 89% sensitivity and 83% specificity in a separate verification set, with similar performance for early and late stage NSCLC.
CONCLUSIONS/SIGNIFICANCE: This study is a significant advance in clinical proteomics in an area of high unmet clinical need. Our analysis exceeds the breadth and dynamic range of proteome interrogated of previously published clinical studies of broad serum proteome profiling platforms including mass spectrometry, antibody arrays, and autoantibody arrays. The sensitivity and specificity of our 12-biomarker panel improves upon published protein and gene expression panels. Separate verification of classifier performance provides evidence against over-fitting and is encouraging for the next development phase, independent validation. This careful study provides a solid foundation to develop tests sorely needed to identify early stage lung cancer.

Andersson U, Schwartzbaum J, Wiklund F, et al.
A comprehensive study of the association between the EGFR and ERBB2 genes and glioma risk.
Acta Oncol. 2010; 49(6):767-75 [PubMed] Related Publications
Glioma is the most common type of adult brain tumor and glioblastoma, its most aggressive form, has a dismal prognosis. Receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR, ERBB2, ERBB3, ERBB4) family, and the vascular endothelial growth factor receptor (VEGFR), play a central role in tumor progression. We investigated the genetic variants of EGFR, ERBB2, VEGFR and their ligands, EGF and VEGF on glioma and glioblastoma risk. In addition, we evaluated the association of genetic variants of a newly discovered family of genes known to interact with EGFR: LRIG2 and LRIG3 with glioma and glioblastoma risk. Methods. We analyzed 191 tag single nucleotide polymorphisms (SNPs) capturing all common genetic variation of EGF, EGFR, ERBB2, LRIG2, LRIG3, VEGF and VEGFR2 genes. Material from four case-control studies with 725 glioma patients (329 of who were glioblastoma patients) and their 1 610 controls was used. Haplotype analyses were conducted using SAS/Genetics software. Results. Fourteen of the SNPs were significantly associated with glioma risk at p< 0.05, and 17 of the SNPs were significantly associated with glioblastoma risk at p< 0.05. In addition, we found that one EGFR haplotype was related to increased glioblastoma risk at p=0.009, Odds Ratio [OR] = 1.67 (95% confidence interval (CI): 1.14, 2.45). The Bonferroni correction made all p-values non-significant. One SNP, rs4947986 next to the intron/exon boundary of exon 7 in EGFR, was validated in an independent data set of 713 glioblastoma and 2 236 controls, [OR] = 1.42 (95% CI: 1.06,1.91). Discussion. Previous studies show that regulation of the EGFR pathway plays a role in glioma progression but the present study is the first to find that certain genotypes of the EGFR gene may be related to glioblastoma risk. Further studies are required to reinvestigate these findings and evaluate the functional significance.

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