LRP1; low density lipoprotein receptor-related protein 1 (12q13.3)

Gene Summary

Gene:LRP1; low density lipoprotein receptor-related protein 1
Summary:The protein encoded by this gene is an endocytic receptor involved in several cellular processes, including intracellular signaling, lipid homeostasis, and clearance of apoptotic cells. In addition, the encoded protein is necessary for the A2M-mediated clearance of secreted amyloid precursor protein and beta-amyloid, the main component of amyloid plaques found in Alzheimer patients. Expression of this gene decreases with age and has been found to be lower than controls in brain tissue from Alzheimer patients. [provided by RefSeq, Jan 2010]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:prolow-density lipoprotein receptor-related protein 1
Updated:12 December, 2014


What does this gene/protein do?
Show (36)


What pathways are this gene/protein implicaed in?
- Alzheimer's disease KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 12 December 2014 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.

  • Low Density Lipoprotein Receptor-Related Protein-1
  • MMP9
  • ATP-Binding Cassette Transporters
  • Transfection
  • Multiple Drug Resistance
  • Extracellular Signal-Regulated MAP Kinases
  • Survival Rate
  • Oligonucleotide Array Sequence Analysis
  • Pharmacogenetics
  • Breast Cancer
  • Ovarian Cancer
  • Oligonucleotides
  • Western Blotting
  • CD Antigens
  • Signal Transduction
  • P-Glycoprotein
  • Stromal Cells
  • Gene Expression Profiling
  • Vault Ribonucleoprotein Particles
  • Cancer Gene Expression Regulation
  • Cell Movement
  • Transcription Factors
  • Proteomics
  • Transforming Growth Factor beta
  • DNA-Binding Proteins
  • Tumor Markers
  • Multidrug Resistance-Associated Proteins
  • Angiogenesis
  • Prostate Cancer
  • Carrier Proteins
  • Chromosome 12
  • Lung Cancer
  • Tissue Array Analysis
  • Neoplasm Metastasis
  • Single Nucleotide Polymorphism
  • Neoplasm Invasiveness
  • Neoplasm Proteins
  • Tumor Suppressor Proteins
  • p53 Protein
Tag cloud generated 12 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (4)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Breast CancerLRP1 and Breast Cancer View Publications4
Prostate CancerLRP1 and Prostate Cancer View Publications3
Ovarian CancerLRP1 and Ovarian Cancer View Publications2
Lung CancerLRP1 and Lung Cancer View Publications2

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

Related Links

Latest Publications: LRP1 (cancer-related)

Huang CH, Wu MY, Chang PM, et al.
In silico identification of potential targets and drugs for non-small cell lung cancer.
IET Syst Biol. 2014; 8(2):56-66 [PubMed] Related Publications
Lung cancer is one of the leading causes of death in both the USA and Taiwan, and it is thought that the cause of cancer could be because of the gain of function of an oncoprotein or the loss of function of a tumour suppressor protein. Consequently, these proteins are potential targets for drugs. In this study, differentially expressed genes are identified, via an expression dataset generated from lung adenocarcinoma tumour and adjacent non-tumour tissues. This study has integrated many complementary resources, that is, microarray, protein-protein interaction and protein complex. After constructing the lung cancer protein-protein interaction network (PPIN), the authors performed graph theory analysis of PPIN. Highly dense modules are identified, which are potential cancer-associated protein complexes. Up- and down-regulated communities were used as queries to perform functional enrichment analysis. Enriched biological processes and pathways are determined. These sets of up- and down-regulated genes were submitted to the Connectivity Map web resource to identify potential drugs. The authors' findings suggested that eight drugs from DrugBank and three drugs from NCBI can potentially reverse certain up- and down-regulated genes' expression. In conclusion, this study provides a systematic strategy to discover potential drugs and target genes for lung cancer.

Related: Non-Small Cell Lung Cancer Lung Cancer Signal Transduction

Wang X, Qian H, Zhang S
Discovery of significant pathways in breast cancer metastasis via module extraction and comparison.
IET Syst Biol. 2014; 8(2):47-55 [PubMed] Related Publications
Discovering significant pathways rather than single genes or small gene sets involved in metastasis is becoming more and more important in the study of breast cancer. Many researches have shed light on this problem. However, most of the existing works are relying on some priori biological information, which may bring bias to the models. The authors propose a new method that detects metastasis-related pathways by identifying and comparing modules in metastasis and non-metastasis gene co-expression networks. The gene co-expression networks are built by Pearson correlation coefficients, and then the modules inferred in these two networks are compared. In metastasis and non-metastasis networks, 36 and 41 significant modules are identified. Also, 27.8% (metastasis) and 29.3% (non-metastasis) of the modules are enriched significantly for one or several pathways with p-value <0.05. Many breast cancer genes including RB1, CCND1 and TP53 are included in these identified pathways. Five significant pathways are discovered only in metastasis network: glycolysis pathway, cell adhesion molecules, focal adhesion, stathmin and breast cancer resistance to antimicrotubule agents, and cytosolic DNA-sensing pathway. The first three pathways have been proved to be closely associated with metastasis. The rest two can be taken as a guide for future research in breast cancer metastasis.

Related: Breast Cancer Signal Transduction

Liu Y, Wang M, Feng H, Li A
Comprehensive study of tumour single nucleotide polymorphism array data reveals significant driver aberrations and disrupted signalling pathways in human hepatocellular cancer.
IET Syst Biol. 2014; 8(2):24-32 [PubMed] Related Publications
The authors describe an integrated method for analysing cancer driver aberrations and disrupted pathways by using tumour single nucleotide polymorphism (SNP) arrays. The authors new method adopts a novel statistical model to explicitly quantify the SNP signals, and therefore infers the genomic aberrations, including copy number alteration and loss of heterozygosity. Examination on the dilution series dataset shows that this method can correctly identify the genomic aberrations even with the existence of severe normal cell contamination in tumour sample. Furthermore, with the results of the aberration identification obtained from multiple tumour samples, a permutation-based approach is proposed for identifying the statistically significant driver aberrations, which are further incorporated with the known signalling pathways for pathway enrichment analysis. By applying the approach to 286 hepatocellular tumour samples, they successfully uncover numerous driver aberration regions across the cancer genome, for example, chromosomes 4p and 5q, which harbour many known hepatocellular cancer related genes such as alpha-fetoprotein (AFP) and ectodermal-neural cortex (ENC1). In addition, they identify nine disrupted pathways that are highly enriched by the driver aberrations, including the systemic lupus erythematosus pathway, the vascular endothelial growth factor (VEGF) signalling pathway and so on. These results support the feasibility and the utility of the proposed method on the characterisation of the cancer genome and the downstream analysis of the driver aberrations and the disrupted signalling pathways.

Related: Liver Cancer Cancer Prevention and Risk Reduction Signal Transduction

Zhang S, Tao Wang H
Association between HLA-G 14-bp insertion/deletion polymorphism and cancer risk: a meta-analysis.
J BUON. 2014 Apr-Jun; 19(2):567-72 [PubMed] Related Publications
PURPOSE: A number of studies have investigated the association between human leukocyte antigen-G (HLA-G) 14-bp insertion/deletion polymorphism and cancer risk, but the results remain controversial. In this study we aimed to clarify whether this association really exists.
METHODS: We carried out a meta-analysis of 8 studies including 1179 cases and 2795 controls from PubMed and Chinese language (CNKI and WanFang) databases to assess the association between the HLA-G 14-bp insertion/deletion polymorphism and cancer risk by pooled odds ratio (OR) and 95% confidence interval (CI).
RESULTS: The results showed that the HLA-G 14-bp insertion/ deletion polymorphism was not associated with total cancer risk in all genetic models (dominant model: OR=0.90, 95% CI-0.70-1.17; recessive model: OR=0.97, 95% CI=0.67-1.42; insertion/deletion (ID) vs deletion/deletion (DD):OR=0.88, 95% CI=0.66-1.18; insertion/insertion (II) vs DD: OR=0.94, 95% CI=0.62-1.41; insertion (I) vs deletion (D): OR=0.95, 95% CI=0.78-1.16). In the subgroup analysis by ethnicity, no significant association was found between Asians and Caucasians. However, subgroup analysis by cancer type showed that the polymorphism was associated with risk of hepatocellular carcinoma.
CONCLUSIONS: This meta-analysis suggests that HLA-G 14-bp insertion/deletion polymorphism may not influence the susceptibility of total cancer, but it is related to risk of hepatocellular carcinoma.

Related: Cancer Prevention and Risk Reduction Polymorphisms

Zheng K, Zhu W, Tan J, et al.
Retrospective analysis of a large patient sample to determine p53 and Ki67 expressions in renal cell carcinoma.
J BUON. 2014 Apr-Jun; 19(2):512-6 [PubMed] Related Publications
PURPOSE: This study aimed to investigate the expression of p53 and Ki67 genes in renal cell carcinoma (RCC) and its possible clinical value.
METHODS: A retrospective analysis of clinical data from 1239 patients with RCC was performed to explore the relationship between the expression of Ki67 and p53 proteins and tumor stage, grade and prognosis.
RESULTS: p53 expression was not significantly correlated with TNM stage and Fuhrman grade (p>0.05); Ki67 expression was significantly correlated with TNM stage and Fuhrman grade (p<0.05). Kaplan-Meier and log-rank survival rate results showed that the prognosis of Ki67 and p53 double-positive group was significantly inferior to the single-positive and negative group (p<0.001). In the multivariate Cox risk regression analysis model, TNM stage, relative risk/RR=3.196, p<0.001), Fuhrman grade (RR=3.196, p<0.001) and Ki67 and p53 double-positive [Ki67 (+) p53 (+) , RR=3.196, p<0.001] were significantly correlated with tumor prognosis, and independent predictors of the patient disease-free survival (DFS).
CONCLUSION: The combined detection of p53 and Ki67 expressions, which are superior to single marker, could be used to improve significantly the accuracy of prognosis of RCC patients.

Related: MKI67 Kidney Cancer TP53

Li B, Liu HY, Guo SH, et al.
A missense mutation (S3660L) in MLL3 gene influences risk of gastric cancer.
J BUON. 2014 Apr-Jun; 19(2):394-7 [PubMed] Related Publications
PURPOSE: Several studies indicated that the expression level of MLL3 gene in gastric cancer tissue was associated with prognosis, and previous studies also suggested that genetic polymorphisms of MLL3 were related to the risk for gastric cancer. The present study aimed to investigate the association of a missense mutation (S3660L) in the MLL3 gene with gastric cancer risk in a Chinese population.
METHODS: In the present study, we identified a novel missense mutation in MLL3 gene (S3660L) by directly sequencing method in 48 gastric cancer patients. To further explore the relation between gastric cancer and this mutation, we selected 354 gastric cancer patients and 377 healthy control subjects and designed a case-control study.
RESULTS: We found that the AG genotype (14.9 vs 6.40%, odds ratio/OR=2.58, 95% CI: 1.33-4.54, p<0.001) and A allele (7.5 vs 3.2%, OR=2.46, 95% CI: 1.55~5.34, p<0.001) were common in the gastric cancer patients than in the control subjects.
CONCLUSION: We concluded that this novel missense (S3660L) mutation in MLL3 gene is likely to increase the gastric cancer risk.

Related: Stomach Cancer Gastric Cancer MLL3 gene

Zheng W, Hu W, Wang Y, et al.
Comparative analysis of gene expression profiles in basal-like carcinomas of the breast.
Anal Quant Cytopathol Histpathol. 2014; 36(2):82-90 [PubMed] Related Publications
OBJECTIVE: To compare basal-like breast carcinoma (BLBC) gene expression profiles to normal mammary epithelium in order to determine the characteristic gene expression patterns associated with the tumor.
STUDY DESIGN: The gene expression profiles of 12 cases of BLBC were analyzed using a human mRNA genome expression profiling chip containing 48,804 probes in an attempt to characterize molecular mechanism involved in the carcinogenesis of BLBC.
RESULTS: The identified 99 genes were upregulated more than fourfold fold-change (FC) value over their levels in normal mammary ductal epithelial cells, and 43 genes were downregulated to less than fivefold FC value compared to normal epithelial cells. Verification of selected genes by semiquantitative reverse transcription polymerase chain reaction was performed to confirm the expression data obtained by microarray analysis. Most of the abnormal expressed genes were related to DNA binding, transcription and its factor, cell receptors, cell signals and transmitted proteins, metabolism-related proteins, and protein synthesis-related genes.
CONCLUSION: The difference of gene expression profiles might be of benefit for selecting the relative genes of the basal-like carcinoma as the therapy target and to further the understanding of the development of BLBC.

Related: Breast Cancer Basal Cell Carcinoma

Zhang H, Yang R
Resveratrol inhibits VEGF gene expression and proliferation of hepatocarcinoma cells.
Hepatogastroenterology. 2014 Mar-Apr; 61(130):410-2 [PubMed] Related Publications
BACKGROUND/AIMS: Resveratrol is known to have potent anti-inflammatory and antioxidant effects and to inhibit platelet aggregation and growth of a variety of cancer cells. In the paper, we investigated the effects of Resveratrol (Res) on expression ofVEGF gene in human hepatocarcinoma cell cells and cell proliferation.
METHODOLOGY: HepG2 cells were treated with different concentrations of Res (0, 10, 20, 40 micromol/L) and rent time (24, 48, 72h). Cell proliferation was examined by MTT method and the expression of VEGF gene was analyzed by RT-PCR and Western blot.
RESULTS: Res could inhibit expression of VEGF gene, the inhibitory effect of Res increased with the increasing of concentration of Res and treatment time.
CONCLUSIONS: Our results suggest that Res can significantly inhibit the proliferation of HepG2 cells and exerts an anti-tumor effect by repressing the expression of VEGF gene.

Related: Liver Cancer VEGFA

Hibi K, Mizukami H, Saito M, et al.
p16 Methylation is frequently detected in the serum of metastatic colorectal cancer patients.
Hepatogastroenterology. 2014 Mar-Apr; 61(130):354-6 [PubMed] Related Publications
For the purpose of detection of colorectal cancers, we tried to detect p16 methylation in the serum of colorectal cancer patients using quantitative methylation-specific polymerase chain reaction (qMSP). Out of 211 serum samples derived from colorectal cancer patients, 14 (7%) exhibited p16 methylation in their serum DNA by qMSP. After completion of qMSP analysis in all specimens, clinicopathological data were correlated with the molecular analysis. Interestingly, a significant difference was observed in the presence of distant metastasis (P = 0.0420). Moreover, a trend was shown toward preferentially developing lymph node metastasis (P = 0.0547), thus suggesting that p16 methylation in serum could be detected more frequently in metastatic colorectal cancer patients. High sensitivity of qMSP makes it possible to detect smaller amounts of tumor DNA in the serum. In principle, the methylation status of a primary tumor is not required in advance to detect circulating tumor DNA, suggesting that qMSP can be used as a screening method for cancer.

Related: Colorectal (Bowel) Cancer CDKN2A

Cao W, Zhou G, Qiu J, et al.
Research on the epigenetic modification of pancreatic cancer vaccine.
Hepatogastroenterology. 2014 Mar-Apr; 61(130):272-7 [PubMed] Related Publications
Pancreatic cancer is characterized as a type of gastrointestinal tumor with a poor prognosis and high degree of malignancy. CIITA gene was found highly methylated in pancreatic carcinoma cell line PANC-1 and responsible for the low expression of MHC-II that may lead to immune evasion. Here, we tried to prepare pancreatic cancer vaccine with PANC-1 cells via epigenetic modification to enhance the MHC-II expression. Then the vaccine was injected into C57BL/6J mice and the effect was examined. Our study found that the vaccine could promote the proliferation of antigen-specific T cells, enhance the killing activity of cytotoxic lymphocytes (CTL), promote Th1-type cells mediated secretion of cytokines IFN-gamma and IL-2 while inhibiting Th2-type cells mediated secretion of IL-4, and inhibit the secretion of TGF-beta. Generally, the epigenetically modified vaccine could enhance the body's anti-tumor immune response, providing feasibility research on cancer vaccine for therapy of pancreatic cancer.

Related: Cytokines Cancer of the Pancreas Pancreatic Cancer

Kirby R
Optimising the management of early prostate cancer.
Practitioner. 2014; 258(1770):15-8, 2 [PubMed] Related Publications
One in eight men in the UK will be diagnosed with prostate cancer during their lifetime. The risk of prostate cancer is strongly age-related and is also linked with a Western lifestyle. Other risk factors include Afro-Caribbean ethnic origin and a positive family history. The more first-degree relatives affected the greater the risk of developing the disease. More than 70 familial prostate cancer susceptibility genes, including the important breast cancer gene BRCA2, have now been identified. A suspicion of a diagnosis of prostate cancer is usually based on either induration or nodularity of the prostate on digital rectal examination or, more commonly, a rise in serum prostate specific antigen (PSA) level. The usual cut-off point for PSA is taken as 4 ng/ml, but in men below 65 a value of more than 2.5 ng/ml should raise suspicion. A progressive rise in PSA over time may also indicate the possibility of the presence of a cancer within the prostate. When prostate cancer is suspected, increasingly urologists are requesting multiparametric magnetic resonance imaging of the gland before deciding whether or not a biopsy is indicated. The Gleason grading of any cancer identified is an important part of the decision-making process concerning the need for active treatment, as opposed to surveillance alone. Gleason pattern 6 cancers are regarded as low risk, Gleason 7 intermediate risk and 8-10 high risk. In patients diagnosed with intermediate- or high-risk prostate cancer further investigations are required to determine the local extent of the disease and to exclude the presence of metastases.

Related: Prostate Cancer

Suwannalert P, Kariya R, Suzu I, Okada S
The effects of Salacia reticulata on anti-cellular oxidants and melanogenesis inhibition in alpha-MSH-stimulated and UV irradiated B16 melanoma cells.
Nat Prod Commun. 2014; 9(4):551-4 [PubMed] Related Publications
The purposes of this study were to investigate the inhibitory effects of Salacia reticulata Tul. root extract on cellular oxidants and melanogenesis in B16 melanoma cells. Cells treated with non-toxic doses of S. reticulata root extract were investigated for their effects on melanogenesis, cellular tyrosinase activity and cellular oxidant scavenging activity. The results indicated that S. reticulata extract inhibited melanin synthesis and tyrosinase activity in alpha-MSH-induced or UV-irradiated B16 melanoma cells in a dose dependent manner. Additionally, the extract also exhibited anti-cellular oxidants in UV-induced radical melanoma cells. Altogether, these results suggested that S. reticulata root extract has roles in suppression of melanogenesis and oxidant inhibition. S. reticulata root extract may be a potential source for the development of pharmaceutical products for treatment of skin hyperpigmentation disorders.

Altinay S, Kusaslan R
Gastrointestinal autonomic nerve tumour of jejunum presenting as a perforated mass.
J Pak Med Assoc. 2014; 64(4):461-4 [PubMed] Related Publications
Gastrointestinal autonomic nerve tumour (GANT) is a rare mesenchymal neoplasm of the gastrointestinal tract arising from the neural plexus of the intestinal wall. Herein, we present a 70-year-old male patient presenting with a clinical picture of acute abdomen. Examination of the specimen obtained from the small bowel by means of complete resection revealed a relatively soft submucosal mass measuring 4.5 x 3 cm in size with spindle morphology and high mitotic activity (> 10 mitoses per 50 high-power fields). The tumour cells were strong positive for c-kit (CD117), S-100 protein and glial fibrillary acidic protein (GFAP), but did not harbour mutations in the c-kit and PDGFR genes. The diagnosis was based on light microscopy and immunohistochemical verification. We started tyrosine kinase inhibitor 400 mg/day. The patient is currently alive without metastasis at 28 months postoperatively. He is under close follow-up and survival data of the patient will be presented in the later studies.

Related: Gastrointestinal Stromal Tumors Soft Tissue Sarcomas Imatinib (Glivec)

Mazibrada J, Longo L, Vatrano S, et al.
Differential expression of HER2, STAT3, SOX2, IFI16 and cell cycle markers during HPV-related head and neck carcinogenesis.
New Microbiol. 2014; 37(2):129-43 [PubMed] Related Publications
The aim of this study was to analyze protein and gene expression of HER2 in 224 head and neck precancerous and malignant lesions by immunohistochemistry and FISH analysis. In parallel, expression of pStat3, Sox2, IFI16 and p16, Ki67 was evaluated. Immunohistochemical analysis was assessed on formalin-fixed paraffin-embedded (FFPE) tissue specimens. A combined method for HPV detection consisting of p16 immunostaining and two PCR probes was applied. HER2 gene status was evaluated by FISH analysis. HPV DNA was detected in 24% of cases with predominant HPV16 genotype. HPV-positive lesions had higher HER2, pStat3 and within carcinoma group, and higher IFI16 expression compared to the HPV-negative group (Fig. 1A-B-C). A strong positive correlation between Sox2 and proliferative activity was observed, whereas IFI16 expression displayed a negative relationship with Sox2 and Ki67 activity. The most striking result was higher pStat3 expression in HPV-positive lesions and its strong positive correlation with IFI16 expression. The presence of HPV may induce upregulation of HER2/neu, pStat3 and IFI16. High levels and a strong positive correlation between pStat3 and IFI16 suggest their synergistic pro-apoptotic effects in HPV-positive lesions.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology SOX2 gene

Noh JM, Choi DH, Baek H, et al.
Genetic anticipation of familial breast cancer with or without BRCA mutation in the Korean population.
Cancer Genet. 2014; 207(4):160-3 [PubMed] Related Publications
We investigated genetic anticipation of breast or ovarian cancer in patients with familial breast cancer. Among 201 patients with breast cancer who had a family history of breast or ovarian cancer, 95 families had affected familial members in the previous generation. Of these families, 2 were excluded because of insufficient data. From the 93 eligible families, 112 and 111 members were identified in the previous and proband generations, respectively. BRCA mutations were detected in 26 (28.0%) of the 93 probands. The median age at diagnosis of the first generation was 57 years and of the second generation was 40 years, which was a significant difference. The result from the mixed-effects model also demonstrated significant genetic anticipation (P < 0.0001). The expected age difference at onset of breast or ovarian cancer between the two generations was 17.06 years. BRCA mutation status did not influence the generational difference in age at diagnosis (17.99 vs. 16.62 y, P = 0.3973). Genetic counseling and early screening should be provided to women whose parent had a breast or ovarian cancer diagnosis.

Related: Breast Cancer Ovarian Cancer

Kluth M, Reynolds K, Rink M, et al.
Reduced membranous MET expression is linked to bladder cancer progression.
Cancer Genet. 2014; 207(4):147-52 [PubMed] Related Publications
The MET protein is involved in the malignant progression of different tumors. This study aimed to analyze the relationship of MET expression with tumor phenotype and clinical outcome in bladder cancer and the role of gene amplification for MET overexpression. A bladder cancer tissue microarray containing 686 bladder cancers was analyzed by immunohistochemistry and by fluorescence in situ hybridization. MET immunostaining was seen in normal urothelium and was recorded in 459 of 560 analyzable urothelial carcinomas (82.0%). Low MET staining was associated with a more unfavorable tumor phenotype. MET staining was seen in 89.8% of 266 pTa, 81.1% of 132 pT1, and 69.4% of 160 pT2-4 cancers (P < 0.0001). MET staining was detectable in 92.4% of 66 grade 1, 85.6% of 257 grade 2, and 75.1% of 237 grade 3 cancers (P = 0.001). MET expression status was not associated with overall or tumor-specific survival in muscle-invasive cancers (pT2-4), tumor progression in pT1 cancers, or recurrences in pTa tumors. Only four of the analyzed tumors (0.8%) showed amplification of the MET gene. We conclude that MET is not overexpressed in urothelial cancer but rather downregulated in a fraction of cancers. Accordingly, rare amplification of the genomic area including the MET gene was not associated with MET protein overexpression.

Related: FISH MET gene Bladder Cancer Bladder Cancer - Molecular Biology

Battaglia P, Baritono E, Remo A, et al.
KRAS mutations and M2PK upregulation in stool samples from individuals with positive fecal occult blood tests screened for colorectal cancer.
Tumori. 2014 Mar-Apr; 100(2):122-7 [PubMed] Related Publications
BACKGROUND: Screening for colorectal cancer (CRC) requires non-invasive methods of high diagnostic sensitivity and specificity. We evaluated the measurement of genetic and protein biomarkers of CRC in stool samples with the aim of testing their clinical utility in a CRC screening program.
PATIENTS AND METHODS: Individuals aged 53-75 years who were at risk of CRC and immunochemical fecal occult blood test (iFOBT) positive were invited to submit stool samples for molecular testing prior to colonoscopy. KRAS codon 12 Gly→Asp, Gly, Val, and codon 13 Gly→Cys gene mutations were tested using an in-house real-time ARMS PCR method. M2PK levels in stool samples were measured utilizing a commercial ELISA kit.
RESULTS: At colonoscopy, 7.6% of patients were found to have CRC, 50% had adenomas, 10.6% had hyperplastic polyps, 20.2% had diverticulosis and hemorrhoids, and 11.6% had normal mucosa. The best sensitivity for CRC (50%) was found in those cases where M2PK and KRAS abnormalities coexisted. M2PK showed a detection rate of 40.3% for adenomas but the combination of M2PK and KRAS abnormalities was found in only 5.7% of adenomas (P <0.01). iFOBT was false positive in 31.8% of cases in which colonoscopy excluded neoplastic lesions, while the coexistence of molecular and enzymatic abnormalities was more specific with false positive rates between 8.3% and 9.0% (P <0.05).
CONCLUSION: Our molecular screening approach demonstrates that detection of cancer-associated biomarkers measured in iFOBT-positive stool samples could help separate true from false positives in a FOBT-based screening process. M2PK showed particular promise for the detection of CRC and adenomas.

Related: Colorectal (Bowel) Cancer Screening for Colorectal (Bowel) Cancer Cancer Screening and Early Detection KRAS gene

Guo Y, Takeuchi I, Karnan S, et al.
Array-comparative genomic hybridization profiling of immunohistochemical subgroups of diffuse large B-cell lymphoma shows distinct genomic alterations.
Cancer Sci. 2014; 105(4):481-9 [PubMed] Related Publications
Diffuse large B-cell lymphoma (DLBCL) displays striking heterogeneity at the clinical, genetic and molecular levels. Subtypes include germinal center B-cell-like (GCB) DLBCL and activated B-cell-like (ABC) DLBCL, according to microarray analysis, and germinal center type or non-germinal center type by immunohistochemistry. Although some reports have described genomic aberrations based upon microarray classification system, genomic aberrations based upon immunohistochemical classifications have rarely been reported. The present study aimed to ascertain the relationship between genomic aberrations and subtypes identified by immunohistochemistry, and to study the pathogenetic character of Chinese DLBCL. We conducted immunohistochemistry using antibodies against CD10, BCL6 and MUM1 in 59 samples of DLBCL from Chinese patients, and then performed microarray-based comparative genomic hybridization for each case. Characteristic genomic differences were found between GCB and non-GCB DLBCL from the array data. The GCB type was characterized by more gains at 7q (7q22.1, P < 0.05) and losses at 16q (P ≤ 0.05), while the non-GCB type was characterized by gains at 11q24.3 and 3q13.2 (P < 0.05). We found completely different mutations in BCL6+ and BCL6- non-GCB type DLBCL, whereby the BCL6- group had a higher number of gains at 1q and a loss at 14q32.13 (P ≤ 0.005), while the BCL6+ group showed a higher number of gains at 14q23.1 (P = 0.15) and losses at 6q (P = 0.07). The BCL6- group had a higher frequency of genomic imbalances compared to the BCL6+ group. In conclusion, the BCL6+ and BCL6- non-GCB type of DLBCL appear to have different mechanisms of pathogenesis.

Related: CGH BCL6

Dunleavy K, Wilson WH
Appropriate management of molecular subtypes of diffuse large B-cell lymphoma.
Oncology (Williston Park). 2014; 28(4):326-34 [PubMed] Related Publications
In recent years, we have made huge strides in our understanding of the molecular complexity of diffuse large B-cell lymphoma (DLBCL). New technologies, such as gene expression profiling, RNA interference screening, and DNA sequencing, have identified several new signaling pathways and therapeutic targets for drug development. While we once considered DLBCL to be a single disease entity, recent insights have helped identify the existence of at least three distinct molecular diseases: a germinal center B-cell-like subtype, an activated B-cell-like subtype, and a primary mediastinal B-cell lymphoma subtype. All three subtypes originate from different stages of B-cell differentiation and are characterized by distinct mechanisms of oncogenic activation. This classification of DLBCL has laid the foundation for the development of new agents and novel strategies that target individual subtypes.

Yang B, Liu C, Diao L, et al.
A polymorphism at the microRNA binding site in the 3' untranslated region of C14orf101 is associated with non-Hodgkin lymphoma overall survival.
Cancer Genet. 2014; 207(4):141-6 [PubMed] Related Publications
MicroRNAs (miRNAs) can bind to the 3' untranslated regions (UTRs) of messenger RNAs, where they interfere with translation and thereby regulate cell differentiation, apoptosis, and tumorigenesis. Genetic polymorphisms in the 3' UTRs targeted by miRNAs alter the strength of miRNA binding in a manner that affects the behavior of individual miRNAs. In this study, four miRNA binding-site single nucleotide polymorphisms (SNPs) located in the 3' UTR of RYR3 (rs1044129), C14orf101 (rs4901706), KIAA0423 (rs1053667), and GOLGA7 (rs11337) were genotyped in non-Hodgkin lymphoma (NHL) patients to assess their relationships with cancer risk and overall survival. rs4901706, located in the 3' UTR of C14orf101, was shown to be independently related to overall survival in NHL patients by multivariate analysis (relative risk, 1.770; 95% CI, 1.046-2.996; P = 0.033). The prognostic value of this SNP on tumor overall survival was supported in diffuse large B-cell lymphoma patients with a P value of 0.095 and validated in T-cell lymphoma patients with a P value of 0.037.

Related: Non Hodgkin's Lymphoma

Oshrine BR, Olsen MN, Heneghan M, et al.
Acquired isochromosome 12p, somatic TP53 and PTEN mutations, and a germline ATM variant in an adolescent male with concurrent acute megakaryoblastic leukemia and mediastinal germ cell tumor.
Cancer Genet. 2014; 207(4):153-9 [PubMed] Related Publications
Previous reports have described an association between hematologic malignancies (HMs) and extragonadal germ cell tumor (GCT). Most patients have been adolescent males with mediastinal nonseminomatous GCT. Although a variety of HMs have been reported, there is a striking predilection toward acute megakaryoblastic leukemia (AMKL). Shared cytogenetic anomalies--particularly isochromosome 12p [i(12p)]--have suggested common clonal origins to the tumors. We report the case of a 17-year-old boy presenting with AMKL and a synchronous mediastinal GCT, with the characteristic i(12p) in both neoplasms. The common clonal origin of the AMKL and GCT was further confirmed with massively parallel sequencing, which identified somatic TP53 and PTEN mutations, as well as a rare germline ATM variant. Although these represent commonly mutated genes in cancer, this combination of mutations is not typically associated with either GCT or AMKL, suggesting that these tumors may represent unique biologic entities when they co-occur.

Related: Chromosome 12 FISH Germ Cell Tumors PTEN TP53

Alvarez-Argote J, Bauer FA, Dasanu CA
CD5 negative mantle cell lymphoma: a different clinical entity?
Conn Med. 2014; 78(4):211-4 [PubMed] Related Publications
We report herein a 77-year-old patient with CD5 negative mantle cell lymphoma (MCL). We further review the existing literature on clinicolaboratory features of this rare MCL subtype. Although most of the patients in the literature (including ours) had advanced stage at diagnosis, splenomegaly, and bone marrow involvement, they displayed prompt and durable responses to conventional treatment. We postulate that CD5 surface antigen expression could have prognostic implications in MCL. Further research and a larger number of patients are necessary in order to validate these findings.

Related: Mantle Cell Lymphoma

Kato T, Franconi CP, Sheridan MB, et al.
Analysis of the t(3;8) of hereditary renal cell carcinoma: a palindrome-mediated translocation.
Cancer Genet. 2014; 207(4):133-40 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
It has emerged that palindrome-mediated genomic instability generates DNA-based rearrangements. The presence of palindromic AT-rich repeats (PATRRs) at the translocation breakpoints suggested a palindrome-mediated mechanism in the generation of several recurrent constitutional rearrangements: the t(11;22), t(17;22), and t(8;22). To date, all reported PATRR-mediated translocations include the PATRR on chromosome 22 (PATRR22) as a translocation partner. Here, the constitutional rearrangement, t(3;8)(p14.2;q24.1), segregating with renal cell carcinoma in two families, is examined. The chromosome 8 breakpoint lies in PATRR8 in the first intron of the RNF139 (TRC8) gene, whereas the chromosome 3 breakpoint is located in an AT-rich palindromic sequence in intron 3 of the FHIT gene (PATRR3). Thus, the t(3;8) is the first PATRR-mediated, recurrent, constitutional translocation that does not involve PATRR22. Furthermore, we detect de novo translocations similar to the t(11;22) and t(8;22), involving PATRR3 in normal sperm. The breakpoint on chromosome 3 is in proximity to FRA3B, the most common fragile site in the human genome and a site of frequent deletions in tumor cells. However, the lack of involvement of PATRR3 sequence in numerous FRA3B-related deletions suggests that there are several different DNA sequence-based etiologies responsible for chromosome 3p14.2 genomic rearrangements.

Related: Chromosome 3 Chromosome 8 Kidney Cancer RNF139

Tang H, Zhang P, Xiang Q, et al.
Let-7 g microRNA sensitizes fluorouracil-resistant human hepatoma cells.
Pharmazie. 2014; 69(4):287-92 [PubMed] Related Publications
Let-7 microRNA is expressed in lower lever in a variety of human tumors and is involved in tumorigenesis. This study investigated the inhibitory effect of the let-7g microRNA on the expression of the HMGA2 gene in the fluorouracil (5-Fu)-resistant human hepatoma cell line Bel-7402/5-Fu, and the effect of let-7 g microRNA on drug sensitization in Bel-7402/5-Fu cells. Let-7 g microRNA and negative microRNA plasmids were constructed and transient transfected into Bel-7402/5-Fu cells. Expression levels of HMGA2 mRNA and protein in microRNA transient transfectants were clearly reduced as compared with negative microRNA transfectants and untreated cells. Flow cytometry revealed increased in S phase in let-7 g microRNA cells. dimethylthiazol-diphenyltetrazolium bromide (MTT) results indicated that microRNA transfectants had a higher cell inhibition rate than the negative vector or untreated cells after treatment with 0.13-13 microg/ml 5-Fu. In addition, cyclin A was down-regulated in the let-7 g transfectants cells.The results showed that let-7 g microRNA contributed to an increase of 5-Fu-induced cell cycle inhibit in human hepatoma cell and sensitized cells to 5-Fu, leading to increased the effectiveness of the drug in treating hepatoma cancer.

Related: Fluorouracil HMGA2 gene Liver Cancer

He MY, An Y, Gao YJ, et al.
Screening of RB1 gene mutations in Chinese patients with retinoblastoma and preliminary exploration of genotype-phenotype correlations.
Mol Vis. 2014; 20:545-52 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
PURPOSE: Retinoblastoma (RB) sets the paradigm for hereditary cancer syndromes, for which medical care can change depending on the results of genetic testing. In this study, we screened constitutional mutations in the RB1 gene via a method combining DNA sequencing and multiplex ligation-dependent probe amplification (MLPA), and performed a preliminary exploration of genotype-phenotype correlations.
METHODS: The peripheral blood of 85 retinoblastoma probands, including 39 bilateral and 46 unilateral, was collected, and genomic DNA was extracted. DNA sequencing was conducted first. MLPA analysis was applied for patients with bilateral RB with negative sequencing results and unilateral probands whose age at diagnosis was less than 1 year old.
RESULTS: Thirty-four distinct mutations were identified in 40 (47.1%) of the 85 probands (36 bilateral and four unilateral), of which 20% (8/40) was identified by MLPA. The total detection rate in bilateral cases was 92.3% (36/39). Of the total mutations identified, 77.5% (31/40) probands with a mean age of 10.7 months at diagnosis had null mutations, and 22.5% (9/40) with a mean age of 13.5 months at diagnosis had in-frame mutations. Of the 31 probands with null mutations, bilateral RB accounted for 96.8% (30/31). Of the nine probands with in-frame mutations, 66.7% had bilateral RB. There were seven new mutations of RB1 identified in this report, including six null mutations and one missense mutation. Clinical staging of the tumor did not show obvious differences between patients with null mutations and in-frame mutations.
CONCLUSIONS: Our results confirm that the type of mutation is related to age of onset and the laterality, but not staging of the retinoblastoma tumor. MLPA is a reliable method for detecting gross deletion or duplication of the RB1 gene. The combination of sequencing and MLPA improves the clinical diagnosis of RB.

Related: Retinoblastoma RB1

Seftor EA, Seftor RE, Weldon DS, et al.
Melanoma tumor cell heterogeneity: a molecular approach to study subpopulations expressing the embryonic morphogen nodal.
Semin Oncol. 2014; 41(2):259-66 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
As the frequency of melanoma increases, current treatment strategies are struggling to significantly impact patient survival. One of the critical issues in designing efficient therapies is understanding the composition of heterogeneous melanoma tumors in order to target cancer stem cells (CSCs) and drug-resistant subpopulations. In this review, we summarize recent findings pertinent to the reemergence of the embryonic Nodal signaling pathway in melanoma and its significance as a prognostic biomarker and therapeutic target. In addition, we offer a novel molecular approach to studying the functional relevance of Nodal-expressing subpopulations and their CSC phenotype.

Related: Melanoma Signal Transduction

Curry JM, Sprandio J, Cognetti D, et al.
Tumor microenvironment in head and neck squamous cell carcinoma.
Semin Oncol. 2014; 41(2):217-34 [PubMed] Related Publications
The tumor microenvironment (TME) of head and neck squamous cell carcinoma (HNSCC) is comprised of cancer-associated fibroblasts (CAFs), immune cells, and other supporting cells. Genetic changes in the carcinoma cells, such as alterations to TP53, NOTCH1, and specific gene expression profiles, contribute to derangements in cancer and microenvironment cells such as increased ROS, overproduction of cytokines, and epithelial to mesenchymal transition (EMT). CAFs are among the most critical elements of the TME contributing to proliferation, invasion, and metastasis. The adaptive immune response is suppressed in HNSCC through overexpression of cytokines, triggered apoptosis of T cells, and alterations in antigen processing machinery. Overexpression of critical cytokines, such as transforming growth factor-β (TGF-β), contributes to EMT, immune suppression, and evolution of CAFs. Inflammation and hypoxia are driving forces in angiogenesis and altered metabolism. HNSCC utilizes glycolytic and oxidative metabolism to fuel tumorigenesis via coupled mechanisms between cancer cell regions and cells of the TME. Increased understanding of the TME in HNSCC illustrates that the long-held notion of "condemned mucosa" reflects a process that extends beyond the epithelial cells to the entire tissue comprised of each of these elements.

Related: Cytokines Head and Neck Cancers Head and Neck Cancers - Molecular Biology Cancer Prevention and Risk Reduction

Cheon H, Borden EC, Stark GR
Interferons and their stimulated genes in the tumor microenvironment.
Semin Oncol. 2014; 41(2):156-73 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Constitutive expression of interferons (IFNs) and activation of their signaling pathways have pivotal roles in host responses to malignant cells in the tumor microenvironment. IFNs are induced by the innate immune system and in tumors through stimulation of Toll-like receptors (TLRs) and through other signaling pathways in response to specific cytokines. Although in the oncologic context IFNs have been thought of more as exogenous pharmaceuticals, the autocrine and paracrine actions of endogenous IFNs probably have even more critical effects on neoplastic disease outcomes. Through high-affinity cell surface receptors, IFNs modulate transcriptional signaling, leading to regulation of more than 2,000 genes with varying patterns of temporal expression. Induction of the gene products by both unphosphorylated and phosphorylated STAT1 after ligand binding results in alterations in tumor cell survival, inhibition of angiogenesis, and augmentation of actions of T, natural killer (NK), and dendritic cells. The interferon-stimulated gene (ISG) signature can be a favorable biomarker of immune response but, in a seemingly paradoxical finding, a specific subset of the full ISG signature indicates an unfavorable response to DNA-damaging interventions such as radiation. IFNs in the tumor microenvironment thus can alter the emergence, progression, and regression of malignancies.

Related: Apoptosis Cytokines Cancer Prevention and Risk Reduction Angiogenesis and Cancer Signal Transduction

Wang W, Li Y, Zhang X, et al.
Evaluating the significance of expression of CEA mRNA and levels of CEA and its related proteins in colorectal cancer patients.
J Surg Oncol. 2014; 109(5):440-4 [PubMed] Related Publications
OBJECTIVE: To explore the clinical significance of expression of CEA mRNA and serum CEA and the related proteins in colorectal cancer (CRC).
METHODS: Blood samples were collected from 370 CRC patients and 350 controls. CEA mRNA was determined by RT-PCR and levels of CEA, CA19-9, CA242, and CA724 were examined with chemiluminescence.
RESULTS: The positive rate of jointly detecting serum CEA, CA19-9, CA242, and CA724 was significantly higher than CEA mRNA expressions (P < 0.01), both positive rates were significantly correlated with TNM stage, lymph node, and visceral metastasis. The positive rate of jointly detecting in patients with poorly differentiated tumor was significantly higher than that in patients with highly differentiated tumor (P < 0.01). By contrast, CEA mRNA expression was not related with histopathologic grading. Postoperative follow-up found that all patients with high levels of CEA mRNA and serum CEA and the related proteins had liver, lung, pelvis, or other distant metastases.
CONCLUSIONS: These results suggest that high expressions of CEA mRNA and high levels of serum CEA and the related proteins are associated with the incidence and advanced of CRC. In addition, joint detection of serum CEA and the related proteins is more sensitivity than examination of serum CEA mRNA.

Related: Colorectal (Bowel) Cancer

Kim HA, Lee JK, Kim EK, et al.
Serum human epidermal growth factor receptor 2 levels as a real-time marker for tumor burden in breast cancer patients.
J Surg Oncol. 2014; 109(5):421-5 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: Human epidermal growth factor receptor 2 (HER2) status, an important factor in the treatment of breast cancer patients, is usually determined using primary tumor tissue samples; however, the HER2 status of metastatic lesions may differ from that of the primary tumor, but biopsies cannot be performed in all cases. Here, we investigated whether serum HER2 levels can serve as an alternative to assessments of HER2 expression in cancer tissues.
METHODS: Between April 2008 and July 2009, serum HER2 levels were evaluated in 295 patients with newly diagnosed breast cancer, 1,068 patients under follow-up care without recurrence after curative surgery, and 82 patients with disease recurrence.
RESULTS: Among 303 patients with histologically confirmed HER2-positive tumors, the rates of serum HER2 elevation were 9.2% in preoperative patients, 0.9% in patients under follow-up care without recurrence, and 44.0% in patients with recurrent disease; for patients with HER2-negative primary tumors, the corresponding values were 0.8%, 2.6%, and 15.8%, respectively.
CONCLUSION: Our results suggest that serum HER2 could be a useful real-time marker for tumor burden and recurrence in patients with HER2-positive disease.

Related: Breast Cancer FISH


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Cite this page: Cotterill SJ. LRP1, Cancer Genetics Web: http://www.cancerindex.org/geneweb/LRP1.htm Accessed: date

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