Gene Summary

Gene:PROC; protein C (inactivator of coagulation factors Va and VIIIa)
Aliases: PC, APC, PROC1, THPH3, THPH4
Summary:This gene encodes a vitamin K-dependent plasma glycoprotein. The encoded protein is cleaved to its activated form by the thrombin-thrombomodulin complex. This activated form contains a serine protease domain and functions in degradation of the activated forms of coagulation factors V and VIII. Mutations in this gene have been associated with thrombophilia due to protein C deficiency, neonatal purpura fulminans, and recurrent venous thrombosis.[provided by RefSeq, Dec 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:vitamin K-dependent protein C
Source:NCBIAccessed: 25 June, 2015


What does this gene/protein do?
Show (17)
Pathways:What pathways are this gene/protein implicaed in?
Show (4)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 25 June 2015 using data from PubMed using criteria.

Literature Analysis

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

  • MicroRNAs
  • Genetic Predisposition
  • Mutation
  • Mice, Transgenic
  • Brain Tumours
  • Breast Cancer
  • Base Sequence
  • Angiogenesis
  • Lung Cancer
  • RNA-Binding Proteins
  • Apoptosis
  • RNA Interference
  • Cell Proliferation
  • Chromosome 2
  • Phosphorylation
  • Cancer Gene Expression Regulation
  • Neoplasm Invasiveness
  • Prostate Cancer
  • Nuclear Proteins
  • Biological Models
  • Neoplasm Proteins
  • Gene Expression Profiling
  • Up-Regulation
  • Knockout Mice
  • Neoplastic Cell Transformation
  • HEK293 Cells
  • Messenger RNA
  • Gene Knockdown Techniques
  • Adenocarcinoma
  • Bladder Cancer
  • Randomized Controlled Trials
  • Immunohistochemistry
  • Western Blotting
  • Single Nucleotide Polymorphism
  • Antineoplastic Agents
  • Neoplasm Metastasis
  • Cell Differentiation
  • Molecular Sequence Data
  • Drug Resistance
Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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

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

Latest Publications: PROC (cancer-related)

Socolov D, Anghelache I, Ilea C, et al.
Benign breast disease and the risk of breast cancer in the next 15 years.
Rev Med Chir Soc Med Nat Iasi. 2015 Jan-Mar; 119(1):135-40 [PubMed] Related Publications
AIM: Fibrocystic mastosis (FCM) is defined by the totality of dystrophic changes of the mammary tissue, the grouping in the form of fibrosis of epithelial, cystic, metaplastic and hyperplastic alterations. A very good estimation of the cancer risk is related specifically to the microscopic aspect. Other factors, the family history as well as the presence of an inherited gene determining the increase in the risk of breast cancer are also considered. But, if a woman known with fibrocystic mastosis has not undergone any biopsy, then it is impossible to calculate the specific individual risk of developing cancer.
MATERIAL AND METHODS: The data collected as a study material and considered refer to: the total num- ber of cases investigated and diagnosed with fibrocystic mastosis, the annual distribution of this disease cases, the distribution of the cases according to age groups, admission reasons, clinical examination, personal pathologic history clinically significant for the basic disease (the main diagnosis), the family medical history significant for the basic disease, the anatomopathological diagnosis.
RESULTS: Between 2004 and 2006, at "Cuza Vodă" Obstetrics and Gynecology Hospital of Iaşi, a maximum number of cases is noticed in 2006, when there were 147 cases, and the lowest number of cases was in 2005. There was high frequency of the anatomopathological examinations that highlighted the presence of fibrocystic lesions (both proliferative and non-proliferative), and the second most often diagnosis is fibroadenoma. Though fibrocystic mastosis is not clearly defined, it is still admitted that in order to support this diagnosis it is first compulsory to exclude malignant tumours.
CONCLUSIONS: Only in 5% of the women with fibrocystic mastosis cellular changes can be revealed in the form of atypical hyperplasia, which are a risk factor for cancer. The lesion that delimits cancer from non-cancer is ductal carcinoma in situ. An incidence of over 20% is present in the countries that use mammographic screening programmes, mammographic surveillance programmes and programmes for the guided localization of nonpalpable lesions of the mammary gland.

Yoshii M, Tanaka H, Ohira M, et al.
Regulation of neutrophil infiltration into peritoneal cavity by laparoscopic gastrectomy.
Hepatogastroenterology. 2015 Mar-Apr; 62(138):546-50 [PubMed] Related Publications
BACKGROUND/AIMS: Laparoscopic surgery is a minimally invasive operation developed for treating gastrointestinal malignancies. We aimed to characterize the differences in the intra-abdominal environment following open and laparoscopic surgeries.
METHODOLOGY: We investigated data of 48 patients who underwent gastrectomy between 2010 and 2012. We analyzed the mRNA expression of chemokines, indoleamine 2, 3-dioxygenase (IDO), and so on in peritoneal lavage fluid with real-time RT-PCR. We also determined the leukocyte population and calculated the granulocyte/lymphocyte (G/L) ratio in peritoneal lavage fluid using flow cytometry.
RESULTS: CCL3 mRNA was significantly upregulated, whereas IDO mRNA was significantly downregulated, in the open group compared to the laparoscopic surgery group. Flow cytometry revealed that the G/L ratio was significantly higher in the open group.
CONCLUSIONS: We suggest that the production of chemokines and neutrophil infiltration into the abdominal cavity may be suppressed in the laparoscopic surgery. Thus, laparoscopic surgery may be beneficial in preserving local immunity.

Mavaddat N, Pharoah PD, Michailidou K, et al.
Prediction of breast cancer risk based on profiling with common genetic variants.
J Natl Cancer Inst. 2015; 107(5) [PubMed] Related Publications
BACKGROUND: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking.
METHODS: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates.
RESULTS: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer.
CONCLUSIONS: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.

Rebbeck TR, Mitra N, Wan F, et al.
Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.
JAMA. 2015; 313(13):1347-61 [PubMed] Related Publications
IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.
OBJECTIVE: To identify mutation-specific cancer risks for carriers of BRCA1/2.
DESIGN, SETTING, AND PARTICIPANTS: Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.
EXPOSURES: Mutations of BRCA1 or BRCA2.
MAIN OUTCOMES AND MEASURES: Breast and ovarian cancer risks.
RESULTS: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.
CONCLUSIONS AND RELEVANCE: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

Horsburgh S, Robson-Ansley P, Adams R, Smith C
Exercise and inflammation-related epigenetic modifications: focus on DNA methylation.
Exerc Immunol Rev. 2015; 21:26-41 [PubMed] Related Publications
Epigenetics is the study of mitotically or meiotically heritable phenotypes that occur as a result of modifications to DNA, thereby regulating gene expression independently of changes in base sequence due to manipulation of the chromatin structure. These modifications occur through a variety of mechanisms, such as DNA methylation, post-translational histone modifications, and non-coding RNAs, and can cause transcriptional suppression or activation depending on the location within the gene. Environmental stimuli, such as diet and exercise, are thought to be able to regulate these mechanisms, with inflammation as a probable contributory factor. Research into these areas is still in its infancy however. This review will focus on DNA methylation in the context of inflammation (both pro- and anti-inflammatory processes) and exercise. The complexity and relative shortcomings of some existing techniques for studying epigenetics will be highlighted, and recommendations for future study approaches made.

Xu Q, Liu JW, Yuan Y
Comprehensive assessment of the association between miRNA polymorphisms and gastric cancer risk.
Mutat Res Rev Mutat Res. 2015 Jan-Mar; 763:148-60 [PubMed] Related Publications
Single nucleotide polymorphisms (SNPs) in pri- or pre-microRNAs (miRNAs) were found to be associated with gastric cancer risk. The aim of this study was to systematically review with update meta-analysis for the association of miRNA SNPs with gastric cancer risk. We systematically reviewed a total of 31 SNPs in the precursor genes of 29 miRNAs associated with overall cancer risk. Meanwhile, 13 case-control studies with a total of 9044 gastric cancer cases and 11,762 controls were included in a meta-analysis of five highly studied pre-miRNA SNPs (miR-146a rs2910164, miR-196a2 rs11614913, miR-499 rs3746444, miR-149 rs2292832 and miR-27a rs895819). Our results show both the homozygous miR-27a rs895819 and the miR-149 rs2292832 heterozygote genotype were associated with a decreased risk of gastric cancer when compared with wild type. In the stratified analysis, in some subgroup, heterozygous miR-146a rs2910164 was associated with a decreased risk of gastric cancer; and the variant genotype of miR-196a-2 rs11614913 was associated with an increased risk. No association was found between miR-499 rs3746444 and gastric cancer risk. In summary, miR-27a rs895819 and miR-149 rs2292832 are of potential forewarning ability for gastric cancer risk.

Bei L, Xiao-Dong T, Yu-Fang G, et al.
DNA repair gene XRCC3 Thr241Met polymorphisms and lung cancer risk: a meta-analysis.
Bull Cancer. 2015; 102(4):332-9 [PubMed] Related Publications
BACKGROUND: The X-ray repair cross-complementing group 3 (XRCC3) is a highly suspected candidate gene for cancer susceptibility, and a large amount studies have examined the association of the rs861539 in XRCC3 (Thr241Met) with lung cancer risk in various populations. However, the results remain inconclusive.
METHODS: The electronic database of PubMed, Medline, Embase and CNKI (China National Knowledge Infrastructure) were searched for case-control studies published up to December 05, 2013. A systematic review and meta-analysis was performed to evaluate the relationship between XRCC3 Thr241Met polymorphism and lung cancer risk. Data were extracted and pooled odds ratio (OR) with its 95% confidence intervals (CI) were calculated.
RESULTS: Total 21 studies, including 6880 lung cancer cases and 8329 controls, were available for meta-analysis. Overall, our results showed that the XRCC3 Thr241Met polymorphism was not associated with risk of lung cancer in all genetic contrast models (P>0.05). Stratified analyses by ethnicity (Asians, Caucasians and mixed population) showed similar results. Additionally, no evidence of publication bias was observed by using the funnel plot.
CONCLUSIONS: There is no clear evidence showing a significant correlation between XRCC3 Thr241Met polymorphism and lung cancer risk in total population and stratified analysis by ethnicity. However, studies assessing the gene-gene interactions should be considered to further estimate this gene variant in lung cancer risk.

Cromer MK, Choi M, Nelson-Williams C, et al.
Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas.
Proc Natl Acad Sci U S A. 2015; 112(13):4062-7 [PubMed] Free Access to Full Article Related Publications
Insulinomas are pancreatic islet tumors that inappropriately secrete insulin, producing hypoglycemia. Exome and targeted sequencing revealed that 14 of 43 insulinomas harbored the identical somatic mutation in the DNA-binding zinc finger of the transcription factor Yin Yang 1 (YY1). Chromatin immunoprecipitation sequencing (ChIP-Seq) showed that this T372R substitution changes the DNA motif bound by YY1. Global analysis of gene expression demonstrated distinct clustering of tumors with and without YY1(T372R) mutations. Genes showing large increases in expression in YY1(T372R) tumors included ADCY1 (an adenylyl cyclase) and CACNA2D2 (a Ca(2+) channel); both are expressed at very low levels in normal β-cells and show mutation-specific YY1 binding sites. Both gene products are involved in key pathways regulating insulin secretion. Expression of these genes in rat INS-1 cells demonstrated markedly increased insulin secretion. These findings indicate that YY1(T372R) mutations are neomorphic, resulting in constitutive activation of cAMP and Ca(2+) signaling pathways involved in insulin secretion.

Nan H, Hutter CM, Lin Y, et al.
Association of aspirin and NSAID use with risk of colorectal cancer according to genetic variants.
JAMA. 2015; 313(11):1133-42 [PubMed] Article available free on PMC after 17/03/2016 Related Publications
IMPORTANCE: Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer.
OBJECTIVE: To identify common genetic markers that may confer differential benefit from aspirin or NSAID chemoprevention, we tested gene × environment interactions between regular use of aspirin and/or NSAIDs and single-nucleotide polymorphisms (SNPs) in relation to risk of colorectal cancer.
DESIGN, SETTING, AND PARTICIPANTS: Case-control study using data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia, and Germany and including colorectal cancer cases (n=8634) and matched controls (n=8553) ascertained between 1976 and 2011. Participants were all of European descent.
EXPOSURES: Genome-wide SNP data and information on regular use of aspirin and/or NSAIDs and other risk factors.
RESULTS: Regular use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer (prevalence, 28% vs 38%; odds ratio [OR], 0.69 [95% CI, 0.64-0.74]; P = 6.2 × 10(-28)) compared with nonregular use. In the conventional logistic regression analysis, the SNP rs2965667 at chromosome 12p12.3 near the MGST1 gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P = 4.6 × 10(-9) for interaction). Aspirin and/or NSAID use was associated with a lower risk of colorectal cancer among individuals with rs2965667-TT genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.61-0.70]; P = 7.7 × 10(-33)) but with a higher risk among those with rare (4%) TA or AA genotypes (prevalence, 35% vs 29%; OR, 1.89 [95% CI, 1.27-2.81]; P = .002). In case-only interaction analysis, the SNP rs16973225 at chromosome 15q25.2 near the IL16 gene showed a genome-wide significant interaction with use of aspirin and/or NSAIDs (P = 8.2 × 10(-9) for interaction). Regular use was associated with a lower risk of colorectal cancer among individuals with rs16973225-AA genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.62-0.71]; P = 1.9 × 10(-30)) but was not associated with risk of colorectal cancer among those with less common (9%) AC or CC genotypes (prevalence, 36% vs 39%; OR, 0.97 [95% CI, 0.78-1.20]; P = .76).
CONCLUSIONS AND RELEVANCE: In this genome-wide investigation of gene × environment interactions, use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer, and this association differed according to genetic variation at 2 SNPs at chromosomes 12 and 15. Validation of these findings in additional populations may facilitate targeted colorectal cancer prevention strategies.

Lin HY, Shi H, Li CY, et al.
LEP and LEPR polymorphisms in non-Hodgkin lymphoma risk: a systematic review and pooled analysis.
J BUON. 2015 Jan-Feb; 20(1):261-8 [PubMed] Related Publications
PURPOSE: The purpose of this systematic meta-analysis was to evaluate the association between leptin (LEP) and leptin receptor (LEPR) gene polymorphisms and non-Hodgkin lymphoma (NHL) risk.
METHODS: All studies published up to July 2014 on the association between LEP and LEPR polymorphisms and NHL risk were identified by searching PubMed, Web of Science, EMBASE, and Google Scholar. Odds ratios (ORs) with 95% confidence intervals (CIs) for LEP and LEPR polymorphisms and NHL were calculated with fixed-effects and random-effects models.
RESULTS: LEP G2528A polymorphism was associated with increased, yet not statistically significant risk of NHL (homozygote comparison, OR=1.27, 95% CI=1.01-1.60, p=0.63; heterozygote comparison, OR=1.13, 95% CI=0.86-1.49, p=0.14; dominant model, OR=1.18, 95% CI=0.99-1.41, p=0.21; recessive model, OR=1.18, 95% CI=0.97-1.43, p=0.78; additive model, OR=1.14, 95% CI=1.01-1.28, p=0.52). Significant decrease of NHL risk was found in LEP A19G polymorphism, while no links were detected with the LEPR polymorphisms studied. In subgroup analysis, the pooled results showed that LEP A19G polymorphism was associated with decreased risk of follicular lymphoma (FL) (homozygote comparison, OR=0.56, 95% CI=0.37-0.85, p=0.69). However, no evidence of a significant association was observed in diffuse large B-cell lymphoma (DLBCL) for variant genotypes of all single nucleotide polymorphisms (SNPs).
CONCLUSIONS: LEP G2548A polymorphism contributes to NHL susceptibility. Also, our results provide evidence that LEP A19G polymorphism is associated with decreased risk of NHL, especially in FL. Further large-scale and well-designed studies are needed to confirm this association.

Lee YH, Gyu Song G
Vitamin D receptor FokI, BsmI, TaqI, ApaI, and EcoRV polymorphisms and susceptibility to melanoma: a meta-analysis.
J BUON. 2015 Jan-Feb; 20(1):235-43 [PubMed] Related Publications
PURPOSE: The purpose of this study was to examine whether vitamin D receptor (lVDR) polymorphisms are associated with susceptibility to melanoma.
METHODS: A meta-analysis was carried out to investigate the association between the VDR FokI, BsmI, TaqI, ApaI, and EcoRV polymorphisms and susceptibility to melanoma.
RESULTS: A total of 11 studies were evaluated, which included 4,413 patients and 4,072 controls (all European). The meta-analysis revealed no association between melanoma and the BsmI B allele (odds ratio/OR=0.901, 95% confidence interval/CI=0.783-1.036, p=0.144). However, an association was shown between melanoma and the Bb+bb genotype (OR=0.868, 95% CI=0.767-0.982, p=0.025). No association was noticed between melanoma and FokI polymorphism (OR for the F allele=1.016, 95% CI=0.869-1.189, p=0.839). Moreover, melanoma risk was not associated with the TaqI, ApaI, and EcoRV polymorphisms (OR for the T allele=0.986, 95% CI=0.842-1.156, p=0.864; OR for the A allele=0.949, 95% CI=0.842-1.069, p=0.388; OR for the E allele=0.993, 95% CI=0.875-1.126, p=0.911, respectively).
CONCLUSIONS: This meta-analysis demonstrated that the VDR BsmI polymorphism is associated with susceptibility to melanoma in Europeans, suggesting that carrying the VDR BsmI B allele may be a protective factor against melanoma development.

Jones MF, Hara T, Francis P, et al.
The CDX1-microRNA-215 axis regulates colorectal cancer stem cell differentiation.
Proc Natl Acad Sci U S A. 2015; 112(13):E1550-8 [PubMed] Article available free on PMC after 30/09/2015 Related Publications
The transcription factor caudal-type homeobox 1 (CDX1) is a key regulator of differentiation in the normal colon and in colorectal cancer (CRC). CDX1 activates the expression of enterocyte genes, but it is not clear how the concomitant silencing of stem cell genes is achieved. MicroRNAs (miRNAs) are important mediators of gene repression and have been implicated in tumor suppression and carcinogenesis, but the roles of miRNAs in differentiation, particularly in CRC, remain poorly understood. Here, we identified microRNA-215 (miR-215) as a direct transcriptional target of CDX1 by using high-throughput small RNA sequencing to profile miRNA expression in two pairs of CRC cell lines: CDX1-low HCT116 and HCT116 with stable CDX1 overexpression, and CDX1-high LS174T and LS174T with stable CDX1 knockdown. Validation of candidate miRNAs identified by RNA-seq in a larger cell-line panel revealed miR-215 to be most significantly correlated with CDX1 expression. Quantitative ChIP-PCR and promoter luciferase assays confirmed that CDX1 directly activates miR-215 transcription. miR-215 expression is depleted in FACS-enriched cancer stem cells compared with unsorted samples. Overexpression of miR-215 in poorly differentiated cell lines causes a decrease in clonogenicity, whereas miR-215 knockdown increases clonogenicity and impairs differentiation in CDX1-high cell lines. We identified the genome-wide targets of miR-215 and found that miR-215 mediates the repression of cell cycle and stemness genes downstream of CDX1. In particular, the miR-215 target gene BMI1 has been shown to promote stemness and self-renewal and to vary inversely with CDX1. Our work situates miR-215 as a link between CDX1 expression and BMI1 repression that governs differentiation in CRC.

McClellan JS, Dove C, Gentles AJ, et al.
Reprogramming of primary human Philadelphia chromosome-positive B cell acute lymphoblastic leukemia cells into nonleukemic macrophages.
Proc Natl Acad Sci U S A. 2015; 112(13):4074-9 [PubMed] Article available free on PMC after 30/09/2015 Related Publications
BCR-ABL1(+) precursor B-cell acute lymphoblastic leukemia (BCR-ABL1(+) B-ALL) is an aggressive hematopoietic neoplasm characterized by a block in differentiation due in part to the somatic loss of transcription factors required for B-cell development. We hypothesized that overcoming this differentiation block by forcing cells to reprogram to the myeloid lineage would reduce the leukemogenicity of these cells. We found that primary human BCR-ABL1(+) B-ALL cells could be induced to reprogram into macrophage-like cells by exposure to myeloid differentiation-promoting cytokines in vitro or by transient expression of the myeloid transcription factor C/EBPα or PU.1. The resultant cells were clonally related to the primary leukemic blasts but resembled normal macrophages in appearance, immunophenotype, gene expression, and function. Most importantly, these macrophage-like cells were unable to establish disease in xenograft hosts, indicating that lineage reprogramming eliminates the leukemogenicity of BCR-ABL1(+) B-ALL cells, and suggesting a previously unidentified therapeutic strategy for this disease. Finally, we determined that myeloid reprogramming may occur to some degree in human patients by identifying primary CD14(+) monocytes/macrophages in BCR-ABL1(+) B-ALL patient samples that possess the BCR-ABL1(+) translocation and clonally recombined VDJ regions.

Sun XX, He X, Yin L, et al.
The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc.
Proc Natl Acad Sci U S A. 2015; 112(12):3734-9 [PubMed] Article available free on PMC after 24/09/2015 Related Publications
c-Myc protein stability and activity are tightly regulated by the ubiquitin-proteasome system. Aberrant stabilization of c-Myc contributes to many human cancers. c-Myc is ubiquitinated by SCF(Fbw7) (a SKP1-cullin-1-F-box complex that contains the F-box and WD repeat domain-containing 7, Fbw7, as the F-box protein) and several other ubiquitin ligases, whereas it is deubiquitinated and stabilized by ubiquitin-specific protease (USP) 28. The bulk of c-Myc degradation appears to occur in the nucleolus. However, whether c-Myc is regulated by deubiquitination in the nucleolus is not known. Here, we report that the nucleolar deubiquitinating enzyme USP36 is a novel c-Myc deubiquitinase. USP36 interacts with and deubiquitinates c-Myc in cells and in vitro, leading to the stabilization of c-Myc. This USP36 regulation of c-Myc occurs in the nucleolus. Interestingly, USP36 interacts with the nucleolar Fbw7γ but not the nucleoplasmic Fbw7α. However, it abolished c-Myc degradation mediated both by Fbw7γ and by Fbw7α. Consistently, knockdown of USP36 reduces the levels of c-Myc and suppresses cell proliferation. We further show that USP36 itself is a c-Myc target gene, suggesting that USP36 and c-Myc form a positive feedback regulatory loop. High expression levels of USP36 are found in a subset of human breast and lung cancers. Altogether, these results identified USP36 as a crucial and bono fide deubiquitinating enzyme controlling c-Myc's nucleolar degradation pathway.

Wang S, Lv C, Jin H, et al.
A common genetic variation in the promoter of miR-107 is associated with gastric adenocarcinoma susceptibility and survival.
Mutat Res. 2014; 769:35-41 [PubMed] Related Publications
BACKGROUND: Global miRNA expression profile has been widely used to characterize human cancers. It is well established that genetic variants in miRNAs can modulate miRNA biogenesis and disease risk.
METHODS: Genome-wide miRNA microarray was employed for assessment of miRNA expression profile of gastric adenocarcinoma (GAC). The variants of significantly dysregulated miRNA were genotyped in test (715 cases and 804 controls) and validation (940 cases and 1050 controls) subject sets.
RESULTS: MiRNA microarray revealed that 12 miRNAs including miR-107 significantly dysregulated in GAC tissues. The sequencing of the promoter of miR-107 identified 3 SNPs (rs11185777, rs78591545, and rs2296616) with minor allele frequency (MAF)>5%. Analyzing their association with GAC risk and prognosis revealed that the C allele of rs2296616 (T>C) was significantly associated with the decreased risk of GAC among the test, validation and combined sets (TC/CC vs. TT, adjusted OR=0.39, 95% CI=0.31-0.49 for the combined set). However, the C allele was related to an unfavorable prognosis of Cardia GAC (CGAC) (adjusted HR=1.49, 95% CI=1.01-2.20). In vivo evidence showed that the individuals with the rs2296616C allele had lower miR-107 expression compared with the homozygous T allele carriers.
CONCLUSION: miR-107 is dysregulated in GAC pathogenesis and the SNP rs2296616 may play a role in the process.

Raimondi S, Pasquali E, Gnagnarella P, et al.
BsmI polymorphism of vitamin D receptor gene and cancer risk: a comprehensive meta-analysis.
Mutat Res. 2014; 769:17-34 [PubMed] Related Publications
The VDR gene is an important regulator of the vitamin D pathway, and the role of some of its polymorphisms on cancer risk was previously investigated. A trend of cancer risk reduction with the VDR BsmI B allele was observed for many cancer sites. We performed a comprehensive meta-analysis to investigate the role of VDR BsmI polymorphism on cancer risk, even according to different ethnicities. Summary odds ratios (SORs) were calculated with random-effects models and maximum likelihood estimation. We categorized studies into three groups ("moderate", "high" and "very high confidence") according to departure from Hardy-Weinberg equilibrium in controls, reported minor allele frequency and genotyping quality controls. The meta-analysis included 73 studies with 45,218 cases and 52,057 controls. We found a significant 6-7% reduction of cancer risk at any site respectively for carriers of Bb genotype (SOR; 95%CI: 0.94; 0.90-0.99) and for carriers of BsmI BB genotype (SOR; 95%CI: 0.93; 0.89-0.98) compared to bb carriers, and they remain statistically significant when we restricted the analysis to at least "high confidence" studies. For skin cancer, a significant risk reduction was observed for Bb carriers (SOR; 95%CI: 0.86; 0.76-0.98). We also found a significant reduction of colorectal cancer risk for BB and Bb+BB genotypes carriers, but these SORs were no more significant when we restricted the analysis to studies with "high confidence". When the analysis was stratified by ethnicity, we still observed a significant decreased risk for both Bb and BB compared to bb genotype among Caucasians: SORs (95%CI) for any cancer site were 0.97 (0.93-1.00) and 0.95 (0.91-0.99), respectively. Among other ethnic groups the inverse association was still present, but did not reach statistical significance. In conclusion, we suggest a weak effect of BsmI B allele in reducing cancer risk at any site, especially of the skin.

Dasgupta M, Dermawan JK, Willard B, Stark GR
STAT3-driven transcription depends upon the dimethylation of K49 by EZH2.
Proc Natl Acad Sci U S A. 2015; 112(13):3985-90 [PubMed] Article available free on PMC after 30/09/2015 Related Publications
Several transcription factors, including p53, NF-κB, and STAT3, are modified by the same enzymes that also modify histones, with important functional consequences. We have identified a previously unrecognized dimethylation of K49 of STAT3 that is crucial for the expression of many IL-6-dependent genes, catalyzed by the histone-modifying enzyme enhancer of zeste homolog 2 (EZH2). Loss of EZH2 is protumorigenic in leukemias, but its overexpression is protumorigenic in solid cancers. Connecting EZH2 to a functionally important methylation of STAT3, which is constitutively activated in many tumors, may help reveal the basis of the opposing roles of EZH2 in liquid and solid tumors and also may identify novel therapeutic opportunities.

Church J, Xhaja X, LaGuardia L, et al.
Desmoids and genotype in familial adenomatous polyposis.
Dis Colon Rectum. 2015; 58(4):444-8 [PubMed] Related Publications
BACKGROUND: Desmoid disease can be a serious, life-threatening complication of familial adenomatous polyposis. The ability to predict patients at increased desmoid risk is important, but a convincing genotype-phenotype correlation for desmoid formation has not yet been described.
PURPOSE: The aim of this study is to assess the relationship between desmoid disease and genotype in patients with familial adenomatous polyposis.
DESIGN: This is a cohort study.
PATIENTS: All patients with familial adenomatous polyposis and a documented pathogenic APC mutation in themselves or a first-degree relative were selected.
MAIN OUTCOMES MEASURES: The comparison of genotype and the presence, stage, and site of desmoid disease are the primary end points of this study.
RESULTS: Three hundred twenty-three patients from 219 families were identified. Mutations spanned the length of the gene, from codon 213 to codon 2051. Desmoid disease was diagnosed in 77 patients from 68 families. Desmoid disease was found in 14.9% of patients with a mutation 5' of codon 400, 23.2% of patients with a mutation from codon 401 to 1400, and in 37.1% of those with a mutation 3' of 1400. All patients with 5' mutations had stage I or II abdominal desmoid disease, and all tumors were stable or shrinking. Twelve percent of patients who had desmoid disease with mutations between codons 400 and 1400 had stage III or IV desmoid disease, and 5 of 42 (12%) tumors were growing at the time of the study. There had been 2 desmoid-related deaths. Almost half (44%) of patients who had desmoid disease with mutations 3' of codon 1400 had stage III or IV disease. Three of 14 tumors were growing (21%), and there were 4 desmoid-related deaths.
LIMITATIONS: This study was conducted at a tertiary referral center, and there was no systematic surveillance for desmoids.
CONCLUSION: Desmoid disease occurs in patients who have familial adenomatous polyposis with almost any APC mutation, although there is an increased propensity in those with a 3' mutation. The incidence and severity of the desmoid disease are related to the site of the mutation.

Michailidou K, Beesley J, Lindstrom S, et al.
Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer.
Nat Genet. 2015; 47(4):373-80 [PubMed] Related Publications
Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.

Wang W, Xiao ZD, Li X, et al.
AMPK modulates Hippo pathway activity to regulate energy homeostasis.
Nat Cell Biol. 2015; 17(4):490-9 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
The Hippo pathway was discovered as a conserved tumour suppressor pathway restricting cell proliferation and apoptosis. However, the upstream signals that regulate the Hippo pathway in the context of organ size control and cancer prevention are largely unknown. Here, we report that glucose, the ubiquitous energy source used for ATP generation, regulates the Hippo pathway downstream effector YAP. We show that both the Hippo pathway and AMP-activated protein kinase (AMPK) were activated during glucose starvation, resulting in phosphorylation of YAP and contributing to its inactivation. We also identified glucose-transporter 3 (GLUT3) as a YAP-regulated gene involved in glucose metabolism. Together, these results demonstrate that glucose-mediated energy homeostasis is an upstream event involved in regulation of the Hippo pathway and, potentially, an oncogenic function of YAP in promoting glycolysis, thereby providing an exciting link between glucose metabolism and the Hippo pathway in tissue maintenance and cancer prevention.

Perera O, Evans A, Pertziger M, et al.
Trefoil factor 3 (TFF3) enhances the oncogenic characteristics of prostate carcinoma cells and reduces sensitivity to ionising radiation.
Cancer Lett. 2015; 361(1):104-11 [PubMed] Related Publications
Trefoil factor 3 (TFF3) is a secreted protein which functions in mucosal repair of the gastrointestinal tract. This is achieved through the combined stimulation of cell migration and prevention of apoptosis and anoikis, thus facilitating repair. Deregulated TFF3 expression at the gene and protein level is implicated in numerous cancers. In prostate cancer TFF3 has previously been reported as a potential biomarker, overexpressed in a subset of primary and metastatic cases. Here we investigated the effect of increased TFF3 expression on prostate cancer cell behaviour. Oncomine analysis demonstrated that TFF3 mRNA expression was upregulated in prostate cancer compared to normal tissue. Forced-expression models were established in the prostate cancer cell lines, DU145 and PC3, by stable transfection of an expression vector containing the TFF3 cDNA. Forced expression of TFF3 significantly increased total cell number and cell viability, cell proliferation and cell survival. In addition, TFF3 enhanced anchorage independent growth, 3-dimensional colony formation, wound healing and cell migration compared to control transfected cell lines. We also observed reduced sensitivity to ionising radiation in stably transfected cell lines. In dose response experiments, forced expression of TFF3 significantly enhanced the regrowth of PC3 cells following ionising radiation compared with control transfected cells. In addition, TFF3 enhanced clonogenic survival of DU145 and PC3 cells. These studies indicate that targeting TFF3 for the treatment of prostate cancer warrants further investigation.

Machiela MJ, Zhou W, Sampson JN, et al.
Characterization of large structural genetic mosaicism in human autosomes.
Am J Hum Genet. 2015; 96(3):487-97 [PubMed] Article available free on PMC after 05/09/2015 Related Publications
Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.

Diao MK, Liu CY, Liu HW, et al.
Integrated HPV genomes tend to integrate in gene desert areas in the CaSki, HeLa, and SiHa cervical cancer cell lines.
Life Sci. 2015; 127:46-52 [PubMed] Related Publications
AIMS: The integration preferences of human papillomavirus (HPV) have been intensively studied and contested over recent years. To disclose the integration preferences of high-risk HPV in cervical cancer, HPV transcriptional sites and features in different cervical cancer cell lines were identified.
MAIN METHODS: In this study, three cervical cancer cell lines (CaSki, HeLa, and SiHa) were subjected for HPV genome status determination by amplification of papillomavirus oncogene transcripts (APOT) assay. The numbers of viral copies in human genomes and numbers of viral-human fusion mRNAs in three HPV-integrated cervical cancer cell lines were measured and analysed.
KEY FINDINGS: The results revealed that the gene desert region 8q24 of the HPV type 18 integrated HeLa cell line and the 13q21-22 region of the HPV type 16 integrated CaSki and SiHa cell lines were hotspots for HPV integration, and the numbers of viral copies in the human genomes of the three cell lines that we detected were not in accordance with those reported in previous studies.
SIGNIFICANCE: Integration of the HPV genome into the host cell chromosome suggests that persistent HPV infection is vital for malignant cell transformation and carcinogenesis. This study provides information to benefit health care professionals seeking more comprehensive and accurate diagnostics for HPV-related disease"? Please check, and amend as necessary.

Yamada HY, Zhang Y, Reddy A, et al.
Tumor-promoting/progressing role of additional chromosome instability in hepatic carcinogenesis in Sgo1 (Shugoshin 1) haploinsufficient mice.
Carcinogenesis. 2015; 36(4):429-40 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
A major etiological risk factor for hepatocellular carcinoma (HCC) is infection by Hepatitis viruses, especially hepatitis B virus and hepatitis C virus. Hepatitis B virus and hepatitis C virus do not cause aggressive activation of an oncogenic pathway, but they transactivate a broad array of genes, cause chronic inflammation, and, through interference with mitotic processes, lead to mitotic error-induced chromosome instability (ME-CIN). However, how ME-CIN is involved in the development of HCC remains unclear. Delineating the effect of ME-CIN on HCC development should help in identifying measures to combat HCC. In this study, we used ME-CIN model mice haploinsufficient in Shugoshin 1 (Sgo1(-/+)) to assess the role of ME-CIN in HCC development. Treatment with the carcinogen azoxymethane caused Sgo1(-/+) ME-CIN model mice to develop HCCs within 6 months, whereas control mice developed no HCC (P < 0.003). The HCC development was associated with expression of early HCC markers (glutamine synthetase, glypican 3, heat shock protein 70, and the serum marker alpha fetoprotein), although without fibrosis. ME-CIN preceded the expression of HCC markers, suggesting that ME-CIN is an important early event in HCC development. In 12-month-old untreated Sgo1 mice, persistent DNA damage, altered gene expression, and spontaneous HCCs were observed. Sgo1 protein accumulated in response to DNA damage in vitro. Overall, Sgo1(-/+)-mediated ME-CIN strongly promoted/progressed development of HCC in the presence of an initiator carcinogen, and it had a mild initiator effect by itself. Use of the ME-CIN model mice should help in identifying drugs to counteract the effects of ME-CIN and should accelerate anti-HCC drug development.

Shen Z, Hou X, Chen B, et al.
NOTCH3 gene polymorphism is associated with the prognosis of gliomas in Chinese patients.
Medicine (Baltimore). 2015; 94(9):e482 [PubMed] Related Publications
Recent studies show that NOTCH3 is involved in the glioma development and it is also a prognostic factor for glioma patients. However, the gene polymorphism of NOTCH3 in gliomas prognosis remains unknown.A total of 266 patients were enrolled into this study. The NOTCH3 gene polymorphism at 3 loci, including C>T polymorphism at nucleotide 381, C>A polymorphism at 474 and G>A polymorphism at 684 were determined. All patients received the surgical treatment and/or chemotherapy and/or radiotherapy.We found that the 684G>A polymorphism affects the tumor NOTCH3 expression level and is closely associated with a higher tumor grade, poorer tumor differentiation, and karnofsky performance score in these glioma patients. More importantly, the 684G>A polymorphism is significantly associated with the prognosis of these patients regardless of their treatment manner.Our study indicates that the NOTCH3 gene 684G>A polymorphism may be used as a prognosis marker for gliomas.

Turner KM, Sun Y, Ji P, et al.
Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression.
Proc Natl Acad Sci U S A. 2015; 112(11):3421-6 [PubMed] Article available free on PMC after 17/09/2015 Related Publications
Akt is a robust oncogene that plays key roles in the development and progression of many cancers, including glioma. We evaluated the differential propensities of the Akt isoforms toward progression in the well-characterized RCAS/Ntv-a mouse model of PDGFB-driven low grade glioma. A constitutively active myristoylated form of Akt1 did not induce high-grade glioma (HGG). In stark contrast, Akt2 and Akt3 showed strong progression potential with 78% and 97% of tumors diagnosed as HGG, respectively. We further revealed that significant variations in polarity and hydropathy values among the Akt isoforms in both the pleckstrin homology domain (P domain) and regulatory domain (R domain) were critical in mediating glioma progression. Gene expression profiles from representative Akt-derived tumors indicated dominant and distinct roles for Akt3, consisting primarily of DNA repair pathways. TCGA data from human GBM closely reflected the DNA repair function, as Akt3 was significantly correlated with a 76-gene signature DNA repair panel. Consistently, compared with Akt1 and Akt2 overexpression models, Akt3-expressing human GBM cells had enhanced activation of DNA repair proteins, leading to increased DNA repair and subsequent resistance to radiation and temozolomide. Given the wide range of Akt3-amplified cancers, Akt3 may represent a key resistance factor.

Selvanathan SP, Graham GT, Erkizan HV, et al.
Oncogenic fusion protein EWS-FLI1 is a network hub that regulates alternative splicing.
Proc Natl Acad Sci U S A. 2015; 112(11):E1307-16 [PubMed] Article available free on PMC after 17/09/2015 Related Publications
The synthesis and processing of mRNA, from transcription to translation initiation, often requires splicing of intragenic material. The final mRNA composition varies based on proteins that modulate splice site selection. EWS-FLI1 is an Ewing sarcoma (ES) oncoprotein with an interactome that we demonstrate to have multiple partners in spliceosomal complexes. We evaluate the effect of EWS-FLI1 on posttranscriptional gene regulation using both exon array and RNA-seq. Genes that potentially regulate oncogenesis, including CLK1, CASP3, PPFIBP1, and TERT, validate as alternatively spliced by EWS-FLI1. In a CLIP-seq experiment, we find that EWS-FLI1 RNA-binding motifs most frequently occur adjacent to intron-exon boundaries. EWS-FLI1 also alters splicing by directly binding to known splicing factors including DDX5, hnRNP K, and PRPF6. Reduction of EWS-FLI1 produces an isoform of γ-TERT that has increased telomerase activity compared with wild-type (WT) TERT. The small molecule YK-4-279 is an inhibitor of EWS-FLI1 oncogenic function that disrupts specific protein interactions, including helicases DDX5 and RNA helicase A (RHA) that alters RNA-splicing ratios. As such, YK-4-279 validates the splicing mechanism of EWS-FLI1, showing alternatively spliced gene patterns that significantly overlap with EWS-FLI1 reduction and WT human mesenchymal stem cells (hMSC). Exon array analysis of 75 ES patient samples shows similar isoform expression patterns to cell line models expressing EWS-FLI1, supporting the clinical relevance of our findings. These experiments establish systemic alternative splicing as an oncogenic process modulated by EWS-FLI1. EWS-FLI1 modulation of mRNA splicing may provide insight into the contribution of splicing toward oncogenesis, and, reciprocally, EWS-FLI1 interactions with splicing proteins may inform the splicing code.

Faber AC, Farago AF, Costa C, et al.
Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer.
Proc Natl Acad Sci U S A. 2015; 112(11):E1288-96 [PubMed] Article available free on PMC after 17/09/2015 Related Publications
BH3 mimetics such as ABT-263 induce apoptosis in a subset of cancer models. However, these drugs have shown limited clinical efficacy as single agents in small-cell lung cancer (SCLC) and other solid tumor malignancies, and rational combination strategies remain underexplored. To develop a novel therapeutic approach, we examined the efficacy of ABT-263 across >500 cancer cell lines, including 311 for which we had matched expression data for select genes. We found that high expression of the proapoptotic gene Bcl2-interacting mediator of cell death (BIM) predicts sensitivity to ABT-263. In particular, SCLC cell lines possessed greater BIM transcript levels than most other solid tumors and are among the most sensitive to ABT-263. However, a subset of relatively resistant SCLC cell lines has concomitant high expression of the antiapoptotic myeloid cell leukemia 1 (MCL-1). Whereas ABT-263 released BIM from complexes with BCL-2 and BCL-XL, high expression of MCL-1 sequestered BIM released from BCL-2 and BCL-XL, thereby abrogating apoptosis. We found that SCLCs were sensitized to ABT-263 via TORC1/2 inhibition, which led to reduced MCL-1 protein levels, thereby facilitating BIM-mediated apoptosis. AZD8055 and ABT-263 together induced marked apoptosis in vitro, as well as tumor regressions in multiple SCLC xenograft models. In a Tp53; Rb1 deletion genetically engineered mouse model of SCLC, the combination of ABT-263 and AZD8055 significantly repressed tumor growth and induced tumor regressions compared with either drug alone. Furthermore, in a SCLC patient-derived xenograft model that was resistant to ABT-263 alone, the addition of AZD8055 induced potent tumor regression. Therefore, addition of a TORC1/2 inhibitor offers a therapeutic strategy to markedly improve ABT-263 activity in SCLC.

Kannan K, Coarfa C, Chao PW, et al.
Recurrent BCAM-AKT2 fusion gene leads to a constitutively activated AKT2 fusion kinase in high-grade serous ovarian carcinoma.
Proc Natl Acad Sci U S A. 2015; 112(11):E1272-7 [PubMed] Article available free on PMC after 17/09/2015 Related Publications
High-grade serous ovarian cancer (HGSC) is among the most lethal forms of cancer in women. Excessive genomic rearrangements, which are expected to create fusion oncogenes, are the hallmark of this cancer. Here we report a cancer-specific gene fusion between BCAM, a membrane adhesion molecule, and AKT2, a key kinase in the PI3K signaling pathway. This fusion is present in 7% of the 60 patient cancers tested, a significant frequency considering the highly heterogeneous nature of this malignancy. Further, we provide direct evidence that BCAM-AKT2 is translated into an in-frame fusion protein in the patient's tumor. The resulting AKT2 fusion kinase is membrane-associated, constitutively phosphorylated, and activated as a functional kinase in cells. Unlike endogenous AKT2, whose activity is tightly regulated by external stimuli, BCAM-AKT2 escapes the regulation from external stimuli. Moreover, a BCAM-AKT2 fusion gene generated via chromosomal translocation using the CRISPR/Cas9 system leads to focus formation in both OVCAR8 and HEK-293T cell lines, suggesting that BCAM-AKT2 is oncogenic. Together, the results indicate that BCAM-AKT2 expression is a new mechanism of AKT2 kinase activation in HGSC. BCAM-AKT2 is the only fusion gene in HGSC that is proven to translate an aberrant yet functional kinase fusion protein with oncogenic properties. This recurrent genomic alteration is a potential therapeutic target and marker of a clinically relevant subtype for tailored therapy of HGSC.

Qian J, Hassanein M, Hoeksema MD, et al.
The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers.
Proc Natl Acad Sci U S A. 2015; 112(11):3469-74 [PubMed] Article available free on PMC after 17/09/2015 Related Publications
Aberrant expression of RNA-binding proteins has profound implications for cellular physiology and the pathogenesis of human diseases such as cancer. We previously identified the Fragile X-Related 1 gene (FXR1) as one amplified candidate driver gene at 3q26-29 in lung squamous cell carcinoma (SCC). FXR1 is an autosomal paralog of Fragile X mental retardation 1 and has not been directly linked to human cancers. Here we demonstrate that FXR1 is a key regulator of tumor progression and its overexpression is critical for nonsmall cell lung cancer (NSCLC) cell growth in vitro and in vivo. We identified the mechanisms by which FXR1 executes its regulatory function by forming a novel complex with two other oncogenes, protein kinase C, iota and epithelial cell transforming 2, located in the same amplicon via distinct binding mechanisms. FXR1 expression is a candidate biomarker predictive of poor survival in multiple solid tumors including NSCLCs. Because FXR1 is overexpressed and associated with poor clinical outcomes in multiple cancers, these results have implications for other solid malignancies.

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