APC

Gene Summary

Gene:APC; adenomatous polyposis coli
Aliases: GS, DP2, DP3, BTPS2, DP2.5, PPP1R46
Location:5q21-q22
Summary:This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:adenomatous polyposis coli protein
HPRD
Source:NCBIAccessed: 27 February, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 28 February 2015 using data from PubMed using criteria.

Literature Analysis

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

Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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: APC (cancer-related)

Faller WJ, Jackson TJ, Knight JR, et al.
mTORC1-mediated translational elongation limits intestinal tumour initiation and growth.
Nature. 2015; 517(7535):497-500 [PubMed] Article available free on PMC after 22/07/2015 Related Publications
Inactivation of APC is a strongly predisposing event in the development of colorectal cancer, prompting the search for vulnerabilities specific to cells that have lost APC function. Signalling through the mTOR pathway is known to be required for epithelial cell proliferation and tumour growth, and the current paradigm suggests that a critical function of mTOR activity is to upregulate translational initiation through phosphorylation of 4EBP1 (refs 6, 7). This model predicts that the mTOR inhibitor rapamycin, which does not efficiently inhibit 4EBP1 (ref. 8), would be ineffective in limiting cancer progression in APC-deficient lesions. Here we show in mice that mTOR complex 1 (mTORC1) activity is absolutely required for the proliferation of Apc-deficient (but not wild-type) enterocytes, revealing an unexpected opportunity for therapeutic intervention. Although APC-deficient cells show the expected increases in protein synthesis, our study reveals that it is translation elongation, and not initiation, which is the rate-limiting component. Mechanistically, mTORC1-mediated inhibition of eEF2 kinase is required for the proliferation of APC-deficient cells. Importantly, treatment of established APC-deficient adenomas with rapamycin (which can target eEF2 through the mTORC1-S6K-eEF2K axis) causes tumour cells to undergo growth arrest and differentiation. Taken together, our data suggest that inhibition of translation elongation using existing, clinically approved drugs, such as the rapalogs, would provide clear therapeutic benefit for patients at high risk of developing colorectal cancer.

Guo H, Nagy T, Pierce M
Post-translational glycoprotein modifications regulate colon cancer stem cells and colon adenoma progression in Apc(min/+) mice through altered Wnt receptor signaling.
J Biol Chem. 2014; 289(45):31534-49 [PubMed] Article available free on PMC after 07/11/2015 Related Publications
Deletion of GnT-V (MGAT5), which synthesizes N-glycans with β(1,6)-branched glycans, reduced the compartment of cancer stem cells (CSC) in the her-2 mouse model of breast cancer, leading to delay of tumor onset. Because GnT-V levels are also commonly up-regulated in colon cancer, we investigated their regulation of colon CSC and adenoma development. Anchorage-independent cell growth and tumor formation induced by injection of colon tumor cells into NOD/SCID mice were positively associated with GnT-V levels, indicating regulation of proliferation and tumorigenicity. Using Apc(min/+) mice with different GnT-V backgrounds, knock-out of GnT-V had no significant effect on the number of adenoma/mouse, but adenoma size was significantly reduced and accompanied increased survival of Apc(min/+) mice with GnT-V deletion (p < 0.01), suggesting an inhibition in the progression of colon adenoma caused by deletion of GnT-V. Decreased expression levels of GnT-V down-regulated the population of colon (intestine) CSC, affecting their ability for self-renewal and tumorigenicity in NOD/SCID mice. Furthermore, altered nuclear translocation of β-catenin and expression of Wnt target genes were positively associated with expression levels of GnT-V, indicating the regulation of canonical Wnt/β-catenin signaling. By overexpressing the Wnt receptor, FZD-7, in colon cancer cells, we found that FZD-7 receptors expressed N-linked β(1,6) branching, indicating that FZD-7 can be modified by GnT-V. The aberrant Wnt signaling observed after modulating GnT-V levels is likely to result from altered N-linked β(1,6) branching on FZD-7, thereby affecting Wnt signaling, the compartment of CSC, and tumor progression.

Suman S, Moon BH, Thakor H, et al.
Wip1 abrogation decreases intestinal tumor frequency in APC(Min/+) mice irrespective of radiation quality.
Radiat Res. 2014; 182(3):345-9 [PubMed] Related Publications
Low-linear energy transfer (low-LET) γ-ray exposure is a risk factor for colorectal cancer (CRC). Due to their high-LET nature, energetic iron ions found in space are expected to pose greater CRC risks to astronauts undertaking long-duration space missions beyond low Earth orbit. Wild-type p53-induced phosphatase 1 (Wip1) is important for cellular DNA damage response and its abrogation has been shown to inhibit spontaneous intestinal tumorigenesis in APC(Min/+) mice, a well-studied mouse model of human CRC. However, the relationship of Wip1 to radiation-induced intestinal tumorigenesis, especially by energetic iron ions, has not been investigated in APC(Min/+) mice. We have previously reported that there is a greater intestinal tumorigenic potential of iron-ion radiation relative to (137)Cs γ rays, so the purpose of the current study was to investigate whether Wip1 abrogation could influence high-LET dependent intestinal tumorigenesis in APC(Min/+) mice. Intestinal tumor frequency and grade were assessed in APC(Min/+)/Wip1(-/-) mice and results were compared to those in APC(Min/+)/Wip1(+/+) mice after exposure to a mean absorbed dose of 2 Gy from (137)Cs γ rays or 1.6 Gy from 1 GeV/n iron ions. Cellular differentiation and proliferation were also assessed in the intestinal tumors of sham-irradiated and irradiated mice. Decreased tumor frequency and lower tumor grade were observed in APC(Min/+)/Wip1(-/-) relative to APC(Min/+)/Wip1(+/+) mice. Notably, a similar decrease (∼6-fold in both groups) in tumor number was observed in sham-irradiated and γ-irradiated APC(Min/+)/Wip1(-/-) relative to APC(Min/+)/Wip1(+/+) mice. However, tumorigenesis in the energetic iron-ion exposed group was reduced ∼8-fold in APC(Min/+)/Wip1(-/-) relative to APC(Min/+)/Wip1(+/+) mice. A significantly lower proliferation/differentiation index in tumors of iron-ion exposed APC(Min/+)/Wip1(-/-) relative to APC(Min/+)/Wip1(+/+) mice suggests that reduced proliferation and enhanced differentiation as a result of Wip1 abrogation maybe involved. In conclusion, the current study demonstrated that the absence of Wip1 blocked radiation-induced intestinal tumorigenesis irrespective of radiation quality and has implications for developing preventive strategies against the tumorigenic potential of radiation exposure on earth and in outer space.

Rebel H, der Spek CD, Salvatori D, et al.
UV exposure inhibits intestinal tumor growth and progression to malignancy in intestine-specific Apc mutant mice kept on low vitamin D diet.
Int J Cancer. 2015; 136(2):271-7 [PubMed] Related Publications
Mortality from colorectal cancer increases with latitude and decreases with ambient UV radiation. We investigated whether moderate UV dosages could inhibit intestinal tumor development and whether this corresponded with UV-induced vitamin D. FabplCre;Apc(15lox/+) mice, which develop intestinal tumors, and their parents were put on a vitamin D-deficient diet. Next to a control group, one group was vitamin D supplemented and another one group was daily UV irradiated from 6 weeks of age. Vitamin D statuses after 6 weeks of treatment were markedly increased: mean ± SD from 7.7 ± 1.9 in controls to 75 ± 15 nmol/l with vitamin D supplementation (no gender difference), and to 31 ± 13 nmol/l in males and 85 ± 17 nmol/l in females upon UV irradiation. The tumor load (area covered by tumors) at 7.5 months of age was significantly reduced in both the vitamin D-supplemented group (130 ± 25 mm(2), p = 0.018) and the UV-exposed group (88 ± 9 mm(2), p < 0.0005; no gender differences) compared to the control group (202 ± 23 mm(2)). No reductions in tumor numbers were found. Only UV exposure appeared to reduce progression to malignancy (p = 0.014). Our experiments clearly demonstrate for the first time an inhibitory effect of moderate UV exposure on outgrowth and malignant progression of primary intestinal tumors, which at least in part can be attributed to vitamin D.

Xue X, Ramakrishnan SK, Shah YM
Activation of HIF-1α does not increase intestinal tumorigenesis.
Am J Physiol Gastrointest Liver Physiol. 2014; 307(2):G187-95 [PubMed] Article available free on PMC after 15/07/2015 Related Publications
The hypoxic response is mediated by two transcription factors, hypoxia-inducible factor (HIF)-1α and HIF-2α. These highly homologous transcription factors are induced in hypoxic foci and regulate cell metabolism, angiogenesis, cell proliferation, and cell survival. HIF-1α and HIF-2α are activated early in cancer progression and are important in several aspects of tumor biology. HIF-1α and HIF-2α have overlapping and distinct functions. In the intestine, activation of HIF-2α increases inflammation and colon carcinogenesis in mouse models. Interestingly, in ischemic and inflammatory diseases of the intestine, activation of HIF-1α is beneficial and can reduce intestinal inflammation. HIF-1α is a critical transcription factor regulating epithelial barrier function following inflammation. The beneficial value of pharmacological agents that chronically activate HIF-1α is decreased due to the tumorigenic potential of HIFs. The present study tested the hypothesis that chronic activation of HIF-1α may enhance colon tumorigenesis. Two models of colon cancer were assessed, a sporadic and a colitis-associated colon cancer model. Activation of HIF-1α in intestinal epithelial cells does not increase carcinogenesis or progression of colon cancer. Together, the data provide proof of principle that pharmacological activation of HIF-1α could be a safe therapeutic strategy for inflammatory bowel disease.

Powell AE, Vlacich G, Zhao ZY, et al.
Inducible loss of one Apc allele in Lrig1-expressing progenitor cells results in multiple distal colonic tumors with features of familial adenomatous polyposis.
Am J Physiol Gastrointest Liver Physiol. 2014; 307(1):G16-23 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Individuals with familial adenomatous polyposis (FAP) harbor a germline mutation in adenomatous polyposis coli (APC). The major clinical manifestation is development of multiple colonic tumors at a young age due to stochastic loss of the remaining APC allele. Extracolonic features, including periampullary tumors, gastric abnormalities, and congenital hypertrophy of the retinal pigment epithelium, may occur. The objective of this study was to develop a mouse model that simulates these features of FAP. We combined our Lrig1-CreERT2/+ mice with Apcfl/+ mice, eliminated one copy of Apc in leucine-rich repeats and immunoglobulin-like domains protein 1 (Lrig1)-positive (Lrig1(+)) progenitor cells with tamoxifen injection, and monitored tumor formation in the colon by colonoscopy and PET. Initial loss of one Apc allele in Lrig1(+) cells results in a predictable pattern of preneoplastic changes, culminating in multiple distal colonic tumors within 50 days of induction, as well as the extracolonic manifestations of FAP mentioned above. We show that tumor formation can be monitored by noninvasive PET imaging. This inducible stem cell-driven model recapitulates features of FAP and offers a tractable platform on which therapeutic interventions can be monitored over time by colonoscopy and noninvasive imaging.

Hainova K, Adamcikova Z, Ciernikova S, et al.
Intestinal flora of FAP patients containing APC-like sequences.
Neoplasma. 2014; 61(3):283-90 [PubMed] Related Publications
Colorectal cancer mortality is one of the most common cause of cancer-related mortality. A multiple risk factors are associated with colorectal cancer, including hereditary, enviromental and inflammatory syndromes affecting the gastrointestinal tract. Familial adenomatous polyposis (FAP) is characterized by the emergence of hundreds to thousands of colorectal adenomatous polyps and FAP syndrome is caused by mutations within the adenomatous polyposis coli (APC) tumor suppressor gene. We analyzed 21 rectal bacterial subclones isolated from FAP patient 41-1 with confirmed 5bp ACAAA deletion within codons 1060-1063 for the presence of APC-like sequences in longest exon 15. The studied section was defined by primers 15Efor-15Erev, what correlates with mutation cluster region (MCR) in which the 75% of all APC germline mutations were detected. More than 90% homology was showed by sequencing and subsequent software comparison. The expression of APC-like sequences was demostrated by Western blot analysis using monoclonal and polyclonal antibodies against APC protein. To study missing link between the DNA analysis (PCR, DNA sequencing) and protein expresion experiments (Western blotting) we analyzed bacterial transcripts containing the 15Efor-15Erev sequence of APC gene by reverse transcription-PCR, what indicated that an APC gene derived fragment may be produced. We observed 97-100 % homology after computer comparison of cDNA PCR products. Our results suggest that presence of APC-like sequences in intestinal/rectal bacteria is enrichment of bacterial genetic information in which horizontal gene transfer between humans and microflora play an important role.

Lozyns'ka MR, Plavski A, Lozyns'kyĭ IuS
[Clinical and genetic features of APC- and MYH-mutation-negative patients with multiple polyposis of large bowel that tested by conventional methods].
Tsitol Genet. 2014 Jan-Feb; 48(1):18-24 [PubMed] Related Publications
The genealogic analysis, molecular and clinical investigations has been carried out in 19 probands with multiple colorectal adenomas (approximately 100 or more). Twelve of these patients (63.1%) were APC and MYH mutation-negative. Three (25%) probands have positive family history. The median of the disease manifestation age in APC-negative patients was intermediate between the median of the disease manifestation age in APC- and MYH-positive patients. Extraintestinal manifestations in the APC-negative probands are more rare than in APC-positive patients. A half of APC- and MYH-negative probands with multiple polyposis had colorectal cancer. APC- and MYH-negative patients formed a genetically heterogenous group.

Nam HJ, van Deursen JM
Cyclin B2 and p53 control proper timing of centrosome separation.
Nat Cell Biol. 2014; 16(6):538-49 [PubMed] Related Publications
Cyclins B1 and B2 are frequently elevated in human cancers and are associated with tumour aggressiveness and poor clinical outcome; however, whether and how B-type cyclins drive tumorigenesis is unknown. Here we show that cyclin B1 and B2 transgenic mice are highly prone to tumours, including tumour types where B-type cyclins serve as prognosticators. Cyclins B1 and B2 both induce aneuploidy when overexpressed but through distinct mechanisms, with cyclin B1 inhibiting separase activation, leading to anaphase bridges, and cyclin B2 triggering aurora-A-mediated Plk1 hyperactivation, resulting in accelerated centrosome separation and lagging chromosomes. Complementary experiments revealed that cyclin B2 and p53 act antagonistically to control aurora-A-mediated centrosome splitting and accurate chromosome segregation in normal cells. These data demonstrate a causative link between B-type cyclin overexpression and tumour pathophysiology, and uncover previously unknown functions of cyclin B2 and p53 in centrosome separation that may be perturbed in many human cancers.

Partin AW, Van Neste L, Klein EA, et al.
Clinical validation of an epigenetic assay to predict negative histopathological results in repeat prostate biopsies.
J Urol. 2014; 192(4):1081-7 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
PURPOSE: The DOCUMENT multicenter trial in the United States validated the performance of an epigenetic test as an independent predictor of prostate cancer risk to guide decision making for repeat biopsy. Confirming an increased negative predictive value could help avoid unnecessary repeat biopsies.
MATERIALS AND METHODS: We evaluated the archived, cancer negative prostate biopsy core tissue samples of 350 subjects from a total of 5 urological centers in the United States. All subjects underwent repeat biopsy within 24 months with a negative (controls) or positive (cases) histopathological result. Centralized blinded pathology evaluation of the 2 biopsy series was performed in all available subjects from each site. Biopsies were epigenetically profiled for GSTP1, APC and RASSF1 relative to the ACTB reference gene using quantitative methylation specific polymerase chain reaction. Predetermined analytical marker cutoffs were used to determine assay performance. Multivariate logistic regression was used to evaluate all risk factors.
RESULTS: The epigenetic assay resulted in a negative predictive value of 88% (95% CI 85-91). In multivariate models correcting for age, prostate specific antigen, digital rectal examination, first biopsy histopathological characteristics and race the test proved to be the most significant independent predictor of patient outcome (OR 2.69, 95% CI 1.60-4.51).
CONCLUSIONS: The DOCUMENT study validated that the epigenetic assay was a significant, independent predictor of prostate cancer detection in a repeat biopsy collected an average of 13 months after an initial negative result. Due to its 88% negative predictive value adding this epigenetic assay to other known risk factors may help decrease unnecessary repeat prostate biopsies.

Wang R, Wang Y, Gao Z, Qu X
The comparative study of acetyl-11-keto-beta-boswellic acid (AKBA) and aspirin in the prevention of intestinal adenomatous polyposis in APC(Min/+) mice.
Drug Discov Ther. 2014; 8(1):25-32 [PubMed] Related Publications
Acetyl-11-keto-beta-BA (AKBA), a component of the gum resin of Boswellia serrata, has been recognized as a promising agent for the prevention of intestinal tumorigenesis. Aspirin, a non-steroidal anti-inflammatory drug (NSAID), has also been considered to have the activity against intestinal tumorigenesis. However, the prevention of colonic cancer is insufficient and no definitive recommendation has been made for clinic use. Herein, we compared the efficacy of AKBA with that of aspirin in an adenomatous polyposis coli intestinal neoplasia consecutive weeks. Mice were sacrificed by anesthetizing. The whole intestine was removed from each mouse. The number, size and histopathology of intestinal adenomatous polyps were examined under microscopy. The adenomatous polyps were removed for further analysis by the assays of western blotting and immunohistochemical staining. AKBA significantly prevented the formation of intestinal adenomatous polyps without toxicity to mice. Statistical analysis indicated that AKBA's activity both in the prevention of small intestinal and colonic polyps was more potently than aspirin. Histopathologic examination revealed that AKBA's effect, that is the reduction of polyp size and degree of dysplasia, was more prominent in larger sized polyps, especially those originating in colon. These effects of AKBA were associated with its role in the induction of apoptosis in carcinomas. The assays of western blotting and immunohistochemistry staining indicated that the efficacy of AKBA might arise from its activity in the modulation of the Wnt/β-catenin pathway and NF-κB/COX-2 pathway in adenomatous polyps. Conclusion, AKBA by oral application prevented intestinal tumorigenesis more potential than aspirin.

Byun AJ, Hung KE, Fleet JC, et al.
Colon-specific tumorigenesis in mice driven by Cre-mediated inactivation of Apc and activation of mutant Kras.
Cancer Lett. 2014; 347(2):191-5 [PubMed] Related Publications
Several genetically engineered mouse (GEM) models of colorectal cancer have been developed and are a mainstay in our efforts to identify means of preventing and treating this disease. Many of these models involve a germline disruption of the adenomatous polyposis coli (Apc) tumor suppressor gene and share the limitation that the great preponderance of tumors appear in the small rather than large intestine. In recent years efforts have been made to increase the similarity of these models to human sporadic colorectal cancer by disrupting Apc in a tissue-specific fashion using the Cre-Lox system so that the genetic aberrations are confined to the colonic epithelium. These models have shown great promise but reproducible and high penetrance colon-specific tumorigenesis has not yet been achieved without invasive techniques to introduce the Cre enzyme. We therefore sought to create a new model with high penetrance colon-specific tumorigenesis but without the need for exogenous Cre administration. We utilized existing mice possessing a conditional knock out for the Apc gene and a latent activated Kras allele and crossed them with mice expressing Cre recombinase solely in the large intestine. Using this approach we generated mice that developed 1-9 colonic adenomas per mouse (average 4.3) but without any tumors in the small intestine or cecum. No invasive tumors were observed. Despite the apparent lack of invasion, the geographical correctness, complete penetrance and intermediate tumor burden make this model a promising addition to our toolkit for the study of colorectal cancer treatment and prevention.

Venincasa VD, Weng C, Berrocal AM
Pigmented ocular fundus lesions in a 6-year-old girl.
JAMA Ophthalmol. 2014; 132(3):351-2 [PubMed] Related Publications

Furlan D, Sahnane N, Bernasconi B, et al.
APC alterations are frequently involved in the pathogenesis of acinar cell carcinoma of the pancreas, mainly through gene loss and promoter hypermethylation.
Virchows Arch. 2014; 464(5):553-64 [PubMed] Related Publications
Genetic and epigenetic alterations involved in the pathogenesis of pancreatic acinar cell carcinomas (ACCs) are poorly characterized, including the frequency and role of gene-specific hypermethylation, chromosome aberrations, and copy number alterations (CNAs). A subset of ACCs is known to show alterations in the APC/β-catenin pathway which includes mutations of APC gene. However, it is not known whether, in addition to mutation, loss of APC gene function can occur through alternative genetic and epigenetic mechanisms such as gene loss or promoter methylation. We investigated the global methylation profile of 34 tumor suppressor genes, CNAs of 52 chromosomal regions, and APC gene alterations (mutation, methylation, and loss) together with APC mRNA level in 45 ACCs and related peritumoral pancreatic tissues using methylation-specific multiplex ligation probe amplification (MS-MLPA), fluorescence in situ hybridization (FISH), mutation analysis, and reverse transcription-droplet digital PCR. ACCs did not show an extensive global gene hypermethylation profile. RASSF1 and APC were the only two genes frequently methylated. APC mutations were found in only 7 % of cases, while APC loss and methylation were more frequently observed (48 and 56 % of ACCs, respectively). APC mRNA low levels were found in 58 % of cases and correlated with CNAs. In conclusion, ACCs do not show extensive global gene hypermethylation. APC alterations are frequently involved in the pathogenesis of ACCs mainly through gene loss and promoter hypermethylation, along with reduction of APC mRNA levels.

Keerthivasan S, Aghajani K, Dose M, et al.
β-Catenin promotes colitis and colon cancer through imprinting of proinflammatory properties in T cells.
Sci Transl Med. 2014; 6(225):225ra28 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
The density and type of lymphocytes that infiltrate colon tumors are predictive of the clinical outcome of colon cancer. High densities of T helper 17 (T(H)17) cells and inflammation predict poor outcome, whereas infiltration by T regulatory cells (Tregs) that naturally suppress inflammation is associated with longer patient survival. However, the role of Tregs in cancer remains controversial. We recently reported that Tregs in colon cancer patients can become proinflammatory and tumor-promoting. These properties were directly linked with their expression of RORγt (retinoic acid-related orphan receptor-γt), the signature transcription factor of T(H)17 cells. We report that Wnt/β-catenin signaling in T cells promotes expression of RORγt. Expression of β-catenin was elevated in T cells, including Tregs, of patients with colon cancer. Genetically engineered activation of β-catenin in mouse T cells resulted in enhanced chromatin accessibility in the proximity of T cell factor-1 (Tcf-1) binding sites genome-wide, induced expression of T(H)17 signature genes including RORγt, and promoted T(H)17-mediated inflammation. Strikingly, the mice had inflammation of small intestine and colon and developed lesions indistinguishable from colitis-induced cancer. Activation of β-catenin only in Tregs was sufficient to produce inflammation and initiate cancer. On the basis of these findings, we conclude that activation of Wnt/β-catenin signaling in effector T cells and/or Tregs is causatively linked with the imprinting of proinflammatory properties and the promotion of colon cancer.

Konsavage WM, Yochum GS
The myc 3' wnt-responsive element suppresses colonic tumorigenesis.
Mol Cell Biol. 2014; 34(9):1659-69 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Mutations in components of the Wnt/β-catenin signaling pathway are commonly found in colorectal cancers, and these mutations cause aberrant expression of genes controlled by Wnt-responsive DNA elements (WREs). While the c-Myc proto-oncogene (Myc) is required for intestinal phenotypes associated with pathogenic Wnt/β-catenin signaling in vivo, the WREs that control Myc expression in this setting have yet to be fully described. Previously, we demonstrated that the Myc 3' WRE was required for intestinal homeostasis and intestinal repair in response to damage. Here, we tested the role of the Myc 3' WRE in intestinal tumorigenesis using two independent mouse models. In comparison to Apc(Min/+) mice, Apc(Min/+) Myc 3' WRE(-/-) mice contained 25% fewer tumors in the small intestine. Deletion of the Myc 3' WRE(-/-) in the Apc(Min/+) background resulted in 4-fold more colonic tumors. In a model of colitis-associated colorectal cancer, the Myc 3' WRE suppressed colonic tumorigenesis, most notably within the cecum. Using chromatin immunoprecipitation and transcript analysis of purified colonic crypts, we found that the Myc 3' WRE is required for the transcriptional regulation of Myc expression in vivo. These results emphasize the critical role of the Myc 3' WRE in maintaining homeostatic Myc expression.

Sharma M, Johnson M, Brocardo M, et al.
Wnt signaling proteins associate with the nuclear pore complex: implications for cancer.
Adv Exp Med Biol. 2014; 773:353-72 [PubMed] Related Publications
Several components of the Wnt signaling pathway have in recent years been linked to the nuclear pore complex. β-catenin, the primary transducer of Wnt signals from the plasma membrane to the nucleus, has been shown to transiently associate with different FG-repeat containing nucleoporins (Nups) and to translocate bidirectionally through pores of the nuclear envelope in a manner independent of classical transport receptors and the Ran GTPase. Two key regulators of β-catenin, IQGAP1 and APC, have also been reported to bind specific Nups or to locate at the nuclear pore complex. The interaction between these Wnt signaling proteins and different Nups may have functional implications beyond nuclear transport in cellular processes that include mitotic regulation, centrosome positioning and cell migration, nuclear envelope assembly/disassembly, and the DNA replication checkpoint. The broad implications of interactions between Wnt signaling proteins and Nups will be discussed in the context of cancer.

Stolfi C, De Simone V, Colantoni A, et al.
A functional role for Smad7 in sustaining colon cancer cell growth and survival.
Cell Death Dis. 2014; 5:e1073 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Initially identified as an inhibitor of transforming growth factor (TGF)-β mainly owing to its ability to bind TGF-β receptor type I and abrogate TGF-β-driven signaling, Smad7 can interact with additional intracellular proteins and regulate TGF-β-independent pathways, thus having a key role in the control of neoplastic processes in various organs. Genome-wide association studies have shown that common alleles of Smad7 influence the risk of colorectal cancer (CRC), even though the contribution of Smad7 in colon carcinogenesis is not fully understood. In this study, we assessed the expression and role of Smad7 in human and mouse models of sporadic CRC. We document a significant increase of Smad7 in human CRC relative to the surrounding nontumor tissues and show that silencing of Smad7 inhibits the growth of CRC cell lines both in vitro and in vivo after transplantation into immunodeficient mice. Knockdown of Smad7 results in enhanced phosphorylation of the cyclin-dependent kinase (CDK)2, accumulation of CRC cells in S phase and enhanced cell death. Smad7-deficient CRC cells have lower levels of CDC25A, a phosphatase that dephosphorylates CDK2, and hyperphosphorylated eukaryotic initiation factor 2 (eIF2)α, a negative regulator of CDC25 protein translation. Consistently, knockdown of Smad7 associates with inactivation of eIF2α, lower CDC25A expression and diminished fraction of proliferating cells in human CRC explants, and reduces the number of intestinal tumors in Apc(min/+) mice. Altogether, these data support a role for Smad7 in sustaining colon tumorigenesis.

Li X, Stevens PD, Liu J, et al.
PHLPP is a negative regulator of RAF1, which reduces colorectal cancer cell motility and prevents tumor progression in mice.
Gastroenterology. 2014; 146(5):1301-12.e1-10 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
BACKGROUND & AIMS: Hyperactivation of the RAS-RAF signaling pathway in colorectal tumors is associated with metastasis and poor outcomes of patients. Little is known about how RAS-RAF signaling is turned off once activated. We investigated how the pH domain and leucine-rich repeat protein phosphatases (PHLPPs) control RAS-RAF signaling and colorectal cancer (CRC) development.
METHODS: We used co-immunoprecipitation assays to identify substrates of PHLPP1 and PHLPP2. We studied phosphorylation of RAF1 in CRC cells that express exogenous PHLPP1 or PHLPP2, or lentiviral-based small hairpin RNAs against their transcripts; we measured effects on cell motility, migration, and invasion in vitro. Tumor progression and survival were analyzed in Phlpp1(-/-) Apc(Min) and Apc(Min)/Phlpp1(-/-) mice. Microarray datasets of colorectal tumor and nontumor tissues were analyzed for PHLPP gene expression.
RESULTS: PHLPP1 and 2 were found to dephosphorylate RAF1 at S338, inhibiting its kinase activity in vitro and in CRC cells. In cells, knockdown of PHLPP1 or PHLPP2 increased the amplitude and duration of RAF-MEK-ERK signaling downstream of epidermal growth factor receptor and KRAS, whereas overexpression had the opposite effect. In addition, knockdown of PHLPP1 or PHLPP2 caused CRC cells to express markers of the epithelial-mesenchymal transition, and increased cell migration and invasion. Apc(Min)/Phlpp1(-/-) mice had decreased survival and developed larger intestinal and colon tumors compared to Apc(Min) mice. Whereas Apc(Min) mice developed mostly low-grade adenomas, 20% of the tumors that developed in Apc(Min)/Phlpp1(-/-) mice were invasive adenocarcinomas. Normal villi and adenomas of Apc(Min)/Phlpp1(-/-) mice had significantly fewer apoptotic cells than Apc(Min) mice. Human CRC patient microarray data revealed that the expression of PHLPP1 or PHLPP2 is positively correlated with CDH1.
CONCLUSIONS: PHLPP1 and PHLPP2 dephosphorylate RAF1 to reduce its signaling, increase the invasive and migratory activities of CRC cells, and activate the epithelial-mesenchymal transition. In Apc(Min) mice, loss of PHLPP1 promotes tumor progression.

Wang H, Pan SY, Pang ZR, et al.
[Quantitative detection of APC/RASSF1A promoter methylation in the plasma of patients with cervical diseases].
Zhonghua Fu Chan Ke Za Zhi. 2013; 48(12):929-34 [PubMed] Related Publications
OBJECTIVE: To quantitatively detect adenomatous polyposis coli(APC) and Ras association domain family 1A( RASSF1A) promoter methylation levels in the plasma of patients with cervical disease and to determine the diagnostic value of the indicators of cervical disease.
METHODS: Preoperative blood samples were collected from 25 cases of healthy women and 118 cases of cervical disease, and tissue samples were also collected from 31 cases of them. The APC/RASSF1A promoter methylation levels of plasma and tissue were determined by duplex real-time quantitative methylation specific PCR (qMSP).
RESULTS: Among 31 paired plasma and tissue samples, true negative rate of APC and RASSF1A genes were all 100%, and true positive rate of APC and RASSF1A genes were 3/5 and 7/9, respectively. In 143 cases of plasma samples, total positive rate of APC and (or) RASSF1A methylation was 3% (2/59) for control/low-grade lesions groups and 48% (40/84) for high-grade lesions/tumor groups (P < 0.01) . RASSF1A methylation rate was related to lymph node metastasis and International Federation of Gynecology and Obstetrics (FIGO) stage (P < 0.05).
CONCLUSION: The plasma APC/RASSF1A methylation detection may be with some application prospect in the diagnosis of cervical diseases.

Vitellaro M, Sala P, Signoroni S, et al.
Risk of desmoid tumours after open and laparoscopic colectomy in patients with familial adenomatous polyposis.
Br J Surg. 2014; 101(5):558-65 [PubMed] Related Publications
BACKGROUND: Desmoid tumour (DT) is a main cause of death after prophylactic colectomy in patients with familial adenomatous polyposis (FAP). The purpose of this study was to evaluate the impact of prophylactic laparoscopic colectomy on the risk of developing DT in patients with FAP.
METHODS: The database of a single institution was reviewed. Patients with classical FAP with defined genotype who underwent either open or laparoscopic colectomy between 1947 and 2011 were included in the study. The impact of various demographic and clinical features on the risk of developing DT was assessed.
RESULTS: A total of 672 patients underwent prophylactic colectomy: 602 by an open and 70 by a laparoscopic approach. With a median (range) follow-up of 132 (0-516) months in the open group and 60 (12-108) months in the laparoscopic group, 98 patients (16·3 per cent) developed DT after an open procedure compared with three (4 per cent) following laparoscopic surgery. The estimated cumulative risk of developing DT at 5 years after surgery was 13·0 per cent in the open group and 4 per cent in the laparoscopic group (P = 0·042). In multivariable analysis, female sex (hazard ratio (HR) 2·18, 95 per cent confidence interval 1·40 to 3·39), adenomatous polyposis coli mutation distal to codon 1400 (HR 3·85, 1·90 to 7·80), proctocolectomy (HR 1·67, 1·06 to 2·61), open colectomy (HR 6·84, 1·96 to 23·98) and year of surgery (HR 1·04, 1·01 to 1·07) were independent risk factors for the diagnosis of DT after prophylactic surgery.
CONCLUSION: Laparoscopic surgery decreased the risk of DT after prophylactic colectomy in patients with FAP.

Manna SK, Tanaka N, Krausz KW, et al.
Biomarkers of coordinate metabolic reprogramming in colorectal tumors in mice and humans.
Gastroenterology. 2014; 146(5):1313-24 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
BACKGROUND & AIMS: There are no robust noninvasive methods for colorectal cancer screening and diagnosis. Metabolomic and gene expression analyses of urine and tissue samples from mice and humans were used to identify markers of colorectal carcinogenesis.
METHODS: Mass spectrometry-based metabolomic analysis of urine and tissues from wild-type C57BL/6J and Apc(Min/+) mice, as well as from mice with azoxymethane-induced tumors, was employed in tandem with gene expression analysis. Metabolic profiling was also performed on colon tumor and adjacent nontumor tissues from 39 patients. The effects of β-catenin activity on metabolic profiles were assessed in mice with colon-specific disruption of Apc.
RESULTS: Thirteen markers were found in urine associated with development of colorectal tumors in Apc(Min/+) mice. Metabolites related to polyamine metabolism, nucleic acid metabolism, and methylation, identified tumor-bearing mice with 100% accuracy, and also accurately identified mice with polyps. Changes in gene expression in tumor samples from mice revealed that derangement of metabolites were a reflection of coordinate metabolic reprogramming in tumor tissue. Similar changes in urinary metabolites were observed in mice with azoxymethane-induced tumors and in mice with colon-specific activation of β-catenin. The metabolic alterations indicated by markers in urine, therefore, appear to occur during early stages of tumorigenesis, when cancer cells are proliferating. In tissues from patients, tumors had stage-dependent increases in 17 metabolites associated with the same metabolic pathways identified in mice. Ten metabolites that were increased in tumor tissues, compared with nontumor tissues (proline, threonine, glutamic acid, arginine, N1-acetylspermidine, xanthine, uracil, betaine, symmetric dimethylarginine, and asymmetric-dimethylarginine), were also increased in urine from tumor-bearing mice.
CONCLUSIONS: Gene expression and metabolomic profiles of urine and tissue samples from mice with colorectal tumors and of colorectal tumor samples from patients revealed pathways associated with derangement of specific metabolic pathways that are indicative of early-stage tumor development. These urine and tissue markers might be used in early detection of colorectal cancer.

Stoddart A, Fernald AA, Wang J, et al.
Haploinsufficiency of del(5q) genes, Egr1 and Apc, cooperate with Tp53 loss to induce acute myeloid leukemia in mice.
Blood. 2014; 123(7):1069-78 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
An interstitial deletion of chromosome 5, del(5q), is the most common structural abnormality in primary myelodysplastic syndromes (MDS) and therapy-related myeloid neoplasms (t-MNs) after cytotoxic therapy. Loss of TP53 activity, through mutation or deletion, is highly associated with t-MNs with a del(5q). We previously demonstrated that haploinsufficiency of Egr1 and Apc, 2 genes lost in the 5q deletion, are key players in the progression of MDS with a del(5q). Using genetically engineered mice, we now show that reduction or loss of Tp53 expression, in combination with Egr1 haploinsufficiency, increased the rate of development of hematologic neoplasms and influenced the disease spectrum, but did not lead to overt myeloid leukemia, suggesting that altered function of additional gene(s) on 5q are likely required for myeloid leukemia development. Next, we demonstrated that cell intrinsic loss of Tp53 in hematopoietic stem and progenitor cells haploinsufficient for both Egr1 and Apc led to the development of acute myeloid leukemia (AML) in 17% of mice. The long latency (234-299 days) and clonal chromosomal abnormalities in the AMLs suggest that additional genetic changes may be required for full transformation. Thus, loss of Tp53 activity in cooperation with Egr1 and Apc haploinsufficiency creates an environment that is permissive for malignant transformation and the development of AML.

Davies EJ, Marsh Durban V, Meniel V, et al.
PTEN loss and KRAS activation leads to the formation of serrated adenomas and metastatic carcinoma in the mouse intestine.
J Pathol. 2014; 233(1):27-38 [PubMed] Related Publications
Mutation or loss of the genes PTEN and KRAS have been implicated in human colorectal cancer (CRC), and have been shown to co-occur despite both playing a role in the PI3' kinase (PI3'K) pathway. We investigated the role of these genes in intestinal tumour progression in vivo, using genetically engineered mouse models, with the aim of generating more representative models of human CRC. Intestinal-specific deletion of Pten and activation of an oncogenic allele of Kras was induced in wild-type (WT) mice and mice with a predisposition to adenoma development (Apc(fl/+) ). The animals were euthanized when they became symptomatic of a high tumour burden. Histopathological examination of the tissues was carried out, and immunohistochemistry used to characterize signalling pathway activation. Mutation of Pten and Kras resulted in a significant life-span reduction of mice predisposed to adenomas. Invasive adenocarcinoma was observed in these animals, with evidence of activation of the PI3'K pathway but no metastasis. However, mutation of Pten and Kras in WT animals not predisposed to adenomas led to perturbed homeostasis of the intestinal epithelium and the development of hyperplastic polyps, dysplastic sessile serrated adenomas and metastasizing adenocarcinomas with serrated features. These studies demonstrate synergism between Pten and Kras mutations in intestinal tumour progression, in an autochthonous and immunocompetent murine model, with potential application to preclinical drug testing. In particular, they show that Pten and Kras mutations alone predispose mice to the spectrum of serrated lesions that reflect the serrated pathway of CRC progression in humans.

Hasty P, Livi CB, Dodds SG, et al.
eRapa restores a normal life span in a FAP mouse model.
Cancer Prev Res (Phila). 2014; 7(1):169-78 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
Mutation of a single copy of the adenomatous polyposis coli (APC) gene results in familial adenomatous polyposis (FAP), which confers an extremely high risk for colon cancer. Apc(Min/+) mice exhibit multiple intestinal neoplasia (MIN) that causes anemia and death from bleeding by 6 months. Mechanistic target of rapamycin complex 1 (mTORC1) inhibitors were shown to improve Apc(Min/+) mouse survival when administered by oral gavage or added directly to the chow, but these mice still died from neoplasia well short of a natural life span. The National Institute of Aging Intervention Testing Program showed that enterically targeted rapamycin (eRapa) extended life span for wild-type genetically heterogeneous mice in part by inhibiting age-associated cancer. We hypothesized that eRapa would be effective in preventing neoplasia and extend survival of Apc(Min/+) mice. We show that eRapa improved survival of Apc(Min/+) mice in a dose-dependent manner. Remarkably, and in contrast to previous reports, most of the Apc(Min/+) mice fed 42 parts per million eRapa lived beyond the median life span reported for wild-type syngeneic mice. Furthermore, chronic eRapa did not cause detrimental immune effects in mouse models of cancer, infection, or autoimmunity, thus assuaging concerns that chronic rapamycin treatment suppresses immunity. Our studies suggest that a novel formulation (enteric targeting) of a well-known and widely used drug (rapamycin) can dramatically improve its efficacy in targeted settings. eRapa or other mTORC1 inhibitors could serve as effective cancer preventatives for people with FAP without suppressing the immune system, thus reducing the dependency on surgery as standard therapy.

Cao H, Song S, Zhang H, et al.
Chemopreventive effects of berberine on intestinal tumor development in Apcmin/+ mice.
BMC Gastroenterol. 2013; 13:163 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
BACKGROUND: Berberine, an isoquinoline alkaloid, has shown inhibitory effects on growth of several tumor cell lines in vitro. The aim of this study was to investigate chemopreventive effects of berberine on intestinal tumor development in Apcmin/+ mice.
METHODS: Four-week old Apcmin/+ mice were treated with 0.05% or 0.1% berberine in drinking water for twelve weeks. The number and the size of tumors were measured to evaluate intestinal tumor development. Tissue sections were prepared for PCNA and Ki-67 immunostaining to detect cell proliferation, and TUNEL assay and cleaved caspase-3 immunostaining for apoptosis. Western blot analysis and immunostaining were performed to detect the activation of Wnt and epidermal growth factor receptor (EGFR) signaling pathways and COX-2 expression in the intestinal tumor cells. The prostaglandin E2 level in the small intestine was detected using ELISA.
RESULTS: Compared with untreated Apcmin/+ mice, the total numbers of tumors in the small intestine and the colon were reduced by 39.6% and 62.5% in 0.05% and 0.1% berberine-treated mice, respectively. The numbers of tumors in proximal, middle, and distal segments of the small intestine in 0.1% berberine-treated mice were significantly reduced by 53.7%, 55.3%, and 76.5% respectively. Berberine treatment also decreased the numbers of all sizes of tumors (>2 mm, 1-2 mm, and <1 mm) in the small intestine. Berberine suppressed tumor cell proliferation and increased apoptosis. Furthermore, berberine decreased the activation levels of Wnt and EGFR signaling pathways, and down-regulated COX-2 expression in intestinal tumor cells and prostaglandin E2 production in the small intestine.
CONCLUSIONS: Berberine inhibits intestinal tumor development, which is correlated with its activity to suppress tumor cell proliferation and increase apoptosis in Apcmin/+ mice. Down-regulation of Wnt and EGFR signaling pathways and COX-2 expression by berberine may be involved in its anti-tumorigenic effects.

Lesko AC, Goss KH, Prosperi JR
Exploiting APC function as a novel cancer therapy.
Curr Drug Targets. 2014; 15(1):90-102 [PubMed] Related Publications
The Adenomatous Polyposis Coli (APC) tumor suppressor is most commonly mutated in colorectal cancers such as familial adenomatous polyposis (FAP); as well as many other epithelial cancers like breast, pancreatic, and lung cancer. APC mutations usually result in a truncated form of the protein lacking the carboxy-terminal region resulting in loss of function. Mutations in APC have been identified in early stages of cancer development making it a gatekeeper of tumor progression and therefore an ideal therapeutic target. APC is best known for its role as a negative regulator of the Wnt/β -catenin pathway. However, APC also mediates several other normal cell functions independently of Wnt/β-catenin signaling such as apical-basal polarity, microtubule networks, cell cycle, DNA replication and repair, apoptosis, and cell migration. Given the vast cellular processes involving APC, the loss of these "normal" functions due to mutation can contribute to chemotherapeutic resistance. Several therapeutic treatments have been explored to restore APC function including the reintroduction of APC into mutant cells, inhibiting pathways activated by the loss of APC, and targeting APCmutant cells for apoptosis. This review will discuss the normal functions of APC as they relate to potential treatments for patients, the role of APC loss in several types of epithelial cancers, and an overview of therapeutic options targeting both the Wnt-dependent and -independent functions of APC.

Aihara H, Kumar N, Thompson CC
Diagnosis, surveillance, and treatment strategies for familial adenomatous polyposis: rationale and update.
Eur J Gastroenterol Hepatol. 2014; 26(3):255-62 [PubMed] Related Publications
Familial adenomatous polyposis is characterized by the development of multiple (>100) colorectal adenomas throughout the colorectum. This disorder can be caused by a germline mutation in the adenomatous polyposis coli gene and can be diagnosed either clinically or genetically. After diagnosis with the condition, patients should undergo prophylactic proctocolectomy with a neoreservoir, usually an ileoanal pouch, at an appropriate time. Individuals with a family history of this disease who have not been diagnosed should be advised to attend genetic counseling and to enroll in appropriate clinical and genetic surveillance programs. Recent progress in endoscopic technology, including high-resolution endoscopy, capsule endoscopy, and double-balloon endoscopy, has made possible more detailed and wide-ranging investigation of the gastrointestinal tract. Although there has been limited evidence, further studies on these new endoscopic technologies might alter the surveillance strategies for familial adenomatous polyposis.

Bottarelli L, Azzoni C, Pizzi S, et al.
Adenomatous polyposis coli gene involvement in ileal enterochromaffin cell neuroendocrine neoplasms.
Hum Pathol. 2013; 44(12):2736-42 [PubMed] Related Publications
The adenomatous polyposis coli gene is a key tumor suppressor gene. Alterations in this gene have been found in most sporadic colon cancers; associated with familial adenomatous polyposis; and found in neoplasms of other organs, such as the liver, stomach, lung, breast, and cerebellar medulloblastoma. In the heterogeneous group of neuroendocrine neoplasms of the gastrointestinal tract, the involvement of adenomatous polyposis coli is debated, and only occasional reports found adenomatous polyposis coli alterations in foregut and midgut neuroendocrine neoplasms, with adenomatous polyposis coli mutations only in the latter. To elucidate the penetrance of adenomatous polyposis coli alterations in ileal neuroendocrine neoplasms, we performed DNA fragment analysis (loss of heterozygosity for 5q22-23 and 5q23) and sequencing on the mutation cluster region of the adenomatous polyposis coli gene on 30 ileal enterochromaffin cell neuroendocrine neoplasms. Adenomatous polyposis coli gene mutations were detected in 23% of cases (7/30); in particular, 57% were missense and 14%, nonsense/frameshift, all novel and different from those reported in colorectal or other cancers. Loss of heterozygosity analysis demonstrated a deletion frequency of 15% (4/27). No association was found with features of tumor progression. Our observations support the involvement of somatic adenomatous polyposis coli alterations in tumorigenesis of ileal enterochromaffin cell neuroendocrine neoplasms; the mechanisms of adenomatous polyposis coli gene inactivation appear to be different from those reported in other tumor types.

Valvezan AJ, Huang J, Lengner CJ, et al.
Oncogenic mutations in adenomatous polyposis coli (Apc) activate mechanistic target of rapamycin complex 1 (mTORC1) in mice and zebrafish.
Dis Model Mech. 2014; 7(1):63-71 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
Truncating mutations in adenomatous polyposis coli (APC) are strongly linked to colorectal cancers. APC is a negative regulator of the Wnt pathway and constitutive Wnt activation mediated by enhanced Wnt-β-catenin target gene activation is believed to be the predominant mechanism responsible for APC mutant phenotypes. However, recent evidence suggests that additional downstream effectors contribute to APC mutant phenotypes. We previously identified a mechanism in cultured human cells by which APC, acting through glycogen synthase kinase-3 (GSK-3), suppresses mTORC1, a nutrient sensor that regulates cell growth and proliferation. We hypothesized that truncating Apc mutations should activate mTORC1 in vivo and that mTORC1 plays an important role in Apc mutant phenotypes. We find that mTORC1 is strongly activated in apc mutant zebrafish and in intestinal polyps in Apc mutant mice. Furthermore, mTORC1 activation is essential downstream of APC as mTORC1 inhibition partially rescues Apc mutant phenotypes including early lethality, reduced circulation and liver hyperplasia. Importantly, combining mTORC1 and Wnt inhibition rescues defects in morphogenesis of the anterior-posterior axis that are not rescued by inhibition of either pathway alone. These data establish mTORC1 as a crucial, β-catenin independent effector of oncogenic Apc mutations and highlight the importance of mTORC1 regulation by APC during embryonic development. Our findings also suggest a new model of colorectal cancer pathogenesis in which mTORC1 is activated in parallel with Wnt/β-catenin signaling.

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