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ABSTRACT: Metformin, a substrate of several poly-specific organic cation transporters, is a widely used biguanide for the treatment of type II diabetes. Recent studies suggest that metformin attenuates mTORC1 signalling by the activation of 5' adenosine monophosphate-activated protein kinase (AMPK) in the presence or absence of a functional hamartin/tuberin (TSC1/TSC2) complex. Metformin has also been reported to inhibit mTORC1 independent of AMPK through p53-dependent regulated in development and DNA damage responses 1 (REDD1) or by inhibiting Rag GTPases. These observations suggest that metformin could have therapeutic potential for tuberous sclerosis, an inherited disorder characterised by the aberrant activation of mTORC1 and the development of tumours in many organs, including the kidneys. In this study, we investigated the effect of metformin on renal lesions in a Tsc1(+/-) mouse model of tuberous sclerosis. Continuous treatment of metformin for 9months at doses of up to 600mg/kg/day had no significant effect on renal lesions in nine treated mice compared to 10 controls. Metformin treatment appeared to attenuate mTORC1 signalling in Tsc1(+/-) kidney tissues but not in renal tumours. Surprisingly, the expression of the organic cation transporters Slc22a1, Slc22a2 and Slc22a3 essential for the cellular uptake of metformin was highly suppressed in renal tumours. Treatment of cultured cells derived from a Tsc1-associated renal tumour with 5-aza-2-deoxycytidine or trichostatin A greatly increased the expression of these genes. These data suggest that the epigenetic suppression of the organic cation transporters in Tsc-associated mouse renal tumours may contribute to the lack of response to metformin treatment.
European journal of cancer (Oxford, England: 1990) 12/2012; · 4.12 Impact Factor
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ABSTRACT: Transgenic mouse models of tuberous sclerosis (TSC) develop renal cysts, cystadenomas, solid adenomas and carcinomas. Identification and characterisation of these lesions in vivo may help in TSC pre-clinical trials. This study was to evaluate T2 weighted MRI for assessment of renal lesions in two Tsc mouse models.
Tsc1(+/-), Tsc2(+/-) and wild type mice were subjected to a first MRI scan at 12 months of age and a second scan 2 months later. One Tsc2(+/-) mouse was treated with rapamycin for two months after the initial scan. Immediately following the second scan, mice were sacrificed and MRI images were compared to renal histological findings.
MRI identified all types of Tsc-associated renal lesions in both Tsc1(+/-) and Tsc2(+/-) mice. The smallest detectable lesions were <0.1 mm(3). Eighty three percent of all renal lesions detected in the first scan were re-identified in the second scan. By MRI, these lesions demonstrated significant growth in the 9 untreated Tsc1(+/-) and Tsc2(+/-) mice but shrinkage in the rapamycin treated Tsc2(+/-) mouse. Between the two scans, MRI also revealed significant increase in both the total number and volume of lesions in untreated mice and decrease in the rapamycin treated mouse, respectively. In comparison to histological analysis MRI detected most cysts and cystadenomas (66%) but only a minority of solid tumours (29%).
These results suggest that T2 weighted MRI may be a useful tool for assessing some renal lesions in pre-clinical studies using Tsc mouse models. However, improved sensitivity for T2 weighted MRI is required, particularly for solid renal lesions.
European journal of radiology 07/2011; 81(9):2069-74. · 2.65 Impact Factor
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D Mark Davies,
Petrus J de Vries,
Simon R Johnson,
Deborah L McCartney,
Jane A Cox,
Andreas L Serra,
Peter C Watson,
Christopher J Howe,
Tim Doyle,
Kate Pointon,
Justin J Cross,
Anne E Tattersfield,
J Chris Kingswood, Julian R Sampson
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ABSTRACT: Renal angiomyolipomas are a frequent manifestation of tuberous sclerosis and sporadic lymphangioleiomyomatosis (LAM). These disorders are associated with mutations of TSC1 or TSC2 that lead to overactivation of mTOR complex 1 (mTORC1), suggesting an opportunity for targeted therapy by using mTORC1 inhibitors. This study investigated the efficacy and safety of the mTORC1 inhibitor sirolimus for treatment of renal angiomyolipomas in patients with these disorders.
In this multicenter phase 2 nonrandomized open label trial, 16 patients with tuberous sclerosis or sporadic LAM and renal angiomyolipoma(s) were treated with oral sirolimus for up to 2 years. Steady-state blood levels were 3 to 10 ng/mL. The primary outcome was change in size of renal angiomyolipomas measured by MRI and assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Secondary outcomes included safety, neurocognitive function, and pulmonary function.
The response rate, by RECIST criteria, was 50%. Summated angiomyolipoma diameters were reduced in all 16 patients and by 30% or more in eight (all from the per protocol group of 10). Forty-one of 48 angiomyolipomas were smaller at the last measurement than at baseline. Most shrinkage occurred during the first year of treatment. There was little change in pulmonary function. Recall memory improved in seven of eight patients with tuberous sclerosis. Adverse events were consistent with the known toxicities of sirolimus.
This study showed sustained regression of renal angiomyolipomas in patients with tuberous sclerosis or sporadic LAM receiving 2 years of sirolimus treatment. Possible effects on pulmonary function and neurocognition require further investigation.
Clinical Cancer Research 06/2011; 17(12):4071-81. · 7.74 Impact Factor
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Elaine A Dunlop,
Kayleigh M Dodd,
Stephen C Land,
Peter A Davies,
Nicole Martins,
Helen Stuart,
Shane McKee,
Chris Kingswood,
Anand Saggar,
Isabel Corderio,
Ana Maria Duarte Medeira,
Helen Kingston, Julian R Sampson,
David Mark Davies,
Andrew R Tee
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ABSTRACT: Tuberous sclerosis complex (TSC) is a genetic condition characterized by the growth of benign tumours in multiple organs, including the brain and kidneys, alongside intellectual disability and seizures. Identification of a causative mutation in TSC1 or TSC2 is important for accurate genetic counselling in affected families, but it is not always clear from genetic data whether a sequence variant is pathogenic or not. In vitro functional analysis could provide support for determining whether an unclassified TSC1 or TSC2 variant is disease-causing. We have performed a detailed functional analysis of four patient-derived TSC2 mutations, E92V, R505Q, H597R and L1624P. One mutant, E92V, functioned similarly to wild-type TSC2, whereas H597R and L1624P had abnormal function in all assays, consistent with available clinical and segregation information. One TSC2 mutation, R505Q, was identified in a patient with intellectual disability, seizures and autistic spectrum disorder but who did not fulfil the diagnostic criteria for TSC. The R505Q mutation was also found in two relatives, one with mild learning difficulties and one without apparent phenotypic abnormality. R505Q TSC2 exhibited partially disrupted function in our assays. These data highlight the difficulties of assessing pathogenicity of a mutation and suggest that multiple lines of evidence, both genetic and functional, are required to assess the pathogenicity of some mutations.
European journal of human genetics: EJHG 03/2011; 19(7):789-95. · 3.56 Impact Factor
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Maartje Nielsen,
Liza N van Steenbergen,
Natalie Jones,
Stefanie Vogt,
Hans F A Vasen,
Hans Morreau,
Stefan Aretz, Julian R Sampson,
Olaf M Dekkers,
Maryska L G Janssen-Heijnen,
Frederik J Hes
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ABSTRACT: MUTYH-associated polyposis is a recessively inherited disorder characterized by a lifetime risk of colorectal cancer that is up to 100%. Because specific histological and molecular genetic features of MUTYH-associated polyposis colorectal cancers might influence tumor behavior and patient survival, we compared survival between patients with MUTYH-associated polyposis colorectal cancer and matched control patients with colorectal cancer from the general population.
In this retrospective multicenter cohort study from Europe, 147 patients with MUTYH-associated polyposis colorectal cancer were compared with 272 population-based control patients with colorectal cancer who were matched for country, age at diagnosis, year of diagnosis, stage, and subsite of colorectal cancer. Kaplan-Meier survival and Cox regression analyses were used to compare survival between patients with MUTYH-associated polyposis colorectal cancer and control patients with colorectal cancer. All statistical tests were two-sided.
Five-year survival for patients with MUTYH-associated polyposis colorectal cancer was 78% (95% confidence interval [CI] = 70% to 84%) and for control patients was 63% (95% CI = 56% to 69%) (log-rank test, P = .002). After adjustment for differences in age, stage, sex, subsite, country, and year of diagnosis, survival remained better for MUTYH-associated polyposis colorectal cancer patients than for control patients (hazard ratio of death = 0.48, 95% CI = 0.32 to 0.72).
In a European study cohort, we found statistically significantly better survival for patients with MUTYH-associated polyposis colorectal cancer than for matched control patients with colorectal cancer.
CancerSpectrum Knowledge Environment 11/2010; 102(22):1724-30. · 14.07 Impact Factor
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Astrid A Out,
Carli M J Tops,
Maartje Nielsen,
Marjan M Weiss,
Ivonne J H M van Minderhout,
Ivo F A C Fokkema,
Marie-Pierre Buisine,
Kathleen Claes,
Chrystelle Colas,
Riccardo Fodde, [......],
Rodney J Scott,
Bruno Vankeirsbilck,
Rikke Veggerby Grønlund,
Juul T Wijnen,
Friedrik P Wikman,
Stefan Aretz, Julian R Sampson,
Peter Devilee,
Johan T den Dunnen,
Frederik J Hes
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ABSTRACT: The MUTYH gene encodes a DNA glycosylase involved in base excision repair (BER). Biallelic pathogenic MUTYH variants have been associated with colorectal polyposis and cancer. The pathogenicity of a few variants is beyond doubt, including c.536A4G/p.Tyr179Cys and c.1187G4A/p.Gly396Asp (previously c.494A4G/p.Tyr165Cys and c.1145G4A/p.Gly382Asp).However, for a substantial fraction of the detected variants, the clinical significance remains uncertain,compromising molecular diagnostics and thereby genetic counseling. We have established an interactive MUTYH gene sequence variant database (www.lovd.nl/MUTYH) with the aim of collecting and sharing MUTYH genotype and phenotype data worldwide. To support standard variant description, we chose NM_001128425.1 as the reference sequence. The database includes records with variants per individual, linked to available phenotype and geographic origin data as well as records with in vitro functional and in silico test data. As of April 2010, the database contains 1968 published and 423 unpublished submitted entries, and 230 and 61 unique variants,respectively. This open-access repository allows all involved to quickly share all variants encountered and communicate potential consequences, which will be especially useful to classify variants of uncertain significance.
Human Mutation 11/2010; 31(11):1205-15. · 5.69 Impact Factor
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Stefanie Vogt,
Natalie Jones,
Daria Christian,
Christoph Engel,
Maartje Nielsen,
Astrid Kaufmann,
Verena Steinke,
Hans F Vasen,
Peter Propping, Julian R Sampson,
Frederik J Hes,
Stefan Aretz
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ABSTRACT: MUTYH-associated polyposis (MAP) is characterized by a lifetime risk of colorectal cancer of up to 100%. However, no systematic evaluation of extracolonic manifestations has been reported.
A large cohort of MAP patients was recruited from a European multicenter study. Data were collected on 276 cases from 181 unrelated families. Information on extracolonic tumor spectrum and incidence were evaluated to determine cumulative lifetime risk, which was compared with that of the general population to obtain standardized incidence ratios (SIRs).
Duodenal polyposis occurred in 17% of cases; the relative risk (SIR) of duodenal cancer was 129 (95% confidence interval [CI]: 16-466), whereas the lifetime risk was 4%. The incidence of extraintestinal malignancies among cases was almost twice that of the general population (SIR: 1.9; 95% CI: 1.4-2.5), with a lifetime risk of 38%. We observed a significant increase in the incidence of ovarian, bladder, and skin cancers (SIR: 5.7, 7.2, and 2.8, respectively) and a trend of increased risk of breast cancer among cases. The median ages of onset of these 4 malignancies ranged from 51 to 61 years. In contrast to familial adenomatous polyposis, no desmoid tumors were observed, but sebaceous gland tumors, characteristic of the Muir-Torre variant of Lynch syndrome, occurred in 5 patients.
The relative risks for several extraintestinal malignancies increased in patients with MAP, but based on the spectrum of cancers (which overlaps with that of Lynch syndrome) and the relatively advanced age at onset, intensive surveillance measures other than frequent endoscopy are unlikely to be helpful to patients with MAP.
Gastroenterology 10/2009; 137(6):1976-85.e1-10. · 11.68 Impact Factor
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ABSTRACT: Mutations affecting over 2000 of the 20 000 or so genes in the human genome have been linked so far to specific inherited diseases, most of which are rare and have been poorly understood. Many of the genes involved encode components of intracellular signalling pathways that regulate processes such as the growth, proliferation, differentiation and survival or programmed death of cells during development and the maintenance of tissues and organs. Mutations that change the function of genes encoding signalling proteins thereby cause disorders ranging from birth defects to cancer. For Mendelian disorders, the essentially causal relationship between mutation and disease may present direct opportunities to therapeutically manipulate intracellular signalling. Here, we review recent examples of the use of small-molecule drugs to target components of signalling networks in single-gene disorders. We also consider the limitations of these "molecularly targeted" approaches and the difficulties in their clinical development as therapies for rare genetic diseases.
Journal of Medical Genetics 09/2009; 47(3):145-9. · 6.36 Impact Factor
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Anthony R Dallosso,
Siân Jones,
Duncan Azzopardi,
Valentina Moskvina,
Nada Al-Tassan,
Geraint T Williams,
Shelley Idziaszczyk,
D Rhodri Davies,
Peter Milewski,
Sally Williams,
John Beynon, Julian R Sampson,
Jeremy P Cheadle
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ABSTRACT: Multiple rare nonsynonymous variants in APC predispose to colorectal adenomas. The mechanisms through which such variants act have been unclear, but it has been proposed that a specific ("just-right") level of beta-catenin signaling is required for colorectal tumorigenesis. This appears to be mediated by selection for APC genotypes that retain one, or rarely two, 20 amino acid beta-catenin downregulating repeats (20AARs). We investigated the mechanism through which the variant p.Glu1317Gln (c.3949G>C) contributes to colorectal tumorigenesis. We compared the patterns of somatic APC mutations in tumors from patients with attenuated familial adenomatous polyposis (AFAP) who did, or did not, coinherit p.Glu1317Gln with their AFAP-causing APC mutations. Only 8.2% (4/49) of tumors carrying p.Glu1317Gln had somatic mutations predicted to result in mutant polypeptides retaining a single 20AAR, compared to 62.1% (36/58) of those which did not carry this variant (P=5.64 x 10(-9)). Furthermore, tumors with p.Glu1317Gln often carried somatic mutations that were unusually early or late (downstream of the second 20AAR) in the APC open reading frame. These data support a novel mechanism in which p.Glu1317Gln in combination with other weak mutant APC alleles (generating polypepetides with zero, two, or three 20AARs) can provide the necessary growth advantage for colorectal tumorigenesis.
Human Mutation 07/2009; 30(10):1412-8. · 5.69 Impact Factor
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Natalie Jones,
Stefanie Vogt,
Maartje Nielsen,
Daria Christian,
Petra A Wark,
Diana Eccles,
Emma Edwards,
D Gareth Evans,
Eamonn R Maher,
Hans F Vasen,
Frederik J Hes,
Stefan Aretz, Julian R Sampson
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ABSTRACT: MUTYH-associated polyposis (MAP) is an autosomal recessive disorder caused by mutations in the MUTYH gene. Patients with MAP are at extremely high risk of colorectal cancer, but the risks of colorectal and other cancers in heterozygous carriers of a single MUTYH mutation are uncertain. We performed a retrospective study of cancer incidence and causes of death among obligate MUTYH heterozygote individuals.
MAP index cases were identified from polyposis registers in Germany, The Netherlands, and the United Kingdom. Cancer incidence, cancer mortality, and all-cause mortality data were collected from 347 parents of unrelated MAP index cases and the spouses of 3 index cases who were also found to be heterozygous for single MUTYH mutations. These data were compared with appropriate national sex-, age-, and period-specific population data to obtain standardized mortality ratios (SMR) and standardized incidence ratios (SIR).
There was a 2-fold increase in the incidence of colorectal cancer among parents of MAP cases, compared with the general population (SIR, 2.12; 95% confidence interval [CI]: 1.30-3.28). Their colorectal cancer mortality was not increased significantly (SMR, 1.02; 95% CI: 0.41-2.10) nor was overall cancer risk (SIR, 0.92; 95% CI: 0.70-1.18), cancer mortality (SMR, 1.12; 95% CI: 0.83-1.48), or overall mortality (SMR, 0.94; 95% CI: 0.80-1.08).
The risk of colorectal cancer in heterozygous carriers of single MUTYH mutations who are relatives of patients with MAP is comparable with that of first-degree relatives of patients with sporadic colorectal cancer. Screening measures should be based on this modest increase in risk.
Gastroenterology 04/2009; 137(2):489-94, 494.e1; quiz 725-6. · 11.68 Impact Factor
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Julian R Sampson
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ABSTRACT: Failure in the regulation of mTOR (mammalian target of rapamycin) appears to be critical to the pathogenesis of the inherited disorder tuberous sclerosis and the related lung disease LAM (lymphangioleiomyomatosis). Both diseases are caused by mutations of TSC1 or TSC2 (TSC is tuberous sclerosis complex) that impair GAP (GTPase-activating protein) activity of the TSC1-TSC2 complex for Rheb, leading to inappropriate activity of signalling downstream of mTORC1 (mTOR complex 1). mTOR inhibitors are already used in a variety of clinical settings including as immunosuppressants, anticancer agents and antiproliferative agents in drug-eluting coronary artery stents. They also represent candidate therapies directed to the underlying molecular pathology in tuberous sclerosis and LAM. Phase I/II clinical trials of the mTORC1 inhibitor rapamycin have demonstrated reduction in size of tuberous-sclerosis- and LAM-associated renal tumours (angiomyolipomas) and some evidence for reversible improvement in lung function in patients with LAM. A case series of tuberous-sclerosis-associated brain tumours were also reported to shrink during rapamycin therapy. An important, although variable, feature of the tuberous sclerosis phenotype is learning difficulty. Recent studies in mouse models carrying heterozygous Tsc2 mutations demonstrated improvement in memory and learning deficits following treatment with rapamycin. These promising pre-clinical and early human trials are being followed by larger-scale randomized control trials of mTOR inhibitors for treatment of renal, lung and brain manifestations of TSC1- and TSC2-associated disease.
Biochemical Society Transactions 03/2009; 37(Pt 1):259-64. · 3.71 Impact Factor
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ABSTRACT: MUTYH-associated polyposis (MAP) is an autosomal recessive disorder characterised by adenomatous polyps of the colorectum and a very high risk of colorectal cancer. It appears to be at least as prevalent as autosomal dominant familial adenomatous polyposis (that is caused by truncating mutations in the APC gene) with which it shares important gastroenterological features. It was first recognised as recently as 2002 and its full phenotype and natural history are still being characterised. Key extracolonic manifestations include a predisposition to duodenal adenomas and cancer and a modest increase in risk for several extraintestinal tumours. Testing for mutations in the MUTYH gene is indicated in patients who have multiple colorectal adenomas or a family history suggestive of autosomal recessive colorectal cancer and for the siblings and spouses of patients with MAP in order to inform surveillance and treatment for patients and their families.
Best practice & research. Clinical gastroenterology 02/2009; 23(2):209-18. · 2.48 Impact Factor
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ABSTRACT: Biallelic mutations in the base excision DNA repair gene MUTYH lead to MUTYH-associated polyposis (MAP) and predisposition to colorectal cancer (CRC). Functional studies have demonstrated significant differences in base recognition and glycosylase activity between various MUTYH mutations, notably for the 2 mutations most frequently reported in MAP patients: Y179C and G396D (previously annotated as Y165C and G382D). Our goal was to establish correlations between genotypes and colorectal phenotype of patients with MAP.
In this multicenter study, we analyzed genotype and phenotype data from 257 MAP patients. Data included age at presentation of MAP, polyp count, and the occurrence, location, and age at presentation of CRC.
Patients with a homozygous G396D mutation or compound heterozygous G396D/Y179C mutations presented later with MAP and had a significantly lower hazard of developing CRC than patients with a homozygous Y179C mutation (P < .001). The mean ages of CRC diagnosis in patients were 58 years (homozygous G396D) and 52 years (compound heterozygous G396D/Y179C) versus 46 years (homozygous Y179C; P = .001, linear regression).
Our study identified the phenotypic effects of Y179C as relatively severe and of G396D as relatively mild. These clinical data are in accord with findings from in vitro functional assays. Genotypic stratification may become useful in the development of guidelines for counseling, surveillance, and management of families with MAP.
Gastroenterology 11/2008; 136(2):471-6. · 11.68 Impact Factor
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Mark B Consugar,
Wai C Wong,
Patrick A Lundquist,
Sandro Rossetti,
Vickie J Kubly,
Denise L Walker,
Laureano J Rangel,
Richard Aspinwall,
W Patrick Niaudet,
Seza Ozen, [......],
Milen Velinov,
Eric J Bergstralh,
Kyongtae T Bae,
Arlene B Chapman,
Lisa M Guay-Woodford,
Jared J Grantham,
Vicente E Torres, Julian R Sampson,
Brian D Dawson,
Peter C Harris
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ABSTRACT: Large DNA rearrangements account for about 8% of disease mutations and are more common in duplicated genomic regions, where they are difficult to detect. Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2. PKD1 is located in an intrachromosomally duplicated region. A tuberous sclerosis gene, TSC2, lies immediately adjacent to PKD1 and large deletions can result in the PKD1/TSC2 contiguous gene deletion syndrome. To rapidly identify large rearrangements, a multiplex ligation-dependent probe amplification assay was developed employing base-pair differences between PKD1 and the six pseudogenes to generate PKD1-specific probes. All changes in a set of 25 previously defined deletions in PKD1, PKD2 and PKD1/TSC2 were detected by this assay and we also found 14 new mutations at these loci. About 4% of the ADPKD patients in the CRISP study were found to have gross rearrangements, and these accounted for about a third of base-pair mutation negative families. Sensitivity of the assay showed that about 40% of PKD1/TSC contiguous gene deletion syndrome families contained mosaic cases. Characterization of a family found to be mosaic for a PKD1 deletion is discussed here to illustrate family risk and donor selection considerations. Our assay improves detection levels and the reliability of molecular testing of patients with ADPKD.
Kidney International 10/2008; 74(11):1468-79. · 6.61 Impact Factor
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A R Dallosso,
S Dolwani,
N Jones,
S Jones,
J Colley,
J Maynard,
S Idziaszczyk,
V Humphreys,
J Arnold,
A Donaldson, [......],
I M Frayling,
F J Hes,
R S Houlston,
E R Maher,
M Nielsen,
S Parry,
E Tyler,
V Moskvina,
J P Cheadle, J R Sampson
[show abstract]
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ABSTRACT: MUTYH-associated polyposis (MAP) is a recessive trait characterised by multiple colorectal adenomas and a high risk of colorectal cancer. MUTYH functions in the DNA base excision repair pathway and has a key role in the repair of oxidative DNA damage.
To assess the contribution of inherited variants in genes involved in base excision repair and oxidative DNA damage including MUTYH, OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 to the multiple colorectal adenoma phenotype.
Inherited variants of MUTYH, OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 were sought in 167 unrelated patients with multiple colorectal adenomas whose family histories were consistent with recessive inheritance. These variants were also characterised in approximately 300 population controls.
Thirty-three patients (20%) and no controls were MUTYH homozygotes or compound heterozygotes (ie, carried two mutations) and therefore had MAP. Eight different pathogenic MUTYH mutations were identified, of which four were novel. MAP cases had significantly more adenomas than non-MAP cases (p = 0.0009; exact test for trends in proportions) and presented earlier (p = 0.013; analysis of variance). Twenty-four protein-altering variants were identified upon screening of OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1. However, all combinations of two (or more) variants that were identified at an individual locus in patients were also seen in controls, and no variants were significantly over-represented (or under-represented) in cases.
Multiple rare alleles of MUTYH are associated with autosomal recessive MAP, while OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 do not contribute significantly to autosomal recessive polyposis.
Gut 06/2008; 57(9):1252-5. · 10.11 Impact Factor
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D Mark Davies,
Simon R Johnson,
Anne E Tattersfield,
J Chris Kingswood,
Jane A Cox,
Deborah L McCartney,
Tim Doyle,
Frances Elmslie,
Anand Saggar,
Petrus J de Vries, Julian R Sampson
New England Journal of Medicine 02/2008; 358(2):200-3. · 53.30 Impact Factor
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Duncan Azzopardi,
Anthony R Dallosso,
Kristilyn Eliason,
Brant C Hendrickson,
Natalie Jones,
Edward Rawstorne,
James Colley,
Valentina Moskvina,
Cynthia Frye, Julian R Sampson,
Richard Wenstrup,
Thomas Scholl,
Jeremy P Cheadle
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ABSTRACT: It has been proposed that multiple rare variants in numerous genes collectively account for a substantial proportion of multifactorial inherited predisposition to a variety of diseases, including colorectal adenomas (CRA). We have studied this hypothesis by sequencing the adenomatous polyposis coli (APC) gene in 691 unrelated North American patients with CRAs and 969 matched healthy controls. Rare inherited nonsynonymous variants of APC were significantly overrepresented in patients who did not carry conventional pathogenic mutations in the APC or MutY homologue genes [non-familial adenomatous polyposis (FAP) non-MUTYH-associated polyposis (MAP) patients; 81 of 480, 16.9%] compared with patients with FAP or MAP (20 of 211, 9.5%, P = 0.0113), and this overrepresentation was highest in those non-FAP non-MAP patients with 11 to 99 CRAs (30 of 161, 18.6%, P = 0.0103). Furthermore, significantly more non-FAP non-MAP patients carried rare nonsynonymous variants in the functionally important beta-catenin down-regulating domain compared with healthy controls (32 of 480 versus 37 of 969, P = 0.0166). In silico analyses predicted that approximately 46% of the 61 different variants identified were likely to affect function, and upon testing, 7 of 16 nonsynonymous variants were shown to alter beta-catenin-regulated transcription in vitro. These data suggest that multiple rare nonsynonymous variants in APC play a significant role in predisposing to CRAs.
Cancer Research 02/2008; 68(2):358-63. · 7.86 Impact Factor
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ABSTRACT: Established predisposition genes account for only a small proportion of familial colorectal cancer. Recently, it has been shown that germline mutations in MUTYH predispose to MUTYH-associated polyposis (MAP), an autosomal recessive disorder characterised by multiple colorectal adenomas and carcinomas. MUTYH functions as a base excision repair DNA glycosylase that excises adenines misincorporated opposite 8-oxo-7,8-dihydro-2'-deoxyguanosine, one of the most stable products of oxidative DNA damage. It is the failure to correct this mispair that is thought to give rise to the characteristic signature of G:C-->T:A mutations found in MAP-associated tumours. Here, we review the germline mutation spectrum at the MUTYH locus (comprising 30 truncating and 55 missense/inframe insertion/deletion variants) and the molecular mechanism and biochemical defect(s) underlying this disorder. We also discuss the application of molecular genetic analysis of MUTYH in clinical practice.
DNA Repair 04/2007; 6(3):274-9. · 4.14 Impact Factor
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ABSTRACT: Tuberous sclerosis complex (TSC) is caused by mutations in either the TSC1 or TSC2 gene. Both genes are generally considered to act as tumor suppressors that fulfill Knudson's "two-hit hypothesis" and that function within the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin (mTOR) pathway. We previously generated Tsc1(+/-) mice that are predisposed to renal cysts, which develop into cystadenomas and renal cell carcinomas. Here, we identified somatic Tsc1 mutations (second hits) in approximately 80% of cystadenomas and renal cell carcinomas, but only 31.6% of cysts from Tsc1(+/-) mice (P < 0.0003), raising the possibility that haploinsufficiency for Tsc1 plays a role in cyst formation. Consistent with this proposal, many cysts showed little or no staining for phosphorylated mTOR (53%) and phosphorylated S6 ribosomal protein (37%), whereas >90% of cystadenomas and renal cell carcinomas showed strong staining for both markers (P < 0.0005). We also sought somatic mutations in renal lesions from Tsc1(+/-) Blm(-/-) mice that have a high frequency of somatic loss of heterozygosity, thereby facilitating the detection of second hits. We also found significantly less somatic mutations in cysts as compared with cystadenomas and renal cell carcinomas from these mice (P = 0.017). Our data indicate that although activation of the mTOR pathway is an important step in Tsc-associated renal tumorigenesis, it may not be the key initiating event in this process.
Cancer Research 08/2006; 66(16):7934-8. · 7.86 Impact Factor
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Hayley L Archer,
Julie C Evans,
David S Millar,
Peter W Thompson,
Alison M Kerr,
Helen Leonard,
John Christodoulou,
David Ravine,
Lazarus Lazarou,
Lucy Grove,
Christopher Verity,
Sharon D Whatley,
Daniela T Pilz, Julian R Sampson,
Angus J Clarke
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ABSTRACT: A translocation that disrupted the netrin G1 gene (NTNG1) was recently reported in a patient with the early seizure variant of Rett syndrome (RTT). The netrin G1 protein (NTNG1) has an important role in the developing central nervous system, particularly in axonal guidance, signalling and NMDA receptor function and was a good candidate gene for RTT. We recruited 115 patients with RTT (females: 25 classic and 84 atypical; 6 males) but no mutation in the MECP2 gene. For those 52 patients with epileptic seizure onset in the first 6 months of life, CDKL5 mutations were also excluded. We aimed to determine whether mutations in NTNG1 accounted for a significant subset of patients with RTT, particularly those with the early onset seizure variant and other atypical presentations. We sequenced the nine coding exons of NTNG1 and identified four sequence variants, none of which were likely to be pathogenic. Mutations in the NTNG1 gene appear to be a rare cause of RTT but NTNG1 function demands further investigation in relation to the central nervous system pathophysiology of the disorder.
American Journal of Medical Genetics Part A 05/2006; 140(7):691-4. · 2.39 Impact Factor
