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Malcolm G Dunlop,
Albert Tenesa,
Susan M Farrington,
Stephane Ballereau,
David H Brewster,
Thibaud Koessler,
Paul Pharoah,
Clemens Schafmayer,
Jochen Hampe,
Henry Völzke, [......],
Axel Walther,
David Kerr, Steven Lubbe,
Peter Broderick,
Ian Chandler,
Alan Pittman,
Steven Penegar,
Harry Campbell,
Ian Tomlinson,
Richard S Houlston
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVE: Colorectal cancer (CRC) has a substantial heritable component. Common genetic variation has been shown to contribute to CRC risk. A study was conducted in a large multi-population study to assess the feasibility of CRC risk prediction using common genetic variant data combined with other risk factors. A risk prediction model was built and applied to the Scottish population using available data. DESIGN: Nine populations of European descent were studied to develop and validate CRC risk prediction models. Binary logistic regression was used to assess the combined effect of age, gender, family history (FH) and genotypes at 10 susceptibility loci that individually only modestly influence CRC risk. Risk models were generated from case-control data incorporating genotypes alone (n=39 266) and in combination with gender, age and FH (n=11 324). Model discriminatory performance was assessed using 10-fold internal cross-validation and externally using 4187 independent samples. The 10-year absolute risk was estimated by modelling genotype and FH with age- and gender-specific population risks. RESULTS: The median number of risk alleles was greater in cases than controls (10 vs 9, p<2.2×10(-16)), confirmed in external validation sets (Sweden p=1.2×10(-6), Finland p=2×10(-5)). The mean per-allele increase in risk was 9% (OR 1.09; 95% CI 1.05 to 1.13). Discriminative performance was poor across the risk spectrum (area under curve for genotypes alone 0.57; area under curve for genotype/age/gender/FH 0.59). However, modelling genotype data, FH, age and gender with Scottish population data shows the practicalities of identifying a subgroup with >5% predicted 10-year absolute risk. CONCLUSION: Genotype data provide additional information that complements age, gender and FH as risk factors, but individualised genetic risk prediction is not currently feasible. Nonetheless, the modelling exercise suggests public health potential since it is possible to stratify the population into CRC risk categories, thereby informing targeted prevention and surveillance.
Gut 04/2012; · 10.11 Impact Factor
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European journal of human genetics: EJHG 10/2011; 19(10):1110. · 3.56 Impact Factor
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Ian P M Tomlinson,
Luis G Carvajal-Carmona,
Sara E Dobbins,
Albert Tenesa,
Angela M Jones,
Kimberley Howarth,
Claire Palles,
Peter Broderick,
Emma E M Jaeger,
Susan Farrington, [......],
Polly Newcomb,
John Hopper,
Mark A Jenkins,
Lauri A Aaltonen,
David J Kerr,
Jeremy Cheadle,
Paul Pharoah,
Graham Casey,
Richard S Houlston,
Malcolm G Dunlop
[show abstract]
[hide abstract]
ABSTRACT: Genome-wide association studies (GWAS) have identified 14 tagging single nucleotide polymorphisms (tagSNPs) that are associated with the risk of colorectal cancer (CRC), and several of these tagSNPs are near bone morphogenetic protein (BMP) pathway loci. The penalty of multiple testing implicit in GWAS increases the attraction of complementary approaches for disease gene discovery, including candidate gene- or pathway-based analyses. The strongest candidate loci for additional predisposition SNPs are arguably those already known both to have functional relevance and to be involved in disease risk. To investigate this proposition, we searched for novel CRC susceptibility variants close to the BMP pathway genes GREM1 (15q13.3), BMP4 (14q22.2), and BMP2 (20p12.3) using sample sets totalling 24,910 CRC cases and 26,275 controls. We identified new, independent CRC predisposition SNPs close to BMP4 (rs1957636, P = 3.93×10(-10)) and BMP2 (rs4813802, P = 4.65×10(-11)). Near GREM1, we found using fine-mapping that the previously-identified association between tagSNP rs4779584 and CRC actually resulted from two independent signals represented by rs16969681 (P = 5.33×10(-8)) and rs11632715 (P = 2.30×10(-10)). As low-penetrance predisposition variants become harder to identify-owing to small effect sizes and/or low risk allele frequencies-approaches based on informed candidate gene selection may become increasingly attractive. Our data emphasise that genetic fine-mapping studies can deconvolute associations that have arisen owing to independent correlation of a tagSNP with more than one functional SNP, thus explaining some of the apparently missing heritability of common diseases.
PLoS Genetics 06/2011; 7(6):e1002105. · 8.69 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Mutations in protein kinases can drive cancer through alterations of the kinase activity or by uncoupling kinase activity
from regulation. Changes to protein expression in Aurora A, a mitotic Ser/Thr kinase, are associated with the development
of several human cancers, but the effects of somatic cancer-associated mutations have not been determined. In this study we
show that Aurora A kinase activity is altered in different ways in three somatic cancer-associated mutations located within
the catalytic domain; Aurora A(V174M) shows constitutively increased kinase activity, Aurora A(S155R) activity is decreased
primarily due to misregulation, and Aurora A(S361*) activity is ablated due to loss of structural integrity. These alterations
suggest vastly different mechanisms for the role of these three mutations in human cancer. We have further characterized the
Aurora A(S155R) mutant protein, found that its reduced cellular activity and mislocalization are due to loss of interaction
with TPX2, and deciphered the structural basis of the disruption at 2.5 Å resolution. Previous studies have shown that disruption
of the Aurora A/TPX2 interaction results in defective spindles that generate chromosomal abnormalities. In a panel of 40 samples
from microsatellite instability-positive colon cancer patients, we found one example in which the tumor contained only Aurora
A(S155R), whereas the normal tissue contained only wild-type Aurora A. We propose that the S155R mutation is an example of
a somatic mutation associated with this tumor type, albeit at modest frequency, that could promote aneuploidy through the
loss of regulated interactions between Aurora A and its protein partners.
Journal of Biological Chemistry 11/2009; 284(48):33177-33184. · 4.77 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Mutations in protein kinases can drive cancer through alterations of the kinase activity or by uncoupling kinase activity from regulation. Changes to protein expression in Aurora A, a mitotic Ser/Thr kinase, are associated with the development of several human cancers, but the effects of somatic cancer-associated mutations have not been determined. In this study we show that Aurora A kinase activity is altered in different ways in three somatic cancer-associated mutations located within the catalytic domain; Aurora A(V174M) shows constitutively increased kinase activity, Aurora A(S155R) activity is decreased primarily due to misregulation, and Aurora A(S361*) activity is ablated due to loss of structural integrity. These alterations suggest vastly different mechanisms for the role of these three mutations in human cancer. We have further characterized the Aurora A(S155R) mutant protein, found that its reduced cellular activity and mislocalization are due to loss of interaction with TPX2, and deciphered the structural basis of the disruption at 2.5 A resolution. Previous studies have shown that disruption of the Aurora A/TPX2 interaction results in defective spindles that generate chromosomal abnormalities. In a panel of 40 samples from microsatellite instability-positive colon cancer patients, we found one example in which the tumor contained only Aurora A(S155R), whereas the normal tissue contained only wild-type Aurora A. We propose that the S155R mutation is an example of a somatic mutation associated with this tumor type, albeit at modest frequency, that could promote aneuploidy through the loss of regulated interactions between Aurora A and its protein partners.
Journal of Biological Chemistry 10/2009; 284(48):33177-84. · 4.77 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Genome scans based on gene-centric single nucleotide polymorphisms (SNPs) have been proposed as an efficient approach to identify disease-causing variants that is complementary to scans based on tagging SNPs. Adopting this approach to identify low-penetrance susceptibility alleles for colorectal cancer (CRC) we analysed genotype data from 9109 gene-centric SNPs, 7014 of which were non-synonymous (nsSNPs), in 2873 cases and 2871 controls using Illumina iselect arrays. Overall the distribution of associations was not significantly different from the null. No SNP achieved globally significant association after correction for multiple testing (lowest P value 1.7 x 10(-4), rs727299). We then analysed the dataset incorporating information on the functional consequences of nsSNPs. We used results from the in silico algorithm PolyPhen as prior information to weight the association statistics, with weights estimated from the observed test statistics within predefined groups of SNPs. Incorporating this information did not, however, yield any further evidence of a specific association (lowest P value 2.2 x 10(-4), rs1133950). There was a strong relationship between effect size and SNPs predicted to be damaging (P=1.63 x 10(-5)), however, these variants which are most likely to impact on risk are rare (MAF<5%). Hence although the rationale for searching for low-penetrance cancer susceptibly alleles by conducting genome-wide scans of coding changes is strong, in practice it is likely that natural selection has rendered such alleles to be too rare to be detected by association studies of the size employed.
European journal of human genetics: EJHG 06/2009; 17(11):1507-14. · 3.56 Impact Factor
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[show abstract]
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ABSTRACT: Part of the inherited susceptibility to colorectal cancer (CRC) is caused by the coinheritance of common low risk variants. E-cadherin (CDH1) has an established role in CRC; somatic inactivation of CDH1 is a common early event, and germline mutations can cause early-onset CRC. The -160C>A promoter variant (rs16260) of CDH1 has been reported to influence CDH1 transcription and thereby represents a strong candidate for a predisposition locus. To examine this proposition, we conducted a two-staged association study based on genotyping a total of 5,679 CRC cases and 5,412 controls for rs16260. CDH1-160C>A genotype was associated with CRC risk (p(trend) = 0.001). Compared to common homozygotes, the odds ratios (ORs) of CRC associated with heterozygous and homozygote variant genotype were 0.90 (95% confidence interval [CI]: 0.84-0.97) and 0.81 (95% CI: 0.71-0.93), respectively. In combination with the previously identified 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 risk variants, the risk of CRC increases with an increasing numbers of variant alleles for the 7 loci (OR(per allele) = 1.16; 95% CI: 1.13-1.19; p(trend) = 1.68 x 10(-34)). These data indicate CDH1-160C>A is a risk factor for CRC, and because a high proportion of the European population are carriers of at-risk genotypes, the variant is likely to contribute substantially to the development of CRC. Furthermore, our study underscores the importance of conducting association studies using large sample series to demonstrate polymorphic variants conferring modest relative risks.
International Journal of Cancer 05/2009; 125(7):1622-5. · 5.44 Impact Factor
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Richard S Houlston,
Emily Webb,
Peter Broderick,
Alan M Pittman,
Maria Chiara Di Bernardo, Steven Lubbe,
Ian Chandler,
Jayaram Vijayakrishnan,
Kate Sullivan,
Steven Penegar, [......],
Henry Völzke,
Jenny Chang-Claude,
Michael Hoffmeister,
Hermann Brenner,
Brent W Zanke,
Alexandre Montpetit,
Thomas J Hudson,
Steven Gallinger,
Harry Campbell,
Malcolm G Dunlop
[show abstract]
[hide abstract]
ABSTRACT: Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly influence the risk of developing colorectal cancer (CRC). To enhance power to identify additional loci with similar effect sizes, we conducted a meta-analysis of two GWA studies, comprising 13,315 individuals genotyped for 38,710 common tagging SNPs. We undertook replication testing in up to eight independent case-control series comprising 27,418 subjects. We identified four previously unreported CRC risk loci at 14q22.2 (rs4444235, BMP4; P = 8.1 x 10(-10)), 16q22.1 (rs9929218, CDH1; P = 1.2 x 10(-8)), 19q13.1 (rs10411210, RHPN2; P = 4.6 x 10(-9)) and 20p12.3 (rs961253; P = 2.0 x 10(-10)). These findings underscore the value of large sample series for discovery and follow-up of genetic variants contributing to the etiology of CRC.
Nature Genetics 01/2009; 40(12):1426-35. · 35.53 Impact Factor
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Eli Papaemmanuil,
Luis Carvajal-Carmona,
Gabrielle S Sellick,
Zoe Kemp,
Emily Webb,
Sarah Spain,
Kate Sullivan,
Ella Barclay, Steven Lubbe,
Emma Jaeger, [......],
Hans K Schackert,
Timm O Goecke,
Elke Holinski-Feder,
Peter Propping,
Tom Van Wezel,
Juul Wijnen,
Jean-Baptiste Cazier,
Huw Thomas,
Richard S Houlston,
Ian Tomlinson
[show abstract]
[hide abstract]
ABSTRACT: Previously we have localized to chromosome 3q21-q24, a predisposition locus for colorectal cancer (CRC), through a genome-wide linkage screen (GWLS) of 69 families without familial adenomatous polyposis or hereditary non-polyposis CRC. To further investigate Mendelian susceptibility to CRC, we extended our screen to include a further GWLS of an additional 34 CRC families. We also searched for a disease gene at 3q21-q24 by linkage disequilibrium mapping in 620 familial CRC cases and 960 controls by genotyping 1676 tagging SNPs and sequencing 30 candidate genes from the region. Linkage analysis was conducted using the Affymetrix 10K SNP array. Data from both GWLSs were pooled and multipoint linkage statistics computed. The maximum NPL score (3.01; P=0.0013) across all families was at 3q22, maximal evidence for linkage coming from families segregating rectal CRC. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under a dominant model (HLOD=2.79; P=0.00034), with an estimated 43% of families linked. In the case-control analysis, the strongest association was obtained at rs698675 (P=0.0029), but this was not significant after adjusting for multiple testing. Analysis of candidate gene mapping to the region of maximal linkage on 3q22 failed to identify a causal mutation. There was no evidence for linkage to the previously reported 9q CRC locus (NPL=0.95, P=0.23; HLOD(dominant)=0.40, HLOD(recessive)=0.20). Our findings are consistent with the hypothesis that variation at 3q22 contributes to the risk of CRC, but this is unlikely to be mediated through a restricted set of alleles.
European Journal of HumanGenetics 12/2008; 16(12):1477-86. · 4.40 Impact Factor
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Alan M Pittman,
Emily Webb,
Luis Carvajal-Carmona,
Kimberley Howarth,
Maria Chiara Di Bernardo,
Peter Broderick,
Sarah Spain,
Axel Walther,
Amy Price,
Kate Sullivan, [......],
Jose M Ladero,
Miguel de la Hoya,
Trinidad Caldés,
Iina Niittymäki,
Sari Tuupanen,
Auli Karhu,
Lauri A Aaltonen,
Jean-Baptiste Cazier,
Ian P M Tomlinson,
Richard S Houlston
[show abstract]
[hide abstract]
ABSTRACT: The common single-nucleotide polymorphism (SNP) rs3802842 at 11q23.1 has recently been reported to be associated with risk of colorectal cancer (CRC). To examine this association in detail we genotyped rs3802842 in eight independent case-control series comprising a total of 10 638 cases and 10 457 healthy individuals. A significant association between the C allele of rs3802842 and CRC risk was found (per allele OR = 1.17; 95% confidence interval [CI]: 1.12-1.22; P = 1.08 x 10(-12)) with the risk allele more frequent in rectal than colonic disease (P = 0.02). In combination with 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 variants, the risk of CRC increases with an increasing numbers of variant alleles for the six loci (OR(per allele) = 1.19; 95% CI: 1.15-1.23; P(trend) = 7.4 x 10(-24)). Using the data from our genome-wide association study of CRC, LD mapping and imputation, we were able to refine the location of the causal locus to a 60 kb region and screened for coding changes. The absence of exonic mutations in any of the transcripts (FLJ45803, LOC120376, C11orf53 and POU2AF1) mapping to this region makes the association likely to be a consequence of non-coding effects on gene expression.
Human Molecular Genetics 09/2008; 17(23):3720-7. · 7.64 Impact Factor
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Ian P M Tomlinson,
Emily Webb,
Luis Carvajal-Carmona,
Peter Broderick,
Kimberley Howarth,
Alan M Pittman,
Sarah Spain, Steven Lubbe,
Axel Walther,
Kate Sullivan, [......],
Miguel de la Hoya,
Trinidad Caldés,
Iina Niittymäki,
Sari Tuupanen,
Auli Karhu,
Lauri Aaltonen,
Jean-Baptiste Cazier,
Harry Campbell,
Malcolm G Dunlop,
Richard S Houlston
[show abstract]
[hide abstract]
ABSTRACT: To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 x 10(-13) overall; P = 6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P = 3.3 x 10(-18) overall; P = 9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.
Nature Genetics 05/2008; 40(5):623-30. · 35.53 Impact Factor
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Ian PM Tomlinson,
Emily Webb,
Luis Carvajal-Carmona,
Peter Broderick,
Kimberley Howarth,
Alan M Pittman,
Sarah Spain, Steven Lubbe,
Axel Walther,
Kate Sullivan, [......],
Miguel de la Hoya,
Trinidad Cald|[eacute]|s,
Iina Niittym|[auml]|ki,
Sari Tuupanen,
Auli Karhu,
Lauri Aaltonen,
Jean-Baptiste Cazier,
Harry Campbell,
Malcolm G Dunlop,
Richard S Houlston
[show abstract]
[hide abstract]
ABSTRACT: To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at
Nature Genetics 03/2008; 40(5):623-630. · 35.53 Impact Factor
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Emma Jaeger,
Emily Webb,
Kimberley Howarth,
Luis Carvajal-Carmona,
Andrew Rowan,
Peter Broderick,
Axel Walther,
Sarah Spain,
Alan Pittman,
Zoe Kemp, [......],
Albert Tenesa,
Jean-Baptiste Cazier,
David Kerr,
Richard Gray,
Julian Peto,
Malcolm Dunlop,
Harry Campbell,
Huw Thomas,
Richard Houlston,
Ian Tomlinson
[show abstract]
[hide abstract]
ABSTRACT: We mapped a high-penetrance gene (CRAC1; also known as HMPS) associated with colorectal cancer (CRC) in the Ashkenazi population to a 0.6-Mb region on chromosome 15 containing SCG5 (also known as SGNE1), GREM1 and FMN1. We hypothesized that the CRAC1 locus harbored low-penetrance variants that increased CRC risk in the general population. In a large series of colorectal cancer cases and controls, SNPs near GREM1 and SCG5 were strongly associated with increased CRC risk (for rs4779584, P = 4.44 x 10(-14)).
Nature Genetics 02/2008; 40(1):26-8. · 35.53 Impact Factor
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Peter Broderick,
Luis Carvajal-Carmona,
Alan M Pittman,
Emily Webb,
Kimberley Howarth,
Andrew Rowan, Steven Lubbe,
Sarah Spain,
Kate Sullivan,
Sarah Fielding, [......],
Enric Domingo,
Ella Barclay,
Lynn Martin,
Oliver Sieber,
David Kerr,
Richard Gray,
Julian Peto,
Jean-Baptiste Cazier,
Ian Tomlinson,
Richard S Houlston
[show abstract]
[hide abstract]
ABSTRACT: To identify risk variants for colorectal cancer (CRC), we conducted a genome-wide association study, genotyping 550,163 tag SNPs in 940 individuals with familial colorectal tumor (627 CRC, 313 advanced adenomas) and 965 controls. We evaluated selected SNPs in three replication sample sets (7,473 cases, 5,984 controls) and identified three SNPs in SMAD7 (involved in TGF-beta and Wnt signaling) associated with CRC. Across the four sample sets, the association between rs4939827 and CRC was highly statistically significant (P(trend) = 1.0 x 10(-12)).
Nature Genetics 12/2007; 39(11):1315-7. · 35.53 Impact Factor
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Ian Tomlinson,
Emily Webb,
Luis Carvajal-Carmona,
Peter Broderick,
Zoe Kemp,
Sarah Spain,
Steven Penegar,
Ian Chandler,
Maggie Gorman,
Wendy Wood, [......],
Kenneth Muir,
Richard Logan,
David Kerr,
Elaine Johnstone,
Oliver Sieber,
Richard Gray,
Huw Thomas,
Julian Peto,
Jean-Baptiste Cazier,
Richard Houlston
[show abstract]
[hide abstract]
ABSTRACT: Much of the variation in inherited risk of colorectal cancer (CRC) is probably due to combinations of common low risk variants. We conducted a genome-wide association study of 550,000 tag SNPs in 930 familial colorectal tumor cases and 960 controls. The most strongly associated SNP (P = 1.72 x 10(-7), allelic test) was rs6983267 at 8q24.21. To validate this finding, we genotyped rs6983267 in three additional CRC case-control series (4,361 affected individuals and 3,752 controls; 1,901 affected individuals and 1,079 controls; 1,072 affected individuals and 415 controls) and replicated the association, providing P = 1.27 x 10(-14) (allelic test) overall, with odds ratios (ORs) of 1.27 (95% confidence interval (c.i.): 1.16-1.39) and 1.47 (95% c.i.: 1.34-1.62) for heterozygotes and rare homozygotes, respectively. Analyses based on 1,477 individuals with colorectal adenoma and 2,136 controls suggest that susceptibility to CRC is mediated through development of adenomas (OR = 1.21, 95% c.i.: 1.10-1.34; P = 6.89 x 10(-5)). These data show that common, low-penetrance susceptibility alleles predispose to colorectal neoplasia.
Nature Genetics 09/2007; 39(8):984-8. · 35.53 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The majority of colorectal cancer (CRC) exhibiting the micosatellite instability (MSI) phenotype is due to hypermethylation of the hMLH1 gene promoter. We aimed to test the hypothesis that polymorphisms in genes coding for enzymes involved in folate metabolism play a role in altered promoter-specific hypermethylation and thus predispose to MSI CRC. Analysis of MSI was performed in 1685 CRCs, and polymorphism genotypes were determined in germline DNA for all cases and 2692 cancer-free controls. MSI was observed in 171 cancers (10.1%). Compared to homozygous wild-type individuals, those with MTHFR 677TT genotype were more likely to have MSI than microsatellite stable (MSS) CRC [odds ratio (OR) 1.90; 95% confidence interval (CI): 1.09-3.31]. When MTHFR C677T genotype frequencies in MSS CRC cases were compared to controls, individuals with homozygous variant genotype were at 19% reduced risk of cancer compared to wild type (OR = 0.81; 95% CI: 0.65-1.02). Conversely, when MSI CRC cases were compared to controls, individuals with one or two MTHFR 677T alleles were at 42% increased cancer risk (OR = 1.42; 95% CI: 1.02-1.96). Our observations indicate that MTHFR 677TT homozygous individuals are more likely to develop MSI CRC than those with wild-type genotype, and this common polymorphism has differential influences on MSI and MSS CRC risk. Stratification by MSI status should aid future studies investigating the complex relationships between genotype, environmental factors and CRC risk.
Human Molecular Genetics 06/2007; 16(9):1072-7. · 7.64 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The observation that germline mutations in the oxidative DNA damage repair gene MUTYH cause colorectal cancer (CRC) provides strong evidence that dysregulation of the base excision repair (BER) pathway influences disease susceptibility. It is conceivable that germline sequence variation in other BER pathway genes such as NTHL1, NEIL1, NEIL2, MPG, TDG, UNG and SMUG1 also contribute to CRC susceptibility.
To evaluate whether sequence variants of NTHL1, NEIL1, NEIL2, MPG, TDG, UNG and SMUG1 genes might act as CRC susceptibility alleles, we screened the coding sequence and intron-exon boundaries of these genes in 94 familial CRC cases in which involvement of known genes had been excluded.
Three novel missense variants were identified NEIL2 C367A, TDG3 A196G and UNG2 C262T in patients, which were not observed in 188 healthy control DNAs.
We detected novel germline alterations in NEIL2, TDG and UNG patients with CRC. The results suggest a limited role for NTHL1, NEIL1, NEIL2, MPG, TDG, UNG and SMUG1 in development of CRC.
BMC Cancer 02/2006; 6:243. · 3.01 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Abstract
Background
The observation that germline mutations in the oxidative DNA damage repair gene MUTYH cause colorectal cancer (CRC) provides strong evidence that dysregulation of the base excision repair (BER) pathway influences disease susceptibility. It is conceivable that germline sequence variation in other BER pathway genes such as NTHL1 , NEIL1 , NEIL2 , MPG , TDG , UNG and SMUG1 also contribute to CRC susceptibility.
Methods
To evaluate whether sequence variants of NTHL1 , NEIL1 , NEIL2 , MPG , TDG , UNG and SMUG1 genes might act as CRC susceptibility alleles, we screened the coding sequence and intron-exon boundaries of these genes in 94 familial CRC cases in which involvement of known genes had been excluded.
Results
Three novel missense variants were identified NEIL2 C367A, TDG3 A196G and UNG2 C262T in patients, which were not observed in 188 healthy control DNAs.
Conclusion
We detected novel germline alterations in NEIL2, TDG and UNG patients with CRC. The results suggest a limited role for NTHL1 , NEIL1 , NEIL2 , MPG , TDG , UNG and SMUG1 in development of CRC.
BMC Cancer. 01/2006;
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Ian PM Tomlinson,
Emily Webb,
Luis Carvajal-Carmona,
Peter Broderick,
Kimberley Howarth,
Alan M Pittman,
Sarah Spain, Steven Lubbe,
Axel Walther,
Kate Sullivan, [......],
Miguel de la Hoya,
Trinidad Caldés,
Iina Niittymäki,
Sari Tuupanen,
Auli Karhu,
Lauri Aaltonen,
Jean-Baptiste Cazier,
Harry Campbell,
Malcolm G Dunlop,
Richard S Houlston
