A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21.

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.

Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42,103 individuals.

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.

Perfusion CT vascular parameters do not correlate with immunohistochemically derived microvessel density count in colorectal tumors.

PURPOSE: To determine whether perfusion computed tomography (CT)-derived vascular parameters-namely, blood flow, mean transit time (MTT), volume transfer constant (K(trans)), permeability-surface area product (PS), extracellular extravascular space volume, and vascular volume-correlate with the immunohistologic markers of angiogenesis in colorectal tumors. MATERIALS AND METHODS: This prospective study was approved by the Regional Ethics and Research and Development Committees. The perfusion CT protocol was incorporated in the staging CT after informed consent in 29 patients (14 men, 15 women; mean age, 70 years; age range, 55-94 years). The perfusion parameters were calculated over two regions of interest (ROIs), at the invasive and luminal site defined by two radiologists independently. Accurate representative data were captured manually by correcting for motion artifacts and were analyzed by using Matlab software. The vascular heterogeneity between ROIs was assessed by using the Wilcoxon signed rank test. Perfusion CT parameters were correlated with the microvessel density (MVD) count at both corresponding sites obtained by means of immunohistochemical staining of the selected histologic slide with factor VIII and CD105 antigens by using Spearmen rank coefficient. RESULTS: There was no statistically significant difference found between perfusion CT vascular parameters at the two ROIs by either of the radiologists. The Pearson coefficient for blood flow, MTT, K(trans), and PS at the two ROIs demonstrated good to moderate interobserver variability (for the two ROIs, 0.46 and 0.44; 0.67 and 0.64; 0.41 and 0.72; and 0.86 and 0.56, respectively). None of these parameters correlated with MVD count at the invasive or the luminal site for either of the two antigens. CONCLUSION: Perfusion CT measurements may measure vascularity of colorectal tumors, however, correlation with MVD, which is a morphologic measure, appears inappropriate. © RSNA, 2013.

Relationship between 16 susceptibility loci and colorectal cancer phenotype in 3146 patients.

Recent genome-wide association studies have identified single-nucleotide polymorphisms at 16 genetic loci associated with colorectal cancer risk: rs6691170 (1q41), rs10936599 (3q26.2), rs16892766 (8q23.3), rs6983267 (8q24.21), rs10795668 (10p14), rs3802842 (11q23.1), rs11169552 (12q13.13), rs4444235, rs1957636 (14q22.2), rs4779584 (15q13.3), rs9929218 (16q22.1), rs4939827 (18q21.1), rs10411210 (19q13.11), rs961253 and rs4813802 (20p12.3) and rs4925386 (20q13.33). In the present study, we examined whether these variants are preferentially associated with tumour subtype-tumour site, stage, degree of differentiation and microsatellite instability status-in 3146 patients. Several loci showed statistically significant associations with specific phenotypes notably rs6691170 and rs3802842 associated with microsatellite stable rectal disease; rs4779584, rs961253 and rs4813802 associated with microsatellite stable colonic disease and rs4444235 and rs4925386 with microsatellite instability colonic disease. These findings are consistent with pathogenic variants in loci differentially impacting on distinct morphogenetic pathways consistent with aetiologically different risk factors in the development of colorectal cancer.

Comprehensive evaluation of the impact of 14 genetic variants on colorectal cancer phenotype and risk.

To comprehensively evaluate the impact of recently identified colorectal cancer (CRC) variants at 1q41, 3q26.2, 8q23.3, 8q24.21, 10p14, 11q23.1, 12q13.13, 14q22.2, 15q13.3, 16q22.1, 18q21.1, 19q13.11, 20p12.3, and 20q13.33 on risk and CRC phenotype, the authors analyzed 8,878 cases and 6,051 controls from the United Kingdom ascertained in 1999-2007. The impact of variants on the familial CRC risk was enumerated from age-, sex-, and calendar-specific CRC rates in the 50,924 first-degree relatives of cases. Each of the 14 susceptibility loci independently influences CRC with the risk increasing with increasing number of risk alleles carried (per allele odds ratio = 1.13; P = 2.99 × 10(-58)) and, for those within the upper quintile, there is a 2.3-fold increased risk. In first-degree relatives of cases with ≤17, 18-21, and ≥22 risk alleles, standardized incidence ratios were 1.76, 2.08, and 2.25, respectively. Although the discriminatory attributes of the 14 CRC susceptibility loci for individual risk prediction are poor (area under the curve = 0.58), they may allow subgroups of the population at different CRC risks to be distinguished.

Minimum regions of genomic imbalance in stage I testicular embryonal carcinoma and association of 22q loss with relapse.

Testicular germ cell tumors (TGCT) are the most frequent solid tumor to affect young adult males and are histologically divided into seminomas and nonseminomas (NS). NS comprise undifferentiated embryonal carcinoma (EC) and differentiated tumors with embryonic (teratoma) or extra-embryonic (choriocarcinoma, yolk sac tumor) features. In contrast to other subtypes, EC have uniform cellular morphology and lack normal cell infiltrates, ideal for nucleic acid profiling. EC are under-represented in previous studies due to their relative rarity. To gain insights into NS tumorigenesis, metastatic dissemination and potential markers of relapse, a full tiling path BAC platform was used to obtain array comparative genomic hybridization (aCGH) profiles from 32 formalin fixed paraffin embedded stage I EC samples from patients with follow-up data. In addition to identifying regions previously described in TGCT, novel minimum overlapping regions of gain at 6p21.33, 10q11.21, and 22q13.32 and loss at 22q12.2 were defined and confirmed by fluorescence in situ hybridization analyses. Specifically, the region at 6p21.33 included OCT3/4, the expression of which is involved in the maintenance of pluripotency and the 10q11.21 region contains the gene encoding the RAS activating factor RASGEF1A, the expression of which was demonstrably increased in RNA extracted from these samples. The region of loss at 22q12.2 was more frequently seen in tumors that relapsed and protein expression of genes from 22q12.2 included PIK3IP1, a negative regulator of PI3 kinase signaling was reduced. These data support the role for genes involved in pluripotency and RAS/PI3K signaling in EC development and progression.

MLH1-93G > A is a risk factor for MSI colorectal cancer.

The -93G > A (rs1800734) polymorphism within the core promoter region of the MutL homolog 1 (MLH1) gene has recently been proposed as a low penetrance variant for colorectal cancer (CRC). We evaluated the significance of rs1800734 on CRC risk by genotyping 10 409 CRC cases and 6965 controls. The per allele odds ratio (OR) for all CRC-associated MLH1-93G > A was 1.06 (P = 0.037). Using a subset of 3132 cases with known microsatellite instability (MSI) status, the risk was shown to be confined to microsatellite instability-high (MSI-H) CRC; OR = 1.39 (P = 1.45 × 10(-4)). A meta-analysis of our study and four smaller published studies (totalling 801 cases, 10 890 controls) provided for increased evidence of relationship between MLH1-93G > A and MSI-H CRC risk (P = 3.43 × 10(-12)). The impact of MLH1-93G > A on CRC risk was shown to be independent of the 14 low penetrance loci for CRC identified by recent genome-wide association studies. These data provide further evidence that MLH1-93G > A is a low-penetrance variant for CRC and support the proposition that MLH1-93G > A acts as marker for a somatic event defining a specific CRC subtype.

Refinement of the basis and impact of common 11q23.1 variation to the risk of developing colorectal cancer.

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.

The CDH1-160C>A polymorphism is a risk factor for colorectal cancer.

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.

Relationship between chromosome 18q status and colorectal cancer prognosis: a prospective, blinded analysis of 280 patients.

BACKGROUND: The relationship between chromosome 18q allelic imbalance (AI) and survival in colorectal cancer (CRC) is unclear, and study design may have contributed to inconsistent results previously reported. PATIENTS AND METHODS: Two hundred and eighty tumours from CRC patients participating in a molecular sub-study from a single multicentre trial of adjuvant intra-portal 5-fluorouracil were genotyped at 5 chromosome 18q microsatellite markers, blinded to clinical data and prospective to follow-up. The relationship between overall survival and AI was examined. RESULTS: Two hundred and fifty-five tumours were informative for AI. The overall rate of AI was 49%. AI was not associated with age, tumour site or size. There was no difference in five-year survival rate between patients with (60.0% SE 5.2%) and without AI (61.4% SE 5.0%), even after correcting for covariates (HR=1.17, 95%CI:0.79-1.74, p=0.4). CONCLUSION: Our data does not [corrected] support chromosome 18q AI as an important marker of survival in the adjuvant setting. It should not, therefore, be used outside clinical trials.

Evaluation of NTHL1, NEIL1, NEIL2, MPG, TDG, UNG and SMUG1 genes in familial colorectal cancer predisposition.

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.

Defining a New Prognostic Index for Stage I Nonseminomatous Germ Cell Tumors Using CXCL12 Expression and Proportion of Embryonal Carcinoma.

PURPOSE: Up to 50% of patients diagnosed with stage I nonseminomatous germ cell tumors (NSGCTs) harbor occult metastases. Patients are managed by surveillance with chemotherapy at relapse or adjuvant treatment up front. Late toxicities from chemotherapy are increasingly recognized. Based on a potential biologic role in germ cells/tumors and pilot data, our aim was to evaluate tumor expression of the chemokine CXCL12 alongside previously proposed markers as clinically useful biomarkers of relapse. EXPERIMENTAL DESIGN: Immunohistochemistry for tumor expression of CXCL12 was assessed as a biomarker of relapse alongside vascular invasion, histology (percentage embryonal carcinoma), and MIB1 staining for proliferation in formalin-fixed paraffin-embedded orchidectomy samples from patients enrolled in the Medical Research Council's TE08/22 prospective trials of surveillance in stage I NSGCTs. RESULTS: TE08/TE22 trial patients had a 76.4% 2-year relapse-free rate, and both CXCL12 expression and percentage embryonal carcinoma provided prognostic value independently of vascular invasion (stratified log rank test P = 0.006 for both). There was no additional prognostic value for MIB1 staining. A model using CXCL12, percentage embryonal carcinoma, and VI defines three prognostic groups that were independently validated. CONCLUSIONS: CXCL12 and percentage embryonal carcinoma both stratify patients' relapse risk over and above vascular invasion alone. This is anticipated to improve the stratification of patients and identify high-risk cases to be considered for adjuvant therapy.

A practical guide to constructing and using tissue microarrays.

Tissue microarray (TMA) technology is a robust "high throughput" method of tissue analysis, whereby a large number of patient samples can be examined in a short time using a minimum number of slides. In a TMA, cylinders of tissue are cored out of formalin-fixed, paraffin-embedded tissue blocks and slotted in a regular grid pattern into a blank recipient paraffin wax block. The TMA block is then cut using a standard laboratory microtome. Sections generated are suitable for all in situ techniques, such as immunohistochemistry (IHC) and in situ hybridisation, using essentially the same protocols as are used in conventional sections. The principle advantages of TMAs are that they save valuable biological material and ensure more reproducible reaction conditions while at the same time reducing re-agent costs and laboratory processing. Immunohistochemical studies designed to examine the prognostic utility of TMAs compared with large sections have generally found that they are comparable.

Mismatch repair, minichromosome maintenance complex component 2, cyclin A, and transforming growth factor ß receptor type II as prognostic factors for colorectal cancer: results of a 10-year prospective study using tissue microarray analysis.

BACKGROUND: The expression of genes encoding a number of pathogenetic pathways involved in colorectal cancer could potentially act as prognostic markers. Large prospective studies are required to establish their relevance to disease prognosis. METHODS: We investigated the relevance of 19 markers in 790 patients enrolled in a large randomised trial of 5-fluorouracil using immunohistochemistry and chromogenic in situ hybridisation. The relationship between overall 10-year survival and marker status was assessed. RESULTS: Minichromosome maintenance complex component 2 (MCM2) and cyclin A were significantly associated with overall survival. Elevated MCM2 expression was associated with a better prognosis (HR = 0.63, 95%CI: 0.46 - 0.86). Cyclin A expression above the median predicted an improved patient prognosis (HR = 0.71, 95%CI: 0.53 - 0.95). For mismatch repair deficiency and transforming growth factor ß receptor type II (TGFBRII) overexpression there was a borderline association with a poorer prognosis (HR = 0.69, 95%CI: 0.46 - 1.04 and HR = 2.11, 95%CI: 1.02 - 4.40, respectively). No apparent associations were found for other markers. CONCLUSION: This study identified cell proliferation and cyclin A expression as prognostic indicators of patient outcome in colorectal cancer.

Reduction of off-flavor generation in soybean homogenates: a mathematical model.

UNLABELLED: The generation of off-flavors in soybean homogenates such as n-hexanal via the lipoxygenase (LOX) pathway can be a problem in the processed food industry. Previous studies have examined the effect of using soybean varieties missing one or more of the 3 LOX isozymes on n-hexanal generation. A dynamic mathematical model of the soybean LOX pathway using ordinary differential equations was constructed using parameters estimated from existing data with the aim of predicting how n-hexanal generation could be reduced. Time-course simulations of LOX-null beans were run and compared with experimental results. Model L(2), L(3), and L(12) beans were within the range relative to the wild type found experimentally, with L(13) and L(23) beans close to the experimental range. Model L(1) beans produced much more n-hexanal relative to the wild type than those in experiments. Sensitivity analysis indicates that reducing the estimated K(m) parameter for LOX isozyme 3 (L-3) would improve the fit between model predictions and experimental results found in the literature. The model also predicts that increasing L-3 or reducing L-2 levels within beans may reduce n-hexanal generation. PRACTICAL APPLICATION: This work describes the use of mathematics to attempt to quantify the enzyme-catalyzed conversions of compounds in soybean homogenates into undesirable flavors, primarily from the compound n-hexanal. The effect of different soybean genotypes and enzyme kinetic constants was also studied, leading to recommendations on which combinations might minimize off-flavor levels and what further work might be carried out to substantiate these conclusions.

Implications of familial colorectal cancer risk profiles and microsatellite instability status.

PURPOSE: Estimating familial colorectal cancer (CRC) risk is clinically important in being able to discriminate between high- and low-risk groups. To quantify familial CRC risks associated with mismatch repair (MMR) deficient and microsatellite stable (MSS) tumors, we analyzed 2,941 population-based cases of CRC. PATIENTS AND METHODS: MMR status in CRCs was established by testing for microsatellite instability (MSI). MUTYH status was assigned by screening for Y165C and G382D variants. Age-specific relative and absolute CRC risks in first-degree relatives (FDRs) were calculated, and the most likely genetic models of familial aggregation were derived. RESULTS: CRC risks in FDRs were strongly associated with MSI status (MSI, standardized incidence ratio [SIR] = 4.28, 95% CI, 3.51 to 5.17; MSS, SIR = 1.91, 95% CI, 1.73 to 2.11), early-onset disease (MSI patient age < 55 years, SIR = 10.96, 95% CI, 8.32 to 14.17; MSS patient age < 55 years, SIR = 2.3, 95% CI, 1.88 to 2.85), and having more than one affected FDR (MSI, SIR = 10.00, 95% CI, 7.74 to 12.72; MSS, SIR = 2.78, 95% CI, 2.18 to 3.48). The familial aggregation of CRC associated with MSI cancer was parsimonious with dominant model conferring a high CRC risk at early ages. Approximately 69% of the excess familial risk in FDRs can be ascribed to MSS CRC, and although the pattern of familial risk supports recessive susceptibility in addition to MUTYH, the absolute risk of CRC is at best modest. CONCLUSION: The results from this analysis should enable an individual's risk of CRC to be more accurately estimated, thus maximizing the value of screening programs. Results also have utility in the design of genetic analyses to identify novel disease alleles.

A genome-wide scan of 10 000 gene-centric variants and colorectal cancer risk.

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.

Clinical implications of the colorectal cancer risk associated with MUTYH mutation.

PURPOSE: Biallelic mutations in the base excision DNA repair gene MUTYH predispose to colorectal cancer (CRC). Evidence that monoallelic mutations also confer an elevated CRC risk is controversial. Precise quantification of the CRC risk and the phenotype associated with MUTYH mutations is relevant to the counseling, surveillance, and clinical management of at-risk individuals. METHODS: We analyzed a population-based series of 9,268 patients with CRC and 5,064 controls for the Y179C and G396D MUTYH mutations. We related genotypes to phenotype and calculated genotype-specific CRC risks. RESULTS: Overall, biallelic mutation status conferred a 28-fold increase in CRC risk (95% CI,17.66 to 44.06); this accounted for 0.3% of CRCs in the cohort. Genotype relative risks of CRC were strongly age dependent, but penetrance was incomplete at age 60 years. CRC that developed in the context of biallelic mutations were microsatellite stable. Biallelic mutation carriers were more likely to have proximal CRC (P = 4.0 x 10(-4)) and synchronous polyps (P = 5.7 x 10(-9)) than noncarriers. The performance characteristics of clinicopathologic criteria for the identification of biallelic mutations are poor. Monoallelic mutation was not associated with an increased CRC risk (odds ratio, 1.07; 95% CI, 0.87 to 1.31). CONCLUSION: The high risk and the propensity for proximal disease associated with biallielic MUTYH mutation justify colonoscopic surveillance. Although mutation screening should be directed to patients with APC-negative polyposis and early-onset proximal MSS CRC in whom detection rates will be highest, the expanded phenotype associated with MUTYH mutation needs to be recognized. There is no evidence than monoallelic mutation status per se is clinically important.

Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk.

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)).

Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer.

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.