Integrating genome-wide polygenic risk scores and non-genetic risk to predict colorectal cancer diagnosis: a cohort study in UK Biobank

OBJECTIVE: To evaluate the benefit of combining polygenic risk scores with the QCancer-10 (colorectal cancer) prediction model for non-genetic risk to identify people at highest risk of colorectal cancer. DESIGN: Population based cohort study. SETTING: Data from the UK Biobank study, collected between March 2006 and July 2010. PARTICIPANTS: 434 587 individuals with complete data for genetics and QCancer-10 predictions were included in the QCancer-10 plus polygenic risk score modelling and validation cohorts. MAIN OUTCOME MEASURES: Prediction of colorectal cancer diagnosis by genetic, non-genetic, and combined risk models. Using data from UK Biobank, six different polygenic risk scores for colorectal cancer were developed using LDpred2 polygenic risk score software, clumping, and thresholding approaches, and a model based on genome-wide significant polymorphisms. The top performing genome-wide polygenic risk score and the score containing genome-wide significant polymorphisms were combined with QCancer-10 and performance was compared with QCancer-10 alone. Case-control (logistic regression) and time-to-event (Cox proportional hazards) analyses were used to evaluate risk model performance in men and women. RESULTS: Polygenic risk scores derived using the LDpred2 program performed best, with an odds ratio per standard deviation of 1.584 (95% confidence interval 1.536 to 1.633), and top age and sex adjusted C statistic of 0.733 (95% confidence interval 0.710 to 0.753) in logistic regression models in the validation cohort. Integrated QCancer-10 plus polygenic risk score models out-performed QCancer-10 alone. In men, the integrated LDpred2 model produced a C statistic of 0.730 (0.720 to 0.741) and explained variation of 28.2% (26.3 to 30.1), compared with 0.693 (0.682 to 0.704) and 21.0% (18.9 to 23.1) for QCancer-10 alone. In women, the C statistic for the integrated LDpred2 model was 0.687 (0.673 to 0.702) and explained variation was 21.0% (18.7 to 23.7), compared with 0.645 (0.631 to 0.659) and 12.4% (10.3 to 14.6) for QCancer-10 alone. In the top 20% of individuals at highest absolute risk, the sensitivity and specificity of the integrated LDpred2 models for predicting colorectal cancer diagnosis was 47.8% and 80.3% respectively in men, and 42.7% and 80.1% respectively in women, with increases in absolute risk in the top 5% of risk in men of 3.47-fold and in women of 2.77-fold compared with the median. Illustrative decision curve analysis indicated a small incremental improvement in net benefit with QCancer-10 plus polygenic risk score models compared with QCancer-10 alone. CONCLUSIONS: Integrating polygenic risk scores with QCancer-10 modestly improves risk prediction over use of QCancer-10 alone. Given that QCancer-10 data can be obtained relatively easily from health records, use of polygenic risk score in risk stratified population screening for colorectal cancer currently has no clear justification. The added benefit, cost effectiveness, and acceptability of polygenic risk scores should be carefully evaluated in a real life screening setting before implementation in the general population

Refinement of the associations between risk of colorectal cancer and polymorphisms on chromosomes 1q41 and 12q13.13

In genome-wide association studies (GWASs) of colorectal cancer, we have identified two genomic regions in which pairs of tagging-single nucleotide polymorphisms (tagSNPs) are associated with disease; these comprise chromosomes 1q41 (rs6691170, rs6687758) and 12q13.13 (rs7163702, rs11169552). We investigated these regions further, aiming to determine whether they contain more than one independent association signal and/or to identify the SNPs most strongly associated with disease. Genotyping of additional sample sets at the original tagSNPs showed that, for both regions, the two tagSNPs were unlikely to identify a single haplotype on which the functional variation lay. Conversely, one of the pair of SNPs did not fully capture the association signal in each region. We therefore undertook more detailed analyses, using imputation, logistic regression, genealogical analysis using the GENECLUSTER program and haplotype analysis. In the 1q41 region, the SNP rs11118883 emerged as a strong candidate based on all these analyses, sufficient to account for the signals at both rs6691170 and rs6687758. rs11118883 lies within a region with strong evidence of transcriptional regulatory activity and has been associated with expression of PDGFRB mRNA. For 12q13.13, a complex situation was found: SNP rs7972465 showed stronger association than either rs11169552 or rs7136702, and GENECLUSTER found no good evidence for a two-SNP model. However, logistic regression and haplotype analyses supported a two-SNP model, in which a signal at the SNP rs706793 was added to that at rs11169552. Post-GWAS fine-mapping studies are challenging, but the use of multiple tools can assist in identifying candidate functional variants in at least some cases

Germline MBD4-deficiency causes a multi-tumor predisposition syndrome

We report an autosomal recessive, multi-organ tumor predisposition syndrome, caused by bi-allelic loss-of-function germline variants in the base excision repair (BER) gene MBD4. We identified five individuals with bi-allelic MBD4 variants within four families and these individuals had a personal and/or family history of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma. MBD4 encodes a glycosylase involved in repair of G:T mismatches resulting from deamination of 5′-methylcytosine. The colorectal adenomas from MBD4-deficient individuals showed a mutator phenotype attributable to mutational signature SBS1, consistent with the function of MBD4. MBD4-deficient polyps harbored somatic mutations in similar driver genes to sporadic colorectal tumors, although AMER1 mutations were more common and KRAS mutations less frequent. Our findings expand the role of BER deficiencies in tumor predisposition. Inclusion of MBD4 in genetic testing for polyposis and multi-tumor phenotypes is warranted to improve disease management

Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk

Evidence for an association between compound heterozygosity for germ line mutations in the hemochromatosis (HFE) gene and increased risk of colorectal cancer

Whereas a recent study reported an increased risk of colorectal cancer associated with any HFE germ line mutation (C282Y or H63D), other investigators have concluded there is no increased risk, or that any increase is dependent on polymorphisms in HFE-interacting genes such as the transferrin receptor (TFR). We have established the frequency of HFE mutations in colorectal cancer patients (n = 327) with a family history of the disease and randomly selected controls (n = 322); this design increases greatly the study's power. Genotyping for the TRF S142G polymorphism was also conducted on a large proportion of the study group. Using PCR, restriction enzyme mapping, sequencing followed by data analysis with Fisher's exact test and logistic regression, we show that the presence of any HFE mutation (Y282 or D63) was not associated with colorectal cancer risk (P = 0.57). In contrast, individuals compound heterozygous for both mutations (15 cases versus 5 controls) had thrice the odds of developing colorectal cancer (odds ratio, 3.03; 95% confidence interval, 1.06-8.61) compared with those with a single mutation. This finding did not quite reach statistical significance after allowing for multiple post hoc testing (P observed = 0.038 versus P = 0.025, with Bonferonni correction). Overall, our data indicate that individuals with a single HFE mutation, C282Y or H63D, are unlikely predisposed to develop colorectal cancer. However, risk of colorectal cancer might be increased by compound heterozygosity for the HFE mutations in the small number of subjects studied. TFR gene polymorphism was not an independent risk factor and did not modify the disease risk associated with HFE mutation.</p

Evidence for an association between compound heterozygosity for germ line mutations in the hemochromatosis (HFE) gene and increased risk of colorectal cancer.

Whereas a recent study reported an increased risk of colorectal cancer associated with any HFE germ line mutation (C282Y or H63D), other investigators have concluded there is no increased risk, or that any increase is dependent on polymorphisms in HFE-interacting genes such as the transferrin receptor (TFR). We have established the frequency of HFE mutations in colorectal cancer patients (n = 327) with a family history of the disease and randomly selected controls (n = 322); this design increases greatly the study's power. Genotyping for the TRF S142G polymorphism was also conducted on a large proportion of the study group. Using PCR, restriction enzyme mapping, sequencing followed by data analysis with Fisher's exact test and logistic regression, we show that the presence of any HFE mutation (Y282 or D63) was not associated with colorectal cancer risk (P = 0.57). In contrast, individuals compound heterozygous for both mutations (15 cases versus 5 controls) had thrice the odds of developing colorectal cancer (odds ratio, 3.03; 95% confidence interval, 1.06-8.61) compared with those with a single mutation. This finding did not quite reach statistical significance after allowing for multiple post hoc testing (P(observed) = 0.038 versus P = 0.025, with Bonferonni correction). Overall, our data indicate that individuals with a single HFE mutation, C282Y or H63D, are unlikely predisposed to develop colorectal cancer. However, risk of colorectal cancer might be increased by compound heterozygosity for the HFE mutations in the small number of subjects studied. TFR gene polymorphism was not an independent risk factor and did not modify the disease risk associated with HFE mutation