Jewish cultural and religious factors and uptake of population-based BRCA testing across denominations: a cohort study.

OBJECTIVE: To evaluate the association of Jewish cultural and religious identity and denominational affiliation with interest in, intention to undertake and uptake of population-based BRCA (Breast Cancer Gene)-testing. DESIGN: Cohort-study set within recruitment to GCaPPS-trial (ISRCTN73338115). SETTING: London Ashkenazi-Jewish (AJ) population. POPULATION OR SAMPLE: AJ men and women, >18 years. METHODS: Participants were self-referred, and attended recruitment clinics (clusters) for pre-test counselling. Subsequently consenting individuals underwent BRCA testing. Participants self-identified to one Jewish denomination: Conservative/Liberal/Reform/Traditional/Orthodox/Unaffiliated. Validated scales measured Jewish Cultural-Identity (JI) and Jewish Religious-identity (JR). Four-item Likert-scales analysed initial 'interest' and 'intention to test' pre-counselling. Item-Response-Theory and graded-response models, modelled responses to JI and JR scales. Ordered/multinomial logistic regression modelling evaluated association of JI-scale, JR-scale and Jewish Denominational affiliation on interest, intention and uptake of BRCA testing. MAIN OUTCOME MEASURES: Interest, intention, uptake of BRCA testing. RESULTS: In all, 935 AJ women/men of mean age = 53.8 (S.D = 15.02) years, received pre-test education and counselling through 256 recruitment clinic clusters (median cluster size = 3). Denominational affiliations included Conservative/Masorti = 91 (10.2%); Liberal = 82 (9.2%), Reform = 135 (15.1%), Traditional = 212 (23.7%), Orthodox = 239 (26.7%); and Unaffiliated/Non-practising = 135 (15.1%). Overall BRCA testing uptake was 88%. Pre-counselling, 96% expressed interest and 60% intention to test. JI and JR scores were highest for Orthodox, followed by Conservative/Masorti, Traditional, Reform, Liberal and Unaffiliated Jewish denominations. Regression modelling showed no significant association between overall Jewish Cultural or Religious Identity with either interest, intention or uptake of BRCA testing. Interest, intention and uptake of BRCA testing was not significantly associated with denominational affiliation. CONCLUSIONS: Jewish religious/cultural identity and denominational affiliation do not appear to influence interest, intention or uptake of population-based BRCA testing. BRCA testing was robust across all Jewish denominations. TWEETABLE ABSTRACT: Jewish cultural/religious factors do not affect BRCA testing, with robust uptake seen across all denominational affiliations.

Population structure and relatedness estimates in a Mexican sample.

Population stratification (PS) is a confounding factor in genome-wide association studies (GWASs) and also an interesting process itself. Latin American populations have mixed genetic ancestry, which may account for PS. We have analyzed the relatedness, by means of the identity-by-descent (IBD) estimations, in a sample of 1805 individuals and 1.006.703 autosomal mutations from a case-control study of colorectal cancer in Mexico. When using the recommended protocol for quality control assessment, 402 should have been removed due to relatedness. Our purpose was to analyze this value in the context of an admixed population. For that aim, we reanalyzed the sample using two software designed for admixed populations, obtaining estimates of 110 and 70 related individuals to remove. The results showed that the first estimation of relatedness was an effect of the higher Native American contribution in part of the data samples, being a confounding factor for IBD estimations. We conclude in the importance of considering PS and genetic ancestry in order to avoid spurious results, not only in GWAS but also in relatedness analysis.

Randomised trial of population-based BRCA testing in Ashkenazi Jews: long-term outcomes.

OBJECTIVE: Unselected population-based BRCA testing provides the opportunity to apply genomics on a population-scale to maximise primary prevention for breast-and-ovarian cancer. We compare long-term outcomes of population-based and family-history (FH)/clinical-criteria-based BRCA testing on psychological health and quality of life. DESIGN: Randomised controlled trial (RCT) (ISRCTN73338115) GCaPPS, with two-arms: (i) population-screening (PS); (ii) FH/clinical-criteria-based testing. SETTING: North London Ashkenazi-Jewish (AJ) population. POPULATION/SAMPLE: AJ women/men. METHODS: Population-based RCT (1:1). Participants were recruited through self-referral, following pre-test genetic counselling from the North London AJ population. INCLUSION CRITERIA: AJ women/men >18 years old; exclusion-criteria: prior BRCA testing or first-degree relatives of BRCA-carriers. INTERVENTIONS: Genetic testing for three Jewish BRCA founder-mutations: 185delAG (c.68_69delAG), 5382insC (c.5266dupC) and 6174delT (c.5946delT), for (i) all participants in PS arm; (ii) those fulfilling FH/clinical criteria in FH arm. Linear mixed models and appropriate contrast tests were used to analyse the impact of BRCA testing on psychological and quality-of-life outcomes over 3 years. MAIN OUTCOME MEASURES: Validated questionnaires (HADS/MICRA/HAI/SF12) used to analyse psychological wellbeing/quality-of-life outcomes at baseline/1-year/2-year/3-year follow up. RESULTS: In all, 1034 individuals (691 women, 343 men) were randomised to PS (n = 530) or FH (n = 504) arms. There was a statistically significant decrease in anxiety (P = 0.046) and total anxiety-&-depression scores (P = 0.0.012) in the PS arm compared with the FH arm over 3 years. No significant difference was observed between the FH and PS arms for depression, health-anxiety, distress, uncertainty, quality-of-life or experience scores associated with BRCA testing. Contrast tests showed a decrease in anxiety (P = 0.018), health-anxiety (P < 0.0005) and quality-of-life (P = 0.004) scores in both PS and FH groups over time. Eighteen of 30 (60%) BRCA carriers identified did not fulfil clinical criteria for BRCA testing. Total BRCA prevalence was 2.9% (95% CI 1.97-4.12%), BRCA1 prevalence was 1.55% (95% CI 0.89-2.5%) and BRCA2 prevalence was 1.35% (95% CI 0.74-2.26%). CONCLUSION: Population-based AJ BRCA testing does not adversely affect long-term psychological wellbeing or quality-of-life, decreases anxiety and could identify up to 150% additional BRCA carriers. TWEETABLE ABSTRACT: Population BRCA testing in Ashkenazi Jews reduces anxiety and does not adversely affect psychological health or quality of life.

Attitude towards and factors affecting uptake of population-based BRCA testing in the Ashkenazi Jewish population: a cohort study.

OBJECTIVE: To evaluate factors affecting unselected population-based BRCA testing in Ashkenazi Jews (AJ). DESIGN: Cohort-study set within recruitment to the GCaPPS trial (ISRCTN73338115). SETTING: North London AJ population. POPULATION OR SAMPLE: Ashkenazi Jews women/men >18 years, recruited through self-referral. METHODS: Ashkenazi Jews women/men underwent pre-test counselling for BRCA testing through recruitment clinics (clusters). Consenting individuals provided blood samples for BRCA testing. Data were collected on socio-demographic/family history/knowledge/psychological well-being along with benefits/risks/cultural influences (18-item questionnaire measuring 'attitude'). Four-item Likert-scales analysed initial 'interest' and 'intention-to-test' pre-counselling. Uni- and multivariable logistic regression models evaluated factors affecting uptake/interest/intention to undergo BRCA testing. Statistical inference was based on cluster robust standard errors and joint Wald tests for significance. Item-Response Theory and graded-response models modelled responses to 18-item questionnaire. MAIN OUTCOME MEASURES: Interest, intention, uptake, attitude towards BRCA testing. RESULTS: A total of 935 individuals (women = 67%/men = 33%; mean age = 53.8 (SD = 15.02) years) underwent pre-test genetic-counselling. During the pre-counselling, 96% expressed interest in and 60% indicated a clear intention to undergo BRCA testing. Subsequently, 88% opted for BRCA testing. BRCA-related knowledge (P = 0.013) and degree-level education (P = 0.01) were positively and negatively (respectively) associated with intention-to-test. Being married/cohabiting had four-fold higher odds for BRCA testing uptake (P = 0.009). Perceived benefits were associated with higher pre-counselling odds for interest in and intention to undergo BRCA testing. Reduced uncertainty/reassurance were the most important factors contributing to decision-making. Increased importance/concern towards risks/limitations (confidentiality/insurance/emotional impact/inability to prevent cancer/marriage ability/ethnic focus/stigmatisation) were significantly associated with lower odds of uptake of BRCA testing, and discriminated between acceptors and decliners. Male gender/degree-level education (P = 0.001) had weaker correlations, whereas having children showed stronger (P = 0.005) associations with attitudes towards BRCA testing. CONCLUSIONS: BRCA testing in the AJ population has high acceptability. Pre-test counselling increases awareness of disadvantages/limitations of BRCA testing, influencing final cost-benefit perception and decision-making on undergoing testing. TWEETABLE ABSTRACT: BRCA testing in Ashkenazi Jews has high acceptability and uptake. Pre-test counselling facilitates informed decision-making.

Translational study identifies XPF and MUS81 as predictive biomarkers for oxaliplatin-based peri-operative chemotherapy in patients with esophageal adenocarcinoma.

Oxaliplatin-based chemotherapy is used to treat patients with esophageal adenocarcinoma (EAC), but no biomarkers are currently available for patient selection. We performed a prospective, clinical trial to identify potential biomarkers associated with clinical outcomes. Tumor tissue was obtained from 38 patients with resectable EAC before and after 2 cycles of oxaliplatin-fluorouracil chemotherapy. Pre-treatment mRNA expression of 280 DNA repair (DNAR) genes was tested for association with histopathological regression at surgery, disease-free survival (DFS) and overall survival (OS). High expression of 13 DNA damage repair genes was associated with DFS less than one year (P < 0.05); expression of 11 DNAR genes were associated with worse OS (P < 0.05). From clinical associations with outcomes, two genes, ERCC1 and EME1, were identified as candidate biomarkers. In cell lines in vitro, we showed the mechanism of action related to repair of oxaliplatin-induced DNA damage by depletion and knockout of protein binding partners of the candidate biomarkers, XPF and MUS81 respectively. In clinical samples from the clinical trial, pre-treatment XPF protein levels were associated with pathological response, and MUS81 protein was associated with 1-year DFS. XPF and MUS81 merit further validation in prospective clinical trials as biomarkers that may predict clinical response of EAC to oxaliplatin-based chemotherapy.

Prognostic markers for colorectal cancer: estimating ploidy and stroma.

Background: We report here the prognostic value of ploidy and digital tumour-stromal morphometric analyses using material from 2624 patients with early stage colorectal cancer (CRC). Patients and methods: DNA content (ploidy) and stroma-tumour fraction were estimated using automated digital imaging systems and DNA was extracted from sections of formalin-fixed paraffin-embedded (FFPE) tissue for analysis of microsatellite instability. Samples were available from 1092 patients recruited to the QUASAR 2 trial and two large observational series (Gloucester, n = 954; Oslo University Hospital, n = 578). Resultant biomarkers were analysed for prognostic impact using 5-year cancer-specific survival (CSS) as the clinical end point. Results: Ploidy and stroma-tumour fraction were significantly prognostic in a multivariate model adjusted for age, adjuvant treatment, and pathological T-stage in stage II patients, and the combination of ploidy and stroma-tumour fraction was found to stratify these patients into three clinically useful groups; 5-year CSS 90% versus 83% versus 73% [hazard ratio (HR) = 1.77 (95% confidence interval (95% CI): 1.13-2.77) and HR = 2.95 (95% CI: 1.73-5.03), P < 0.001]. Conclusion: A novel biomarker, combining estimates of ploidy and stroma-tumour fraction, sampled from FFPE tissue, identifies stage II CRC patients with low, intermediate or high risk of CRC disease specific death, and can reliably stratify clinically relevant patient sub-populations with differential risks of tumour recurrence and may support choice of adjuvant therapy for these individuals.

Implications of polygenic risk for personalised colorectal cancer screening.

BACKGROUND: We modelled the utility of applying a personalised screening approach for colorectal cancer (CRC) when compared with standard age-based screening. In this personalised screening approach, eligibility is determined by absolute risk which is calculated from age and polygenic risk score (PRS), where the PRS is relative risk attributable to common genetic variation. In contrast, eligibility in age-based screening is determined only by age. DESIGN: We calculated absolute risks of CRC from UK population age structure, incidence and mortality rate data, and a PRS distribution which we derived for the 37 known CRC susceptibility variants. We compared the number of CRC cases potentially detectable by personalised and age-based screening. Using Genome-Wide Complex Trait Analysis to calculate the heritability attributable to common variation, we repeated the analysis assuming all common CRC risk variants were known. RESULTS: Based on the known CRC variants, individuals with a PRS in the top 1% have a 2.9-fold increased CRC risk over the population median. Compared with age-based screening (aged 60: 10-year absolute risk 1.96% in men, 1.19% in women, as per the UK NHS National Bowel Screening Programme), personalised screening of individuals aged 55-69 at the same risk would lead to 16% fewer men and 17% fewer women being eligible for screening with 10% and 8%, respectively, fewer screen-detected cases. If all susceptibility variants were known, individuals with a PRS in the top 1% would have an estimated 7.7-fold increased risk. Personalised screening would then result in 26% fewer men and women being eligible for screening with 7% and 5% fewer screen-detected cases. CONCLUSION: Personalised screening using PRS has the potential to optimise population screening for CRC and to define those likely to maximally benefit from chemoprevention. There are however significant technical and operational details to be addressed before any such programme is introduced.

A systematic review and meta-analysis of somatic and germline DNA sequence biomarkers of esophageal cancer survival, therapy response and stage.

INTRODUCTION: There is an urgent need for biomarkers to help predict prognosis and guide management of esophageal cancer. This review identifies, evaluates and meta-analyses the evidence for reported somatic and germline DNA sequence biomarkers of outcome and stage. METHODS: A systematic review was carried out of the PubMed, EMBASE and Cochrane databases (20 August 2014), in conjunction with the ASCO Level of Evidence scale for biomarker research. Meta-analyses were carried out for all reported markers associated with outcome measures by more than one study. RESULTS: Four thousand and four articles were identified, 762 retrieved and 182 studies included. There were 65 reported markers of survival or recurrence 12 (18.5%) were excluded due to multiple comparisons. Following meta-analysis, significant associations were seen for six tumor variants (mutant TP53 and PIK3CA, copy number gain of ERBB2/HER2, CCND1 and FGF3, and chromosomal instability/ploidy) and seven germline polymorphisms: ERCC1 rs3212986, ERCC2 rs1799793, TP53 rs1042522, MDM2 rs2279744, TYMS rs34743033, ABCB1 rs1045642 and MTHFR rs1801133. Twelve germline markers of treatment complications were reported; 10 were excluded. Two tumor and 15 germline markers (11 excluded) of chemo (radio)therapy response were reported. Following meta-analysis, associations were demonstrated for mutant TP53, ERCC1 rs11615 and XRCC1 rs25487. There were 41 tumor/germline reported markers of stage; 27 (65.9%) were excluded. CONCLUSIONS: Numerous DNA markers of outcome and stage have been reported, yet few are backed by high-quality evidence. Despite this, a small number of variants appear reliable. These merit evaluation in prospective trials, within the context of high-throughput sequencing and gene expression.

Whole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden.

Bladder cancers are a leading cause of death from malignancy. Molecular markers might predict disease progression and behaviour more accurately than the available prognostic factors. Here we use whole-genome sequencing to identify somatic mutations and chromosomal changes in 14 bladder cancers of different grades and stages. As well as detecting the known bladder cancer driver mutations, we report the identification of recurrent protein-inactivating mutations in CDKN1A and FAT1. The former are not mutually exclusive with TP53 mutations or MDM2 amplification, showing that CDKN1A dysfunction is not simply an alternative mechanism for p53 pathway inactivation. We find strong positive associations between higher tumour stage/grade and greater clonal diversity, the number of somatic mutations and the burden of copy number changes. In principle, the identification of sub-clones with greater diversity and/or mutation burden within early-stage or low-grade tumours could identify lesions with a high risk of invasive progression.

FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium.

BACKGROUND: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. METHODS: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. RESULTS: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. CONCLUSION: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.

A genome-wide association study on copy-number variation identifies a 11q11 loss as a candidate susceptibility variant for colorectal cancer.

Colorectal cancer (CRC) is a complex disease, and therefore its development is determined by the combination of both environmental factors and genetic variants. Although genome-wide association studies (GWAS) of SNP variation have conveniently identified 20 genetic variants so far, a significant proportion of the observed heritability is yet to be explained. Common copy-number variants (CNVs) are one of the most important genomic sources of variability, and hence a potential source to explain part of this missing genetic fraction. Therefore, we have performed a GWAS on CNVs to explore the relationship between common structural variation and CRC development. Phase 1 of the GWAS consisted of 881 cases and 667 controls from a Spanish cohort. Copy-number status was validated by quantitative PCR for each of those common CNVs potentially associated with CRC in phase I. Subsequently, SNPs were chosen as proxies for the validated CNVs for phase II replication (1,342 Spanish cases and 1,874 Spanish controls). Four common CNVs were found to be associated with CRC and were further replicated in Phase II. Finally, we found that SNP rs1944682, tagging a 11q11 CNV, was nominally associated with CRC susceptibility (p value = 0.039; OR = 1.122). This locus has been previously related to extreme obesity phenotypes, which could suggest a relationship between body weight and CRC susceptibility.

Germline CDH1 mutations in bilateral lobular carcinoma in situ.

BACKGROUND: Invasive lobular breast cancer (ILC) and lobular carcinoma in situ (LCIS) are characterised by loss of E-cadherin expression. However germline CDH1 mutations are rare in cases of ILC with no family history of hereditary diffuse gastric cancer (HDGC) and have not been described in women with LCIS. METHODS: We screened the CDH1 gene in 50 cases of bilateral LCIS/ILC using Sanger sequencing and MLPA. RESULTS: Sanger sequencing revealed four pathogenic germline mutations, including a novel splicing mutation (c.48+1G>A). The remaining three (c.1465insC, c.1942G>T, c.2398delC) have been previously described. All four cases had bilateral LCIS +/- ILC and no family history of gastric cancer. CONCLUSION: CDH1 germline mutations have not been previously described in women with LCIS. We have shown that germline CDH1 mutations are associated with early onset of bilateral LCIS with or without ILC in women without a family history of gastric cancer. CDH1 mutation screening should be considered in women with early onset of bilateral LCIS/ILC with no family history of HDGC.

Technical and implementation issues in using next-generation sequencing of cancers in clinical practice.

Next-generation sequencing (NGS) of cancer genomes promises to revolutionise oncology, with the ability to design and use targeted drugs, to predict outcome and response, and to classify tumours. It is continually becoming cheaper, faster and more reliable, with the capability to identify rare yet clinically important somatic mutations. Technical challenges include sequencing samples of low quality and/or quantity, reliable identification of structural and copy number variation, and assessment of intratumour heterogeneity. Once these problems are overcome, the use of the data to guide clinical decision making is not straightforward, and there is a risk of premature use of molecular changes to guide patient management in the absence of supporting evidence. Paradoxically, NGS may simply move the bottleneck of personalised medicine from data acquisition to the identification of reliable biomarkers. Standardised cancer NGS data collection on an international scale would be a significant step towards optimising patient care.

A study of genomic instability in early preneoplastic colonic lesions.

It is difficult to explain the differential rates of progression of premalignant colonic lesions and differences in behaviour of morphologically similar lesions. Heterogeneity for microsatellite instability (MSI) and promoter methylation in driving these phenomena forward may explain this; however, no previous analysis has examined this in detail at the gland level, the smallest unit of colorectal premalignant lesions. We aimed to carry out an analysis of gland level genomic instability for MSI and promoter methylation. MSI occurred significantly more frequently (20%) in colonic glands than has previously been observed in whole colorectal polyps. Significant promoter methylation was seen in MLH1, PMS2, MLH3 and MSH3 as well as significant heterogeneity for both MSI and promoter methylation. Methylation and MSI may have a significant role in driving forward colorectal carcinogenesis, although in the case of MSI, this association is less clear as it occurs significantly more frequently than previously thought, and may simply be a passenger in the adenoma-carcinoma sequence. Promoter methylation in MLH1, MLH3, MSH3 and PMS2 was also found to be significantly associated with MSI and should be investigated further. A total of 273 colorectal glands (126 hyperplastic, 147 adenomatous) were isolated via laser capture microdissection (targeted at regions of MLH1 loss) from 93 colonic polyps and tested for MSI, and promoter methylation of the DNA mismatch repair genes MLH1, MSH2, MLH3, MSH6, PMS2, MGMT and MLH3 via methylation specific multiplex ligation-dependent probe amplification. Logistic regression modelling was then used to identify significant associations between promoter methylation and gland histological type and MSI status.

Pharmacogenomics in colorectal cancer: a genome-wide association study to predict toxicity after 5-fluorouracil or FOLFOX administration.

The development of genotyping technologies has allowed for wider screening for inherited causes of variable outcomes following drug administration. We have performed a genome-wide association study (GWAS) on 221 colorectal cancer (CRC) patients that had been treated with 5-fluorouracil (5-FU), either alone or in combination with oxaliplatin (FOLFOX). A validation set of 791 patients was also studied. Seven SNPs (rs16857540, rs2465403, rs10876844, rs10784749, rs17626122, rs7325568 and rs4243761) showed evidence of association (pooled P-values 0.020, 9.426E-03, 0.010, 0.017, 0.042, 2.302E-04, 2.803E-03) with adverse drug reactions (ADRs). This is the first study to explore the genetic basis of inter-individual variation in toxicity responses to the administration of 5-FU or FOLFOX in CRC patients on a genome-wide scale.

Different APC genotypes in proximal and distal sporadic colorectal cancers suggest distinct WNT/ß-catenin signalling thresholds for tumourigenesis.

Biallelic protein-truncating mutations in the adenomatous polyposis coli (APC) gene are prevalent in sporadic colorectal cancer (CRC). Mutations may not be fully inactivating, instead producing WNT/ß-catenin signalling levels 'just-right' for tumourigenesis. However, the spectrum of optimal APC genotypes accounting for both hits, and the influence of clinicopathological features on genotype selection remain undefined. We analysed 630 sporadic CRCs for APC mutations and loss of heterozygosity (LOH) using sequencing and single-nucleotide polymorphism microarrays, respectively. Truncating APC mutations and/or LOH were detected in 75% of CRCs. Most truncating mutations occurred within a mutation cluster region (MCR; codons 1282-1581) leaving 1-3 intact 20 amino-acid repeats (20AARs) and abolishing all Ser-Ala-Met-Pro (SAMP) repeats. Cancers commonly had one MCR mutation plus either LOH or another mutation 5' to the MCR. LOH was associated with mutations leaving 1 intact 20AAR. MCR mutations leaving 1 vs 2-3 intact 20AARs were associated with 5' mutations disrupting or leaving intact the armadillo-repeat domain, respectively. Cancers with three hits had an over-representation of mutations upstream of codon 184, in the alternatively spliced region of exon 9, and 3' to the MCR. Microsatellite unstable cancers showed hyper-mutation at MCR mono- and di-nucleotide repeats, leaving 2-3 intact 20AARs. Proximal and distal cancers exhibited different preferred APC genotypes, leaving a total of 2 or 3 and 0 to 2 intact 20AARs, respectively. In conclusion, APC genotypes in sporadic CRCs demonstrate 'fine-tuned' interdependence of hits by type and location, consistent with selection for particular residual levels of WNT/ß-catenin signalling, with different 'optimal' thresholds for proximal and distal cancers.

The TERT variant rs2736100 is associated with colorectal cancer risk.

BACKGROUND: Polymorphic variation at the 5p15.33 (TERT-CLPTM1L) locus is associated with the risk of many cancers but a relationship with colorectal cancer (CRC) risk has yet to be defined. METHODS: We used data from six genome-wide association studies (GWAS) of CRC, linkage disequilibrium mapping and imputation, to examine the relationship between 73 single-nucleotide polymorphisms at 5p15.33 and CRC risk in detail. RESULTS: rs2736100, which localises to intron 2 of TERT, provided the strongest evidence of an association with CRC (P=2.28 × 10⁻4). The association was also shown in an independent series of 10 047 CRC cases and 6918 controls (P=0.02). A meta-analysis of all seven studies (totalling 16 039 cases, 16 430 controls) provided increased evidence of association (P=2.49 × 10⁻5; per allele odds ratio=1.07). The association of rs2736100 on CRC risk was shown to be independent of 15 low-penetrance variants previously identified. CONCLUSION: The rs2736100 association demonstrates an influence of variation at 5p15.33 on CRC risk and further evidence that the 5p15.33 (TERT-CLPTM1L) locus has pleiotropic effects (reflecting generic or lineage-specific effects) on cancer risk.

Common genetic variation contributes significantly to the risk of childhood B-cell precursor acute lymphoblastic leukemia.

Recent genome-wide association studies (GWAS) have provided the first unambiguous evidence that common genetic variation influences the risk of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), identifying risk single-nucleotide polymorphisms (SNPs) localizing to 7p12.2, 9p21.3, 10q21.2 and 14q11.2. The testing of SNPs individually for an association in GWA studies necessitates the imposition of a very stringent P-value to address the issue of multiple testing. While this reduces false positives, real associations may be missed and therefore any estimate of the total heritability will be negatively biased. Using GWAS data on 823 BCP-ALL cases by considering all typed SNPs simultaneously, we have calculated that 24% of the total variation in BCP-ALL risk is accounted for common genetic variation (95% confidence interval 6-42%). Our findings provide support for a polygenic basis for susceptibility to BCP-ALL and have wider implications for future searches for novel disease-causing risk variants.

TERC polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres.

BACKGROUND AND AIMS: Shorter telomeres have been associated with increased risk of malignancy, including colorectal cancer (CRC). Telomere length is heritable and may be an intermediate phenotype linked to genetic susceptibility to CRC. METHODS: In a large sample, the study investigated whether candidate single nucleotide polymorphisms (SNP) in 'telomere biology' genes were associated with telomere length in leucocytes. SNP associated with an increased risk of CRC were searched for separately. RESULTS: Carriers of the common allele at SNP rs10936599, near the telomerase RNA component (TERC) locus, had significantly longer telomeres. It was independently found that the same rs10936599 allele was associated with increased risk of both CRC and colorectal adenomas. Neither telomere length nor CRC risk was associated with variation near telomerase reverse transcriptase or other telomere biology genes. In silico analysis showed that SNP rs2293607 was strongly correlated with rs10936599, mapped within TERC transcripts, had a predicted effect on messenger RNA folding and lay at a reported transcription factor binding site. TERC mRNA were expressed, differing only at the alleles of rs2293607, in CRC cell line HCT116. The long-telomere/CRC-risk allele was associated with higher levels of TERC mRNA and the formation of longer telomeres. CONCLUSIONS: Common genetic variation at TERC is associated with both longer telomeres and an increased risk of CRC, a potential mechanism being reduced levels of cell senescence or death. This finding is somewhat paradoxical, given retrospective studies reporting that CRC cases have shorter telomeres than controls. One possibility is that that association actually results from poorer survival in patients with longer telomeres.