Publications by authors named "Richard S Houlston"

364 Publications

Genome-wide association studies of toxicity to oxaliplatin and fluoropyrimidine chemotherapy with or without cetuximab in 1800 patients with advanced colorectal cancer.

Int J Cancer 2021 Jul 16. Epub 2021 Jul 16.

Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff.

Chemotherapies administered at normal therapeutic dosages can cause significant side-effects and may result in early treatment discontinuation. Inter-individual variation in toxicity highlights the need for biomarkers to personalise treatment. We sought to identify such biomarkers by conducting 40 genome-wide association studies, together with gene and gene set analyses, for any toxicity and ten individual toxicities in 1800 patients with advanced colorectal cancer treated with oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab from the MRC COIN and COIN-B trials (385 patients received FOLFOX, 360 FOLFOX + cetuximab, 707 XELOX and 348 XELOX + cetuximab). SNPs, genes and gene sets that reached genome-wide or suggestive significance, were validated in independent patient groups. We found that MROH5 was significantly associated with neutropenia in MAGMA gene analyses in patients treated with XELOX (P = 6.6x10 ) and was independently validated in those receiving XELOX + cetuximab; Pooled P = 3.7x10 . rs13260246 at 8q21.13 was significantly associated with vomiting in patients treated with XELOX (OR = 5.0, 95% CI = 3.0-8.3, P = 9.8x10 ) but was not independently replicated. SNPs at 139 loci had suggestive associations for toxicities and lead SNPs at five of these were independently validated (rs6030266 with diarrhoea, rs1546161 with hand foot syndrome, rs9601722 with neutropenia, rs13413764 with lethargy and rs4600090 with nausea; all with Pooled P's < 5.0x10 ). In conclusion, the association of MROH5 with neutropenia and five other putative biomarkers warrant further investigation for their potential clinical utility. Despite our comprehensive genome-wide analyses of large, well characterised, clinical trials, we found a lack of common variants with modest effect sizes associated with toxicities.
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http://dx.doi.org/10.1002/ijc.33739DOI Listing
July 2021

Partitioned glioma heritability shows subtype-specific enrichment in immune cells.

Neuro Oncol 2021 Mar 20. Epub 2021 Mar 20.

Department of Medicine, Section of Epidemiology and Population Sciences, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, United States.

Background: Epidemiological studies of adult glioma have identified genetic syndromes and 25 heritable risk loci that modify individual risk for glioma, as well increased risk in association with exposure to ionizing radiation and decreased risk in association with allergies. In this analysis we assess whether there is shared genome-wide genetic architecture between glioma and atopic/autoimmune diseases.

Methods: Using summary statistics from a glioma genome-wide association studies (GWAS) meta-analysis, we identified significant enrichment for risk variants associated with gene expression changes in immune cell populations. We also estimated genetic correlations between glioma and autoimmune, atopic, and hematologic traits using LDscore regression, which leverages genome-wide single nucleotide polymorphism (SNP) associations and patterns of linkage disequilibrium.

Results: Nominally significant negative correlations were observed for glioblastoma and primary biliary cirrhosis (rg=-0.26, p=0.0228), and for non-glioblastoma gliomas and celiac disease (rg=-0.32, p=0.0109). Our analyses implicate dendritic cells (GB pHM= 0.0306 and non-GB pHM=0.0186) in mediating both glioblastoma and non-glioblastoma genetic predisposition, with glioblastoma-specific associations identified in natural killer (NK) (pHM=0.0201) and stem cells (pHM=0.0265).

Conclusions: This analysis identifies putative new associations between glioma and autoimmune conditions with genomic architecture that is inversely correlated with that of glioma and that T cells, NK cells, and myeloid cells are involved in mediating glioma predisposition. This provides further evidence that increased activation of the acquired immune system may modify individual susceptibility to glioma.
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http://dx.doi.org/10.1093/neuonc/noab072DOI Listing
March 2021

Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers.

PLoS Genet 2021 03 5;17(3):e1009254. Epub 2021 Mar 5.

University of Salzburg, Department of Biosciences and Cancer Cluster Salzburg, Salzburg, Austria.

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes rel to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites.
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http://dx.doi.org/10.1371/journal.pgen.1009254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968735PMC
March 2021

Genetically predicted physical activity levels are associated with lower colorectal cancer risk: a Mendelian randomisation study.

Br J Cancer 2021 Mar 29;124(7):1330-1338. Epub 2021 Jan 29.

Colon Cancer Genetics Group, Cancer Research UK Edinburgh Centre and Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

Background: We conducted a Mendelian randomisation (MR) study to investigate whether physical activity (PA) causes a reduction of colorectal cancer risk and to understand the contributions of effects mediated through changes in body fat.

Methods: Common genetic variants associated with self-reported moderate-to-vigorous PA (MVPA), acceleration vector magnitude PA (AMPA) and sedentary time were used as instrumental variables. To control for confounding effects of obesity, we included instrumental variables for body mass index (BMI), body fat percentage, waist circumference and arm, trunk and leg fat ratios. We analysed the effect of these instrumental variables in a colorectal cancer genome-wide association study comprising 31,197 cases and 61,770 controls of European ancestry by applying two-sample and multivariable MR study designs.

Results: We found decreased colorectal cancer risk for genetically represented measures of MVPA and AMPA that were additional to effects mediated through genetic measures of obesity. Odds ratio and 95% confidence interval (CI) per standard deviation increase in MVPA and AMPA was 0.56 (0.31, 1.01) and 0.60 (0.41, 0.88), respectively. No association has been found between sedentary time and colorectal cancer risk. The proportion of effect mediated through BMI was 2% (95% CI: 0, 14) and 32% (95% CI: 12, 46) for MVPA and AMPA, respectively.

Conclusion: These findings provide strong evidence to reinforce public health measures on preventing colorectal cancer that promote PA at a population level regardless of body fatness.
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http://dx.doi.org/10.1038/s41416-020-01236-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007642PMC
March 2021

Genome-wide association study identifies risk loci for progressive chronic lymphocytic leukemia.

Nat Commun 2021 01 28;12(1):665. Epub 2021 Jan 28.

Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, Hull, UK.

Prognostication in patients with chronic lymphocytic leukemia (CLL) is challenging due to heterogeneity in clinical course. We hypothesize that constitutional genetic variation affects disease progression and could aid prognostication. Pooling data from seven studies incorporating 842 cases identifies two genomic locations associated with time from diagnosis to treatment, including 10q26.13 (rs736456, hazard ratio (HR) = 1.78, 95% confidence interval (CI) = 1.47-2.15; P = 2.71 × 10) and 6p (rs3778076, HR = 1.99, 95% CI = 1.55-2.55; P = 5.08 × 10), which are particularly powerful prognostic markers in patients with early stage CLL otherwise characterized by low-risk features. Expression quantitative trait loci analysis identifies putative functional genes implicated in modulating B-cell receptor or innate immune responses, key pathways in CLL pathogenesis. In this work we identify rs736456 and rs3778076 as prognostic in CLL, demonstrating that disease progression is determined by constitutional genetic variation as well as known somatic drivers.
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http://dx.doi.org/10.1038/s41467-020-20822-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843618PMC
January 2021

Lack of an association between gallstone disease and bilirubin levels with risk of colorectal cancer: a Mendelian randomisation analysis.

Br J Cancer 2021 Mar 7;124(6):1169-1174. Epub 2021 Jan 7.

Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.

Background: Epidemiological studies of the relationship between gallstone disease and circulating levels of bilirubin with risk of developing colorectal cancer (CRC) have been inconsistent. To address possible confounding and reverse causation, we examine the relationship between these potential risk factors and CRC using Mendelian randomisation (MR).

Methods: We used two-sample MR to examine the relationship between genetic liability to gallstone disease and circulating levels of bilirubin with CRC in 26,397 patients and 41,481 controls. We calculated the odds ratio per genetically predicted SD unit increase in log bilirubin levels (OR) for CRC and tested for a non-zero causal effect of gallstones on CRC. Sensitivity analysis was applied to identify violations of estimator assumptions.

Results: No association between either gallstone disease (P value = 0.60) or circulating levels of bilirubin (OR = 1.00, 95% confidence interval (CI) = 0.96-1.03, P value = 0.90) with CRC was shown.

Conclusions: Despite the large scale of this study, we found no evidence for a causal relationship between either circulating levels of bilirubin or gallstone disease with risk of developing CRC. While the magnitude of effect suggested by some observational studies can confidently be excluded, we cannot exclude the possibility of smaller effect sizes and non-linear relationships.
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http://dx.doi.org/10.1038/s41416-020-01211-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961009PMC
March 2021

Copy number evolution and its relationship with patient outcome-an analysis of 178 matched presentation-relapse tumor pairs from the Myeloma XI trial.

Leukemia 2021 Jul 1;35(7):2043-2053. Epub 2020 Dec 1.

Division of Molecular Pathology, The Institute of Cancer Research, London, UK.

Structural chromosomal changes including copy number aberrations (CNAs) are a major feature of multiple myeloma (MM), however their evolution in context of modern biological therapy is not well characterized. To investigate acquisition of CNAs and their prognostic relevance in context of first-line therapy, we profiled tumor diagnosis-relapse pairs from 178 NCRI Myeloma XI (ISRCTN49407852) trial patients using digital multiplex ligation-dependent probe amplification. CNA profiles acquired at relapse differed substantially between MM subtypes: hyperdiploid (HRD) tumors evolved predominantly in branching pattern vs. linear pattern in t(4;14) vs. stable pattern in t(11;14). CNA acquisition also differed between subtypes based on CCND expression, with a marked enrichment of acquired del(17p) in CCND2 over CCND1 tumors. Acquired CNAs were not influenced by high-dose melphalan or lenalidomide maintenance randomization. A branching evolution pattern was significantly associated with inferior overall survival (OS; hazard ratio (HR) 2.61, P = 0.0048). As an individual lesion, acquisition of gain(1q) at relapse was associated with shorter OS, independent of other risk markers or time of relapse (HR = 2.00; P = 0.021). There is an increasing need for rational therapy sequencing in MM. Our data supports the value of repeat molecular profiling to characterize disease evolution and inform management of MM relapse.
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http://dx.doi.org/10.1038/s41375-020-01096-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257500PMC
July 2021

An enhanced genetic model of relapsed IGH-translocated multiple myeloma evolutionary dynamics.

Blood Cancer J 2020 10 14;10(10):101. Epub 2020 Oct 14.

Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SM2 5NG, UK.

Most patients with multiple myeloma (MM) die from progressive disease after relapse. To advance our understanding of MM evolution mechanisms, we performed whole-genome sequencing of 80 IGH-translocated tumour-normal newly diagnosed pairs and 24 matched relapsed tumours from the Myeloma XI trial. We identify multiple events as potentially important for survival and therapy-resistance at relapse including driver point mutations (e.g., TET2), translocations (MAP3K14), lengthened telomeres, and increased genomic instability (e.g., 17p deletions). Despite heterogeneous mutational processes contributing to relapsed mutations across MM subtypes, increased AID/APOBEC activity is particularly associated with shorter progression time to relapse, and contributes to higher mutational burden at relapse. In addition, we identify three enhanced major clonal evolution patterns of MM relapse, independent of treatment strategies and molecular karyotypes, questioning the viability of "evolutionary herding" approach in treating drug-resistant MM. Our data show that MM relapse is associated with acquisition of new mutations and clonal selection, and suggest APOBEC enzymes among potential targets for therapy-resistant MM.
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http://dx.doi.org/10.1038/s41408-020-00367-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560599PMC
October 2020

Searching for causal relationships of glioma: a phenome-wide Mendelian randomisation study.

Br J Cancer 2021 01 6;124(2):447-454. Epub 2020 Oct 6.

Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK.

Background: The aetiology of glioma is poorly understood. Summary data from genome-wide association studies (GWAS) can be used in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to search for glioma risk factors.

Methods: We performed an MR-PheWAS analysing 316 phenotypes, proxied by 8387 genetic variants, and summary genetic data from a GWAS of 12,488 glioma cases and 18,169 controls. Causal effects were estimated under a random-effects inverse-variance-weighted (IVW-RE) model, with robust adjusted profile score (MR-RAPS), weighted median and mode-based estimates computed to assess the robustness of findings. Odds ratios per one standard deviation increase in each phenotype were calculated for all glioma, glioblastoma (GBM) and non-GBM tumours.

Results: No significant associations (P < 1.58 × 10) were observed between phenotypes and glioma under the IVW-RE model. Suggestive associations (1.58 × 10 < P < 0.05) were observed between leukocyte telomere length (LTL) with all glioma (OR = 3.91, P = 9.24 × 10) and GBM (OR = 4.86, P = 3.23 × 10), but the association was primarily driven by the TERT variant rs2736100. Serum low-density lipoprotein cholesterol and plasma HbA1C showed suggestive associations with glioma (OR = 1.11, P = 1.39 × 10 and OR = 1.28, P = 1.73 × 10, respectively), both associations being reliant on single genetic variants.

Conclusions: Our study provides further insight into the aetiological basis of glioma for which published data have been mixed.
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http://dx.doi.org/10.1038/s41416-020-01083-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852872PMC
January 2021

Prioritisation by FIT to mitigate the impact of delays in the 2-week wait colorectal cancer referral pathway during the COVID-19 pandemic: a UK modelling study.

Gut 2021 06 27;70(6):1053-1060. Epub 2020 Aug 27.

Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK

Objective: To evaluate the impact of faecal immunochemical testing (FIT) prioritisation to mitigate the impact of delays in the colorectal cancer (CRC) urgent diagnostic (2-week-wait (2WW)) pathway consequent from the COVID-19 pandemic.

Design: We modelled the reduction in CRC survival and life years lost resultant from per-patient delays of 2-6 months in the 2WW pathway. We stratified by age group, individual-level benefit in CRC survival versus age-specific nosocomial COVID-19-related fatality per referred patient undergoing colonoscopy. We modelled mitigation strategies using thresholds of FIT triage of 2, 10 and 150 µg Hb/g to prioritise 2WW referrals for colonoscopy. To construct the underlying models, we employed 10-year net CRC survival for England 2008-2017, 2WW pathway CRC case and referral volumes and per-day-delay HRs generated from observational studies of diagnosis-to-treatment interval.

Results: Delay of 2/4/6 months across all 11 266 patients with CRC diagnosed per typical year via the 2WW pathway were estimated to result in 653/1419/2250 attributable deaths and loss of 9214/20 315/32 799 life years. Risk-benefit from urgent investigatory referral is particularly sensitive to nosocomial COVID-19 rates for patients aged >60. Prioritisation out of delay for the 18% of symptomatic referrals with FIT >10 µg Hb/g would avoid 89% of these deaths attributable to presentational/diagnostic delay while reducing immediate requirement for colonoscopy by >80%.

Conclusions: Delays in the pathway to CRC diagnosis and treatment have potential to cause significant mortality and loss of life years. FIT triage of symptomatic patients in primary care could streamline access to colonoscopy, reduce delays for true-positive CRC cases and reduce nosocomial COVID-19 mortality in older true-negative 2WW referrals. However, this strategy offers benefit only in short-term rationalisation of limited endoscopy services: the appreciable false-negative rate of FIT in symptomatic patients means most colonoscopies will still be required.
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http://dx.doi.org/10.1136/gutjnl-2020-321650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447105PMC
June 2021

Pathway Analysis of Renal Cell Carcinoma Genome-Wide Association Studies Identifies Novel Associations.

Cancer Epidemiol Biomarkers Prev 2020 10 30;29(10):2065-2069. Epub 2020 Jul 30.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.

Background: Much of the heritable risk of renal cell carcinoma (RCC) associated with common genetic variation is unexplained. New analytic approaches have been developed to increase the discovery of risk variants in genome-wide association studies (GWAS), including multi-locus testing through pathway analysis.

Methods: We conducted a pathway analysis using GWAS summary data from six previous scans (10,784 cases and 20,406 controls) and evaluated 3,678 pathways and gene sets drawn from the Molecular Signatures Database. To replicate findings, we analyzed GWAS summary data from the UK Biobank (903 cases and 451,361 controls) and the Genetic Epidemiology Research on Adult Health and Aging cohort (317 cases and 50,511 controls).

Results: We identified 14 pathways/gene sets associated with RCC in both the discovery ( < 1.36 × 10, the Bonferroni correction threshold) and replication ( < 0.05) sets, 10 of which include components of the PI3K/AKT pathway. In tests across 2,035 genes in these pathways, associations (Bonferroni corrected < 2.46 × 10 in discovery and replication sets combined) were observed for , and . The strongest SNP signal was for rs12124078 ( = 2.6 × 10; = 1.5 × 10; = 6.9 × 10), a expression quantitative trait locus.

Conclusions: Our pathway analysis implicates genetic variation within the PI3K/AKT pathway as a source of RCC heritability and identifies several promising novel susceptibility genes, including , which warrant further investigation.

Impact: Our findings illustrate the value of pathway analysis as a complementary approach to analyzing GWAS data.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0472DOI Listing
October 2020

Prediction of colorectal cancer risk based on profiling with common genetic variants.

Int J Cancer 2020 12 20;147(12):3431-3437. Epub 2020 Jul 20.

Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK.

Increasing numbers of common genetic variants associated with colorectal cancer (CRC) have been identified. Our study aimed to determine whether risk prediction based on common genetic variants might enable stratification for CRC risk. Meta-analysis of 11 genome-wide association studies comprising 16 871 cases and 26 328 controls was performed to capture CRC susceptibility variants. Genetic prediction models with several candidate polygenic risk scores (PRSs) were generated from Scottish CRC case-control studies (6478 cases and 11 043 controls) and the score with the best performance was then tested in UK Biobank (UKBB) (4800 cases and 20 287 controls). A weighted PRS of 116 CRC single nucleotide polymorphisms (wPRS ) was found with the best predictive performance, reporting a c-statistics of 0.60 and an odds ratio (OR) of 1.46 (95% confidence interval [CI] = 1.41-1.50, per SD increase) in Scottish data set. The predictive performance of this wPRS was consistently validated in UKBB data set with c-statistics of 0.61 and an OR of 1.49 (95% CI = 1.44-1.54, per SD increase). Modeling the levels of PRS with age and sex in the general UK population shows that employing genetic risk profiling can achieve a moderate degree of risk discrimination that could be helpful to identify a subpopulation with higher CRC risk due to genetic susceptibility.
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http://dx.doi.org/10.1002/ijc.33191DOI Listing
December 2020

Leveraging Genome and Phenome-Wide Association Studies to Investigate Genetic Risk of Acute Lymphoblastic Leukemia.

Cancer Epidemiol Biomarkers Prev 2020 08 28;29(8):1606-1614. Epub 2020 May 28.

Children's Health and Discovery Initiative, Department of Pediatrics, Duke University, Durham, North Carolina.

Background: Genome-wide association studies (GWAS) of childhood cancers remain limited, highlighting the need for novel analytic strategies. We describe a hybrid GWAS and phenome-wide association study (PheWAS) approach to uncover genotype-phenotype relationships and candidate risk loci, applying it to acute lymphoblastic leukemia (ALL).

Methods: PheWAS was performed for 12 ALL SNPs identified by prior GWAS and two control SNP-sets using UK Biobank data. PheWAS-traits significantly associated with ALL SNPs compared with control SNPs were assessed for association with ALL risk (959 cases, 2,624 controls) using polygenic score and Mendelian randomization analyses. Trait-associated SNPs were tested for association with ALL risk in single-SNP analyses, with replication in an independent case-control dataset (1,618 cases, 9,409 controls).

Results: Platelet count was the trait most enriched for association with known ALL risk loci. A polygenic score for platelet count (223 SNPs) was not associated with ALL risk ( = 0.82) and Mendelian randomization did not suggest a causal relationship. However, twelve platelet count-associated SNPs were nominally associated with ALL risk in COG data and three were replicated in UK data (rs10058074, rs210142, rs2836441).

Conclusions: In our hybrid GWAS-PheWAS approach, we identify pleiotropic genetic variation contributing to ALL risk and platelet count. Three SNPs known to influence platelet count were reproducibly associated with ALL risk, implicating genomic regions containing , proapoptotic protein , and in platelet production and leukemogenesis.

Impact: Incorporating PheWAS data into association studies can leverage genetic pleiotropy to identify cancer risk loci, highlighting the utility of our novel approach.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415687PMC
August 2020

Reference bias in the Illumina Isaac aligner.

Bioinformatics 2020 11;36(17):4671-4672

Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SM2 5NG 2, UK.

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http://dx.doi.org/10.1093/bioinformatics/btaa514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653636PMC
November 2020

Search for multiple myeloma risk factors using Mendelian randomization.

Blood Adv 2020 05;4(10):2172-2179

Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.

The etiology of multiple myeloma (MM) is poorly understood. Summary data from genome-wide association studies (GWASs) of multiple phenotypes can be exploited in a Mendelian randomization (MR) phenome-wide association study (PheWAS) to search for factors influencing MM risk. We performed an MR-PheWAS analyzing 249 phenotypes, proxied by 10 225 genetic variants, and summary genetic data from a GWAS of 7717 MM cases and 29 304 controls. Odds ratios (ORs) per 1 standard deviation increase in each phenotype were estimated under an inverse variance weighted random effects model. A Bonferroni-corrected threshold of P = 2 × 10-4 was considered significant, whereas P < .05 was considered suggestive of an association. Although no significant associations with MM risk were observed among the 249 phenotypes, 28 phenotypes showed evidence suggestive of association, including increased levels of serum vitamin B6 and blood carnitine (P = 1.1 × 10-3) with greater MM risk and ω-3 fatty acids (P = 5.4 × 10-4) with reduced MM risk. A suggestive association between increased telomere length and reduced MM risk was also noted; however, this association was primarily driven by the previously identified risk variant rs10936599 at 3q26 (TERC). Although not statistically significant, increased body mass index was associated with increased risk (OR, 1.10; 95% confidence interval, 0.99-1.22), supporting findings from a previous meta-analysis of prospective observational studies. Our study did not provide evidence supporting any modifiable factors examined as having a major influence on MM risk; however, it provides insight into factors for which the evidence has previously been mixed.
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http://dx.doi.org/10.1182/bloodadvances.2020001502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252541PMC
May 2020

Genomic landscape of platinum resistant and sensitive testicular cancers.

Nat Commun 2020 05 4;11(1):2189. Epub 2020 May 4.

Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK.

While most testicular germ cell tumours (TGCTs) exhibit exquisite sensitivity to platinum chemotherapy, ~10% are platinum resistant. To gain insight into the underlying mechanisms, we undertake whole exome sequencing and copy number analysis in 40 tumours from 26 cases with platinum-resistant TGCT, and combine this with published genomic data on an additional 624 TGCTs. We integrate analyses for driver mutations, mutational burden, global, arm-level and focal copy number (CN) events, and SNV and CN signatures. Albeit preliminary and observational in nature, these analyses provide support for a possible mechanistic link between early driver mutations in RAS and KIT and the widespread copy number events by which TGCT is characterised.
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http://dx.doi.org/10.1038/s41467-020-15768-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198558PMC
May 2020

Impact of mitochondrial DNA mutations in multiple myeloma.

Blood Cancer J 2020 05 1;10(5):46. Epub 2020 May 1.

Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.

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http://dx.doi.org/10.1038/s41408-020-0315-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195394PMC
May 2020

Genetic predisposition for multiple myeloma.

Leukemia 2020 03 8;34(3):697-708. Epub 2020 Jan 8.

Hematology and Transfusion Medicine, Department of Laboratory Medicine, BMC B13, 221 84, Lund, Sweden.

Multiple myeloma (MM) is the second most common blood malignancy. Epidemiological family studies going back to the 1920s have provided evidence for familial aggregation, suggesting a subset of cases have an inherited genetic background. Recently, studies aimed at explaining this phenomenon have begun to provide direct evidence for genetic predisposition to MM. Genome-wide association studies have identified common risk alleles at 24 independent loci. Sequencing studies of familial cases and kindreds have begun to identify promising candidate genes where variants with strong effects on MM risk might reside. Finally, functional studies are starting to give insight into how identified risk alleles promote the development of MM. Here, we review recent findings in MM predisposition field, and highlight open questions and future directions.
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http://dx.doi.org/10.1038/s41375-019-0703-6DOI Listing
March 2020

Identification of four novel associations for B-cell acute lymphoblastic leukaemia risk.

Nat Commun 2019 11 25;10(1):5348. Epub 2019 Nov 25.

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

There is increasing evidence for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children. To identify new risk variants for B-cell ALL (B-ALL) we conducted a meta-analysis with four GWAS (genome-wide association studies), totalling 5321 cases and 16,666 controls of European descent. We herein describe novel risk loci for B-ALL at 9q21.31 (rs76925697, P = 2.11 × 10), for high-hyperdiploid ALL at 5q31.1 (rs886285, P = 1.56 × 10) and 6p21.31 (rs210143 in BAK1, P = 2.21 × 10), and ETV6-RUNX1 ALL at 17q21.32 (rs10853104 in IGF2BP1, P = 1.82 × 10). Particularly notable are the pleiotropic effects of the BAK1 variant on multiple haematological malignancies and specific effects of IGF2BP1 on ETV6-RUNX1 ALL evidenced by both germline and somatic genomic analyses. Integration of GWAS signals with transcriptomic/epigenomic profiling and 3D chromatin interaction data for these leukaemia risk loci suggests deregulation of B-cell development and the cell cycle as central mechanisms governing genetic susceptibility to ALL.
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http://dx.doi.org/10.1038/s41467-019-13069-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877561PMC
November 2019

Genetic predisposition to mosaic Y chromosome loss in blood.

Nature 2019 11 20;575(7784):652-657. Epub 2019 Nov 20.

Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.
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http://dx.doi.org/10.1038/s41586-019-1765-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887549PMC
November 2019

Comprehensive analysis of colorectal cancer-risk loci and survival outcome: A prognostic role for CDH1 variants.

Eur J Cancer 2020 01 14;124:56-63. Epub 2019 Nov 14.

Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK. Electronic address:

Purpose: Genome-wide association studies have identified common single nucleotide polymorphisms (SNPs) at 83 loci associated with colorectal cancer (CRC) risk in European populations. Because germline variation can also influence patient outcome, we studied the relationship between these SNPs and CRC survivorship.

Experimental Design: For the 83 risk loci, 10 lead SNPs were directly genotyped, 72 were imputed and 1 was not genotyped nor imputed, in 1948 unrelated patients with advanced CRC from the clinical trials COIN and COIN-B (oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab). A Cox survival model was used for each variant, and variants classified by pathway, adjusting for known prognostic factors. We imposed a Bonferroni threshold of P = 6.6 × 10 for multiple testing. We carried out meta-analyses of published risk SNPs associated with survival.

Results: Univariate analysis identified six SNPs associated with overall survival (OS) (P < 0.05); however, only rs9939049 in CDH1 remained significant beyond the Bonferroni threshold (Hazard Ratio [HR] 1.44, 95% Confidence Intervals [CI]: 1.21-1.71, P = 5.0 × 10). Fine mapping showed that rs12597188 was the most significant SNP at this locus and remained significant after adjustment for known prognostic factors beyond multiple testing thresholds (HR 1.23, 95% CI: 1.13-1.34, P = 1.9 × 10). rs12597188 was also associated with poor response to therapy (OR 0.61, 95% CI: 0.42-0.87, P = 6.6 × 10). No combinations of SNPs within pathways were more significantly associated with survival compared with single variants alone, and no other risk SNPs were associated with survival in meta-analyses.

Conclusions: The CRC susceptibility SNP rs9939049 in CDH1 influences patient survival and warrants further evaluation as a prognostic biomarker.
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http://dx.doi.org/10.1016/j.ejca.2019.09.024DOI Listing
January 2020

Modifiable pathways for colorectal cancer: a mendelian randomisation analysis.

Lancet Gastroenterol Hepatol 2020 01 24;5(1):55-62. Epub 2019 Oct 24.

Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.

Background: Epidemiological studies have linked lifestyle, cardiometabolic, reproductive, developmental, and inflammatory factors to the risk of colorectal cancer. However, which specific factors affect risk and the strength of these effects are unknown. We aimed to examine the relationship between potentially modifiable risk factors and colorectal cancer.

Methods: We used a random-effects model to examine the relationship between 39 potentially modifiable risk factors and colorectal cancer in 26 397 patients with colorectal cancer and 41 481 controls (ie, people without colorectal cancer). These population data came from a genome-wide association study of people of European ancestry, which was amended to exclude UK BioBank data. In the model, we used genetic variants as instruments via two-sample mendelian randomisation to limit bias from confounding and reverse causation. We calculated odds ratios per genetically predicted SD unit increase in each putative risk factor (OR) for colorectal cancer risk. We did mendelian randomisation Egger regressions to identify evidence of potential violations of mendelian randomisation assumptions. A Bonferroni-corrected threshold of p=1·3 × 10 was considered significant, and p values less than 0·05 were considered to be suggestive of an association.

Findings: No putative risk factors were significantly associated with colorectal cancer risk after correction for multiple testing. However, suggestive associations with increased risk were noted for genetically predicted body fat percentage (OR 1·14 [95% CI 1·03-1·25]; p=0·0086), body-mass index (1·09 [1·01-1·17]; p=0·023), waist circumference (1·13 [1·02-1·26]; p=0·018), basal metabolic rate (1·10 [1·03-1·18]; p=0·0079), and concentrations of LDL cholesterol (1·14 [1·04-1·25]; p=0·0056), total cholesterol (1·09 [1·01-1·18]; p=0·025), circulating serum iron (1·17 [1·00-1·36]; p=0·049), and serum vitamin B12 (1·21 [1·04-1·42]; p=0·016), although potential pleiotropy among genetic variants used as instruments for vitamin B12 constrains the finding. A suggestive association was also noted between adult height and increased risk of colorectal cancer (OR 1·04 [95% CI 1·00-1·08]; p=0·032). Low blood selenium concentration had a suggestive association with decreased risk of colorectal cancer (OR 0·85 [95% CI 0·75-0·96]; p=0·0078) based on a single variant, as did plasma concentrations of interleukin-6 receptor subunit α (also based on a single variant; 0·98 [0·96-1·00]; p=0·035). Risk of colorectal cancer was not associated with any sex hormone or reproductive factor, serum calcium, or circulating 25-hydroxyvitamin D concentrations.

Interpretation: This analysis identified several modifiable targets for primary prevention of colorectal cancer, including lifestyle, obesity, and cardiometabolic factors, that should inform public health policy.

Funding: Cancer Research UK, UK Medical Research Council Human Genetics Unit Centre, DJ Fielding Medical Research Trust, EU COST Action, and the US National Cancer Institute.
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http://dx.doi.org/10.1016/S2468-1253(19)30294-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026696PMC
January 2020

Lack of association between modifiable exposures and glioma risk: a Mendelian randomization analysis.

Neuro Oncol 2020 02;22(2):207-215

Division of Molecular Pathology, The Institute of Cancer Research, London, UK.

Background: The etiological basis of glioma is poorly understood. We have used genetic markers in a Mendelian randomization (MR) framework to examine if lifestyle, cardiometabolic, and inflammatory factors influence the risk of glioma. This methodology reduces bias from confounding and is not affected by reverse causation.

Methods: We identified genetic instruments for 37 potentially modifiable risk factors and evaluated their association with glioma risk using data from a genome-wide association study of 12 488 glioma patients and 18 169 controls. We used the estimated odds ratio of glioma associated with each of the genetically defined traits to infer evidence for a causal relationship with the following exposures:Lifestyle and dietary factors-height, plasma insulin-like growth factor 1, blood carnitine, blood methionine, blood selenium, blood zinc, circulating adiponectin, circulating carotenoids, iron status, serum calcium, vitamins (A1, B12, B6, E, and 25-hydroxyvitamin D), fatty acid levels (monounsaturated, omega-3, and omega-6) and circulating fetuin-A;Cardiometabolic factors-birth weight, high density lipoprotein cholesterol, low density lipoprotein cholesterol, total cholesterol, total triglycerides, basal metabolic rate, body fat percentage, body mass index, fasting glucose, fasting proinsulin, glycated hemoglobin levels, diastolic and systolic blood pressure, waist circumference, waist-to-hip ratio; andInflammatory factors- C-reactive protein, plasma interleukin-6 receptor subunit alpha and serum immunoglobulin E.

Results: After correction for the testing of multiple potential risk factors and excluding associations driven by one single nucleotide polymorphism, no significant association with glioma risk was observed (ie, PCorrected > 0.05).

Conclusions: This study did not provide evidence supporting any of the 37 factors examined as having a significant influence on glioma risk.
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http://dx.doi.org/10.1093/neuonc/noz209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442418PMC
February 2020

Transcriptome-wide association study of multiple myeloma identifies candidate susceptibility genes.

Hum Genomics 2019 08 20;13(1):37. Epub 2019 Aug 20.

Division of Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK.

Background: While genome-wide association studies (GWAS) of multiple myeloma (MM) have identified variants at 23 regions influencing risk, the genes underlying these associations are largely unknown. To identify candidate causal genes at these regions and search for novel risk regions, we performed a multi-tissue transcriptome-wide association study (TWAS).

Results: GWAS data on 7319 MM cases and 234,385 controls was integrated with Genotype-Tissue Expression Project (GTEx) data assayed in 48 tissues (sample sizes, N = 80-491), including lymphocyte cell lines and whole blood, to predict gene expression. We identified 108 genes at 13 independent regions associated with MM risk, all of which were in 1 Mb of known MM GWAS risk variants. Of these, 94 genes, located in eight regions, had not previously been considered as a candidate gene for that locus.

Conclusions: Our findings highlight the value of leveraging expression data from multiple tissues to identify candidate genes responsible for GWAS associations which provide insight into MM tumorigenesis. Among the genes identified, a number have plausible roles in MM biology, notably APOBEC3C, APOBEC3H, APOBEC3D, APOBEC3F, APOBEC3G, or have been previously implicated in other malignancies. The genes identified in this TWAS can be explored for follow-up and validation to further understand their role in MM biology.
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http://dx.doi.org/10.1186/s40246-019-0231-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700979PMC
August 2019

Insight into genetic predisposition to chronic lymphocytic leukemia from integrative epigenomics.

Nat Commun 2019 08 9;10(1):3615. Epub 2019 Aug 9.

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036, Barcelona, Spain.

Genome-wide association studies have provided evidence for inherited genetic predisposition to chronic lymphocytic leukemia (CLL). To gain insight into the mechanisms underlying CLL risk we analyze chromatin accessibility, active regulatory elements marked by H3K27ac, and DNA methylation at 42 risk loci in up to 486 primary CLLs. We identify that risk loci are significantly enriched for active chromatin in CLL with evidence of being CLL-specific or differentially regulated in normal B-cell development. We then use in situ promoter capture Hi-C, in conjunction with gene expression data to reveal likely target genes of the risk loci. Candidate target genes are enriched for pathways related to B-cell development such as MYC and BCL2 signalling. At 14 loci the analysis highlights 63 variants as the probable functional basis of CLL risk. By integrating genetic and epigenetic information our analysis reveals novel insights into the relationship between inherited predisposition and the regulatory chromatin landscape of CLL.
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http://dx.doi.org/10.1038/s41467-019-11582-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689100PMC
August 2019

Analysis of 153 115 patients with hematological malignancies refines the spectrum of familial risk.

Blood 2019 09 8;134(12):960-969. Epub 2019 Aug 8.

Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany.

Estimating familial cancer risks is clinically important in being able to discriminate between individuals in the population at differing risk for malignancy. To gain insight into the familial risk for the different hematological malignancies and their possible inter-relationship, we analyzed data on more than 16 million individuals from the Swedish Family-Cancer Database. After identifying 153 115 patients diagnosed with a primary hematological malignancy, we quantified familial relative risks (FRRs) by calculating standardized incident ratios (SIRs) in 391 131 of their first-degree relatives. The majority of hematological malignancies showed increased FRRs for the same tumor type, with the highest FRRs being observed for mixed cellularity Hodgkin lymphoma (SIR, 16.7), lymphoplasmacytic lymphoma (SIR, 15.8), and mantle cell lymphoma (SIR, 13.3). There was evidence for pleiotropic relationships; notably, chronic lymphocytic leukemia was associated with an elevated familial risk for other B-cell tumors and myeloproliferative neoplasms. Collectively, these data provide evidence for shared etiological factors for many hematological malignancies and provide information for identifying individuals at increased risk, as well as informing future gene discovery initiatives.
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http://dx.doi.org/10.1182/blood.2019001362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789511PMC
September 2019

Mutational processes contributing to the development of multiple myeloma.

Blood Cancer J 2019 08 6;9(8):60. Epub 2019 Aug 6.

Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.

To gain insight into multiple myeloma (MM) tumorigenesis, we analyzed the mutational signatures in 874 whole-exome and 850 whole-genome data from the CoMMpass Study. We identified that coding and non-coding regions are differentially dominated by distinct single-nucleotide variant (SNV) mutational signatures, as well as five de novo structural rearrangement signatures. Mutational signatures reflective of different principle mutational processes-aging, defective DNA repair, and apolipoprotein B editing complex (APOBEC)/activation-induced deaminase activity-characterize MM. These mutational signatures show evidence of subgroup specificity-APOBEC-attributed signatures associated with MAF translocation t(14;16) and t(14;20) MM; potentially DNA repair deficiency with t(11;14) and t(4;14); and aging with hyperdiploidy. Mutational signatures beyond that associated with APOBEC are independent of established prognostic markers and appear to have relevance to predicting high-risk MM.
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http://dx.doi.org/10.1038/s41408-019-0221-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684612PMC
August 2019

A genome-wide association study identifies susceptibility loci for primary central nervous system lymphoma at 6p25.3 and 3p22.1: a LOC Network study.

Neuro Oncol 2019 08;21(8):1039-1048

(i) National Institute of Health and Medical Research (Inserm) U 1127, Paris, France, (ii) National Center for Scientific Research, Joint Research Unit 7225, Paris, France, (iii) Brain and Spine Institute (ICM), Paris, France, and (iv) Sorbonne University, Pierre and Marie Curie University, Paris 6, Paris, France.

Background: Primary central nervous system lymphoma (PCNSL) is a rare form of extra-nodal non-Hodgkin lymphoma. PCNSL is a distinct subtype of non-Hodgkin lymphoma, with over 95% of tumors belonging to the diffuse large B-cell lymphoma (DLBCL) group. We have conducted a genome-wide association study (GWAS) on immunocompetent patients to address the possibility that common genetic variants influence the risk of developing PCNSL.

Methods: We performed a meta-analysis of 2 new GWASs of PCNSL totaling 475 cases and 1134 controls of European ancestry. To increase genomic resolution, we imputed >10 million single nucleotide polymorphisms using the 1000 Genomes Project combined with UK10K as reference. In addition we performed a transcription factor binding disruption analysis and investigated the patterns of local chromatin by Capture Hi-C data.

Results: We identified independent risk loci at 3p22.1 (rs41289586, ANO10, P = 2.17 × 10-8) and 6p25.3 near EXOC2 (rs116446171, P = 1.95 x 10-13). In contrast, the lack of an association between rs41289586 and DLBCL suggests distinct germline predisposition to PCNSL and DLBCL. We found looping chromatin interactions between noncoding regions at 6p25.3 (rs11646171) with the IRF4 promoter and at 8q24.21 (rs13254990) with the MYC promoter, both genes with strong relevance to B-cell tumorigenesis.

Conclusion: To our knowledge this is the first study providing insight into the genetic predisposition to PCNSL. Our findings represent an important step in defining the contribution of common genetic variation to the risk of developing PCNSL.
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http://dx.doi.org/10.1093/neuonc/noz088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682213PMC
August 2019
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