Interspecies transfer of RAMOSA1 orthologs and promoter cis sequences impacts maize inflorescence architecture.

Grass inflorescences support floral structures that each bear a single grain, where variation in branch architecture directly impacts yield. The maize (Zea mays) RAMOSA1 (ZmRA1) transcription factor acts as a key regulator of inflorescence development by imposing branch meristem determinacy. Here, we show RA1 transcripts accumulate in boundary domains adjacent to spikelet meristems in sorghum (Sorghum bicolor, Sb) and green millet (Setaria viridis, Sv) inflorescences similar as in the developing maize tassel and ear. To evaluate the functional conservation of syntenic RA1 orthologs and promoter cis sequences in maize, sorghum, and setaria, we utilized interspecies gene transfer and assayed genetic complementation in a common inbred background by quantifying recovery of normal branching in highly ramified ra1-R mutants. A ZmRA1 transgene that includes endogenous upstream and downstream flanking sequences recovered normal tassel and ear branching in ra1-R. Interspecies expression of two transgene variants of the SbRA1 locus, modeled as the entire endogenous tandem duplication or just the nonframeshifted downstream copy, complemented ra1-R branching defects and induced unusual fasciation and branch patterns. The SvRA1 locus lacks conserved, upstream noncoding cis sequences found in maize and sorghum; interspecies expression of a SvRA1 transgene did not or only partially recovered normal inflorescence forms. Driving expression of the SvRA1 coding region by the ZmRA1 upstream region, however, recovered normal inflorescence morphology in ra1-R. These data leveraging interspecies gene transfer suggest that cis-encoded temporal regulation of RA1 expression is a key factor in modulating branch meristem determinacy that ultimately impacts grass inflorescence architecture.

COVID-19 prevalence and mortality in patients with cancer and the effect of primary tumour subtype and patient demographics: a prospective cohort study.

BACKGROUND: Patients with cancer are purported to have poor COVID-19 outcomes. However, cancer is a heterogeneous group of diseases, encompassing a spectrum of tumour subtypes. The aim of this study was to investigate COVID-19 risk according to tumour subtype and patient demographics in patients with cancer in the UK. METHODS: We compared adult patients with cancer enrolled in the UK Coronavirus Cancer Monitoring Project (UKCCMP) cohort between March 18 and May 8, 2020, with a parallel non-COVID-19 UK cancer control population from the UK Office for National Statistics (2017 data). The primary outcome of the study was the effect of primary tumour subtype, age, and sex and on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevalence and the case-fatality rate during hospital admission. We analysed the effect of tumour subtype and patient demographics (age and sex) on prevalence and mortality from COVID-19 using univariable and multivariable models. FINDINGS: 319 (30·6%) of 1044 patients in the UKCCMP cohort died, 295 (92·5%) of whom had a cause of death recorded as due to COVID-19. The all-cause case-fatality rate in patients with cancer after SARS-CoV-2 infection was significantly associated with increasing age, rising from 0·10 in patients aged 40-49 years to 0·48 in those aged 80 years and older. Patients with haematological malignancies (leukaemia, lymphoma, and myeloma) had a more severe COVID-19 trajectory compared with patients with solid organ tumours (odds ratio [OR] 1·57, 95% CI 1·15-2·15; p<0·0043). Compared with the rest of the UKCCMP cohort, patients with leukaemia showed a significantly increased case-fatality rate (2·25, 1·13-4·57; p=0·023). After correction for age and sex, patients with haematological malignancies who had recent chemotherapy had an increased risk of death during COVID-19-associated hospital admission (OR 2·09, 95% CI 1·09-4·08; p=0·028). INTERPRETATION: Patients with cancer with different tumour types have differing susceptibility to SARS-CoV-2 infection and COVID-19 phenotypes. We generated individualised risk tables for patients with cancer, considering age, sex, and tumour subtype. Our results could be useful to assist physicians in informed risk-benefit discussions to explain COVID-19 risk and enable an evidenced-based approach to national social isolation policies. FUNDING: University of Birmingham and University of Oxford.

Maize YABBY Genes drooping leaf1 and drooping leaf2 Regulate Plant Architecture.

Leaf architecture directly influences canopy structure, consequentially affecting yield. We discovered a maize (Zea mays) mutant with aberrant leaf architecture, which we named drooping leaf1 (drl1). Pleiotropic mutations in drl1 affect leaf length and width, leaf angle, and internode length and diameter. These phenotypes are enhanced by natural variation at the drl2 enhancer locus, including reduced expression of the drl2-Mo17 allele in the Mo17 inbred. A second drl2 allele, produced by transposon mutagenesis, interacted synergistically with drl1 mutants and reduced drl2 transcript levels. The drl genes are required for proper leaf patterning, development and cell proliferation of leaf support tissues, and for restricting auricle expansion at the midrib. The paralogous loci encode maize CRABS CLAW co-orthologs in the YABBY family of transcriptional regulators. The drl genes are coexpressed in incipient and emergent leaf primordia at the shoot apex, but not in the vegetative meristem or stem. Genome-wide association studies using maize NAM-RIL (nested association mapping-recombinant inbred line) populations indicated that the drl loci reside within quantitative trait locus regions for leaf angle, leaf width, and internode length and identified rare single nucleotide polymorphisms with large phenotypic effects for the latter two traits. This study demonstrates that drl genes control the development of key agronomic traits in maize.

Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus.

BACKGROUND & AIMS: Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations. METHODS: We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls. RESULTS: We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09-1.18; P = 1.8 × 10(-11)) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 × 10(-9)). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87-0.93; P = 3.72 × 10(-9)). CONCLUSIONS: We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.

Correlation of Solid State and Solution Coordination Numbers with Infrared Spectroscopy in Five-, Six-, and Eight-Coordinate Transition Metal Complexes of DOTAM.

Three new DOTAM (1,4,7,10-tetrakis(acetamido)-1,4,7,10-tetraazacyclododecane) complexes have been synthesized and characterized by X-ray crystallography: [Co(DOTAM)]Cl2•3H2O, [Ni(DOTAM)]Cl2•4H2O, and [Cu(DOTAM)](ClO4)2•H2O. Solid state and solution IR spectroscopic features for a series of [M(DOTAM)]2+ complexes (M=Mn, Co, Cu, Ni, Ca, Zn) correlate with solid state and solution coordination numbers. [Co(DOTAM)]2+, [Ni(DOTAM)]2+, and [Zn(DOTAM)]2+ are demonstrated to be six-coordinate in both the solid state and in solution, while [Mn(DOTAM)]2+ and [Ca(DOTAM)]2+ are eight-coordinate in the solid state and remain so in solution. [Cu(DOTAM)]2+, which is five-coordinate by X-ray crystallography, is shown to increase its coordination number in solution to six-coordinate.

DNA polymerase ε and δ exonuclease domain mutations in endometrial cancer.

Accurate duplication of DNA prior to cell division is essential to suppress mutagenesis and tumour development. The high fidelity of eukaryotic DNA replication is due to a combination of accurate incorporation of nucleotides into the nascent DNA strand by DNA polymerases, the recognition and removal of mispaired nucleotides (proofreading) by the exonuclease activity of DNA polymerases δ and ε, and post-replication surveillance and repair of newly synthesized DNA by the mismatch repair (MMR) apparatus. While the contribution of defective MMR to neoplasia is well recognized, evidence that faulty DNA polymerase activity is important in cancer development has been limited. We have recently shown that germline POLE and POLD1 exonuclease domain mutations (EDMs) predispose to colorectal cancer (CRC) and, in the latter case, to endometrial cancer (EC). Somatic POLE mutations also occur in 5-10% of sporadic CRCs and underlie a hypermutator, microsatellite-stable molecular phenotype. We hypothesized that sporadic ECs might also acquire somatic POLE and/or POLD1 mutations. Here, we have found that missense POLE EDMs with good evidence of pathogenic effects are present in 7% of a set of 173 endometrial cancers, although POLD1 EDMs are uncommon. The POLE mutations localized to highly conserved residues and were strongly predicted to affect proofreading. Consistent with this, POLE-mutant tumours were hypermutated, with a high frequency of base substitutions, and an especially large relative excess of G:C>T:A transversions. All POLE EDM tumours were microsatellite stable, suggesting that defects in either DNA proofreading or MMR provide alternative mechanisms to achieve genomic instability and tumourigenesis.

Heritable site-specific mutagenesis using TALENs in maize.

Transcription activator-like effector nuclease (TALEN) technology has been utilized widely for targeted gene mutagenesis, especially for gene inactivation, in many organisms, including agriculturally important plants such as rice, wheat, tomato and barley. This report describes application of this technology to generate heritable genome modifications in maize. TALENs were employed to generate stable, heritable mutations at the maize glossy2 (gl2) locus. Transgenic lines containing mono- or di-allelic mutations were obtained from the maize genotype Hi-II at a frequency of about 10% (nine mutated events in 91 transgenic events). In addition, three of the novel alleles were tested for function in progeny seedlings, where they were able to confer the glossy phenotype. In a majority of the events, the integrated TALEN T-DNA segregated independently from the new loss of function alleles, producing mutated null-segregant progeny in T1 generation. Our results demonstrate that TALENs are an effective tool for genome mutagenesis in maize, empowering the discovery of gene function and the development of trait improvement.

Germline and somatic polymerase ε and δ mutations define a new class of hypermutated colorectal and endometrial cancers.

Polymerases ε and δ are the main enzymes that replicate eukaryotic DNA. Accurate replication occurs through Watson-Crick base pairing and also through the action of the polymerases' exonuclease (proofreading) domains. We have recently shown that germline exonuclease domain mutations (EDMs) of POLE and POLD1 confer a high risk of multiple colorectal adenomas and carcinoma (CRC). POLD1 mutations also predispose to endometrial cancer (EC). These mutations are associated with high penetrance and dominant inheritance, although the phenotype can be variable. We have named the condition polymerase proofreading-associated polyposis (PPAP). Somatic POLE EDMs have also been found in sporadic CRCs and ECs, although very few somatic POLD1 EDMs have been detected. Both the germline and the somatic DNA polymerase EDMs cause an 'ultramutated', apparently microsatellite-stable, type of cancer, sometimes leading to over a million base substitutions per tumour. Here, we present the evidence for POLE and POLD1 as important contributors to the pathogenesis of CRC and EC, and highlight some of the key questions in this emerging field.

Multiprofessional heart failure self-development framework.

OBJECTIVE: Heart failure remains a key public health priority across the globe. The median age of people with heart failure admitted to hospital in the UK is 81 years old. Many such patients transcend the standard interventions that are well characterised and evidenced in guidelines, into holistic aspects surrounding frailty, rehabilitation and social care. Previous published competency frameworks in heart failure have focused on the value of doctors, nurses and pharmacists. We aimed to provide an expert consensus on the minimum heart failure-specific competencies necessary for multiple different healthcare professionals, including physiotherapists, occupational therapists, dietitians and cardiac physiologists. METHODS: The document has been developed focussing on four main parts, (1) establishing a project working group of expert professionals, (2) a literature review of previously existing published curricula and competency frameworks, (3) consensus building, which included developing a structure to the framework with ongoing review of the contents to adapt and be inclusive for each specialty and (4) write up and dissemination to widen the impact of the project. RESULTS: The final competency framework displays competencies across seven sections; knowledge (including subheadings on heart failure syndrome, diagnosis and clinical management); general skills; heart failure-specific skills; clinical autonomy; multidisciplinary team working; teaching and education; and research and development. CONCLUSION: People with heart failure can be complex and have needs that require input from a broad range of specialties. This publication focuses on the vital impact of wider multidisciplinary groups and should help define the generic core heart failure-specific competencies needed to support future pipelines of professionals, who regularly interact with and deliver care for patients with heart failure.

Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes.

Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

Variation in use of extended pulse oximetry testing to guide decisions around home oxygen provision for ex-preterm infants; A nationwide survey of UK neonatal units.

Differences in the diagnostic approach to bronchopulmonary dysplasia (BPD) may contribute to variation in reported BPD rates. We undertook a nationwide survey of UK neonatal units (NNUs) to describe criteria applied by neonatologists to conduct pulse oximetry studies in ex-preterm infants to assess their need for supplemental oxygen near discharge, as well as criteria applied to interpret saturation studies. Responses from 112 (64.7%) NNUs demonstrated wide variation in both criteria used to select infants for assessment and thresholds for interpretation. Neither demonstrated a clear relationship with reported BPD rates. Variation in clinical practice requires further scrutiny to inform and streamline management of ex-preterm infants at risk of BPD, and potentially improve outcomes.

Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries.

Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.

Integrating genome-wide polygenic risk scores and non-genetic risk to predict colorectal cancer diagnosis using UK Biobank data: population based cohort study.

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.

Current concepts in the rehabilitation of rotator cuff related disorders.

Rotator cuff related disorders (RCRD) are common. Exercise-based rehabilitation can improve outcomes, yet uncertainty exists regarding the characteristics of these exercises. This scoping review paper summarises the key characteristics of the exercise-based rehabilitation of rotator cuff related disorders (RCRD). An iterative search process was used to capture the breadth of current evidence and a narrative summary of the data was produced. 57 papers were included. Disagreement around terminology, diagnostic standards, and outcome measures limits the comparison of the data. Rehabilitation should utilise a biopsychosocial approach, be person-centred and foster self-efficacy. Biomedically framed beliefs can create barriers to rehabilitation. Pain drivers in RCRSD are unclear, as is the influence of pain during exercise on outcomes. Expectations and preferences around pain levels should be discussed to allow the co-creation of a programme that is tolerated and therefore engaged with. The optimal parameters of exercise-based rehabilitation remain unclear; however, programmes should be individualised and progressive, with a minimum duration of 12 weeks. Supervised or home-based exercises are equally effective. Following rotator cuff repair, rehabilitation should be milestone-driven and individualised; communication across the MDT is essential. For individuals with massive rotator cuff tears, the anterior deltoid programme is a useful starting point and should be supplemented by functional rehabilitation, exercises to optimise any remaining cuff and the rest of the kinetic chain. In conclusion, exercise-based rehabilitation improves outcomes for individuals with a range of RCRD. The optimal parameters of these exercises remain unclear. Variation exists across current physiotherapy practice and post-operative rehabilitation protocols, reflecting the wide-ranging spectrum of individuals presenting with RCRD. Clinicians should use their communication and rehabilitation expertise to plan an exercise-based program in conjunction with the individual with RCRSD, which is regularly reviewed and adjusted.

Auditory fitness for duty: a review.

BACKGROUND: Auditory fitness for duty (AFFD) refers to the possession of hearing abilities sufficient for safe and effective job performance. In jobs such as law enforcement and piloting, where the ability to hear is critical to job performance and safety, hearing loss can decrease performance, even to the point of being hazardous to self and others. Tests of AFFD should provide an employer with a valid assessment of an employee's ability to perform the job safely, without discriminating against the employee purely on the basis of hearing loss. PURPOSE: The purpose of this review is to provide a basic description of the functional hearing abilities required in hearing-critical occupations, and a summary of current practices in AFFD evaluation. In addition, we suggest directions for research and standardization to ensure best practices in the evaluation of AFFD in the future. RESEARCH DESIGN: We conducted a systematic review of the English-language peer-reviewed literature in AFFD. "Popular" search engines were consulted for governmental regulations and trade journal articles. We also contacted professionals with expertise in AFFD regarding research projects, unpublished material, and current standards. RESULTS: The literature review provided information regarding the functional hearing abilities required to perform hearing-critical tasks, the development of and characteristics of AFFD protocols, and the current implementation of AFFD protocols. CONCLUSIONS: This review paper provides evidence of the need to institute job-specific AFFD protocols, move beyond the pure-tone audiogram, and establish the validity of test protocols. These needs are arguably greater now than in times past.

Evaluating the Integration of Genomics into Cancer Screening Programmes: Challenges and Opportunities.

PURPOSE OF REVIEW: As the costs of genomic testing have fallen, and our understanding of genetic susceptibility to cancers has grown, there has been increasing interest in incorporating testing for cancer susceptibility genes, and polygenic risk estimates, into population cancer screening. A growing body of evidence suggests that this would be both clinically and cost-effective. In this article, we aim to explore the frameworks used to evaluate screening programmes, evaluate whether population screening for cancer susceptibility can be assessed using these standards, and consider additional issues and outcomes of importance in this context. RECENT FINDINGS: There are tensions between traditional approaches of genetic testing (utilising tests with high sensitivity and specificity) and the principles of population screening (in which the screening test typically has low specificity), as well as the frameworks used to evaluate the two. Despite the existence of many screening guidelines, including consensus papers, these often do not align fully with broader considerations of genetic test evaluation. Population screening for genetic risk in cancer shifts the focus from diagnostics to prognostication and has wider implications for personal and familial health than existing screening programmes. In addition, understanding of the prevalence and penetrance of cancer susceptibility genes, required by many screening guidelines, may only be obtainable through population-level testing; prospective multi-disciplinary research alongside implementation will be essential. SUMMARY: Appropriate evaluation of genetic screening for cancer risk will require modification of existing screening frameworks to incorporate additional complexity of outcomes and population values. As evidence supporting population screening for cancer susceptibility mounts, development of an appropriate evaluative framework, and expansion of public dialogue will be key to informing policy.

Pattern Recognition Receptor Polymorphisms as Predictors of Oxaliplatin Benefit in Colorectal Cancer.

BACKGROUND: Constitutional loss of function (LOF) single nucleotide polymorphisms (SNPs) in pattern recognition receptors FPR1, TLR3, and TLR4 have previously been reported to predict oxaliplatin benefit in colorectal cancer. Confirmation of this association could substantially improve patient stratification. METHODS: We performed a retrospective biomarker analysis of the Short Course in Oncology Therapy (SCOT) and COIN/COIN-B trials. Participant status for LOF variants in FPR1 (rs867228), TLR3 (rs3775291), and TLR4 (rs4986790/rs4986791) was determined by genotyping array or genotype imputation. Associations between LOF variants and disease-free survival (DFS) and overall survival (OS) were analyzed by Cox regression, adjusted for confounders, using additive, dominant, and recessive genetic models. All statistical tests were two-sided. RESULTS: Our validation study populations included 2929 and 1948 patients in the SCOT and COIN/COIN-B cohorts, respectively, of whom 2728 and 1672 patients had functional status of all three SNPs determined. We found no evidence of an association between any SNP and DFS in the SCOT cohort, or with OS in either cohort, irrespective of the type of model used. This included models for which an association was previously reported for rs867228 (recessive model, multivariable-adjusted hazard ratio [HR] for DFS in SCOT = 1.19, 95% confidence interval [CI] = 0.99 to 1.45, P = .07; HR for OS in COIN/COIN-B = 0.92, 95% CI = 0.63 to 1.34, P = .66), and rs4986790 (dominant model, multivariable-adjusted HR for DFS in SCOT = 0.86, 95% CI = 0.65 to 1.13, P = .27; HR for OS in COIN/COIN-B = 1.08, 95% CI = 0.90 to 1.31, P = .40). CONCLUSION: In this prespecified analysis of two large clinical trials, we found no evidence that constitutional LOF SNPs in FPR1, TLR3, or TLR4 are associated with differential benefit from oxaliplatin. Our results suggest these SNPs are unlikely to be clinically useful biomarkers.