Principal Investigator: Professor James Allan
Department: Northern Institute for Cancer Research
Institution: Newcastle UniversityTags: 16583, aetiology, AML, GWAS, leukaemia, myeloid, survival
Leukaemia and Lymphoma Research, grant #13044
1a: We will characterise acute myeloid leukaemia (AML) cases for natural variants in the human genome (termed single nucleotide polymorphisms; SNPs) and compare the frequency to healthy control populations. To date we have developed a case series of approximately 3500 AML cases and request access to SNP data from UK biobank participants to use as a control reference group. We also request access to SNP data from all UK Biobank participants who develop AML. Completion of this project will allow us to identify genetic variants associated with risk of developing AML and that affect response to chemotherapy, informing on disease biology.
1b: This project will identify natural variants in the human genome that affect individual risk of developing acute myeloid leukaemia (AML) and determine response to chemotherapy. Completion of this project will identify genes and cellular pathways that are involved in development of this devastating condition and that regulate disease progression. It is anticipated that this project will yield new targets for therapy and allow for the application of personalised medicine to improve the outcome of patients with AML. As such, this project meets the UK Biobank’s purpose because it is health-related and in the public interest.
1c: We have characterised approximately 2500 AML patients of European ancestry for common variants in the human genome. By comparing variant frequencies with UK healthy controls genotyped on the same platform, we have used these data to identify genes putatively associated with risk of AML. As a replication study, we have established an additional case series of approximately 1200 AML patients. As a control reference group for the validation study we request access to genetic variation data from individuals of European ancestry who took part in the UK Biobank study.
1d: We request access to genetic data (Affymetrix Axiom CEL files and genotyping data) from all UK biobank participants. Our request relates to all UK Biobank participants.
We propose to extend our study investigating AML to also include CLL.
Chronic lymphocytic leukaemia (CLL) is defined by an accumulation of >5×109/ml mature CD5 positive (CD5+) clonal B cells, with a characteristic immunophenotype. These cells can accumulate in peripheral blood, bone marrow and lymph nodes. CLL is the commonest leukaemia in the Western world, with an age‐adjusted incidence rate of 4.2 per 100,000 people. It is typically seen in the older population, and the median age at diagnosis is 72 years.
In this project extension we will characterise CLL cases for natural variants in the human genome (termed single nucleotide polymorphisms; SNPs) and compare these to healthy control populations. We will use these data to identify SNPs that associate with risk of developing CLL and that also predict disease progression and outcome in CLL patients.
Previous work and pilot studies investigating the genetic epidemiology of CLL
In addition to our ongoing work on AML, we have also contributed to large international collaborative projects investigating the genetic epidemiology of CLL, which has led to numerous high profile publications (Di Bernardo et al, 2008; Allan et al, 2008; Crowther-Swanepoel et al, 2010; Speedy et al, 2014; Sava et al, 2014; Kandaswamy et al, 2016; Law et al, 2017a; Law et al, 2017b).These studies have been successful in identifying several constitutional genetic variants that associate with risk of developing CLL and prognosis following diagnosis.
UK Biobank CLL Case dataset
In order to continue our studies investigating the genetic epidemiology of CLL we request access to genetic and phenotypic data identifying UK Biobank participants diagnosed with CLL. Specifically, CLL cases will be identified by a diagnosis in the following categories:
2041 Chronic lymphoid leukaemia
C91.1 Chronic lymphocytic leukaemia
We request access to Affymetrix Axiom CEL files and genotyping data from all UK Biobank participants (already approved as part of our AML project). We also request all available demographic, clinical, diagnostic, treatment and survival/outcome data for all UK Biobank CLL cases, including future updates relating to survival and outcome. Specifically, the date of diagnosis and also the date of first treatment are requested, if available.
Methodology and statistical analysis
Data handling, quality control cleaning and statistical analysis will be conducted as described in the original application (#16583).