Academics, clinicians, and students worldwide can join our research community, the Genomics England Clinical Interpretations Partnership (GECIP, for short).
Research projects for Inherited cancer predisposition
Mutational burden in the regulatory network of breast cancer susceptibility genes
Project Lead
Borbala Mifsud
Project Date
08/09/2020
Lay Summary
The majority of the genome is non-coding and therefore variants in these regions do not affect protein structure or function directly. However, there is a large fraction of the non-coding genome that is involved in the regulation of gene activity. We are studying genetic variation present in the regulatory elements of breast cancer risk genes in the NGRL and pwill use in depth computational analysis to understand their effect on breast cancer development.
The majority of the genome is non-coding and therefore variants in these regions do not affect protein structure or function directly. However, there is a large fraction of the non-coding genome that is involved in the regulation of gene activity. We are studying genetic variation present in the regulatory elements of breast cancer risk genes in the NGRL and pwill use in depth computational analysis to understand their effect on breast cancer development.
Reclassification of variants of uncertain significance (VUS) in breast cancer risk genes from the Qatari hereditary cancer screening program
Project Lead
Borbala Mifsud
Project Date
08/09/2020
Lay Summary
Pathogenic variants in breast cancer associated genes confer a high risk for the patient, and there are available prophylactic treatment options. However, patients, who have variants of uncertain significance (VUS) in these genes, are not offered these treatments, as there is no evidence of their increased risk. Patients carrying VUS are offered treatment and prevention based on their personal and family histories until the VUS are reclassified. We aim to perform computational analyses and use prevalence and phenotype association data from the NGRL to reclassify VUS variants, found in 9 breast cancer risk genes in the Qatari hereditary cancer screening program, and validate our results in an in vitro system.
Pathogenic variants in breast cancer associated genes confer a high risk for the patient, and there are available prophylactic treatment options. However, patients, who have variants of uncertain significance (VUS) in these genes, are not offered these treatments, as there is no evidence of their increased risk. Patients carrying VUS are offered treatment and prevention based on their personal and family histories until the VUS are reclassified. We aim to perform computational analyses and use prevalence and phenotype association data from the NGRL to reclassify VUS variants, found in 9 breast cancer risk genes in the Qatari hereditary cancer screening program, and validate our results in an in vitro system.
Genetic mechanisms in Tuberous Sclerosis (TSC) No mutation identified (NMI) patients
Project Lead
Hannah West
Project Date
01/06/2020
Lay Summary
Tuberous Sclerosis Complex (TSC) is a genetic condition which causes the growth of non cancerous tumours in the brain, lungs, heart, skin and kidneys, as well as seizures and intellectually disability. Genetic changes in two genes (called TSC1 and TSC2) are known to cause TSC. In up to 25% of people with symptoms of TSC, a change in these two genes can't be found and these individuals are referred to as 'no mutation identified' (NMI). This may be due to a technical issues associated with a particular method used to find these genetic changes or because the genetic change is found in another gene which is yet to be found. Application of new methods which can 'read' all of an individuals genes to look for genetic changes which cause TSC may help to find the causes of TSC symptoms in NMI patients.
Tuberous Sclerosis Complex (TSC) is a genetic condition which causes the growth of non cancerous tumours in the brain, lungs, heart, skin and kidneys, as well as seizures and intellectually disability. Genetic changes in two genes (called TSC1 and TSC2) are known to cause TSC. In up to 25% of people with symptoms of TSC, a change in these two genes can't be found and these individuals are referred to as 'no mutation identified' (NMI). This may be due to a technical issues associated with a particular method used to find these genetic changes or because the genetic change is found in another gene which is yet to be found. Application of new methods which can 'read' all of an individuals genes to look for genetic changes which cause TSC may help to find the causes of TSC symptoms in NMI patients.
Association between neurofibromatosis type 1 loss-of-function mutation and prognostic outcomes in patients with cancer
Project Lead
Alvina Lai
Project Date
07/11/2019
Lay Summary
Neurofibromatosis type 1 is an autosomal dominant genetic disorder that may predispose individuals to developing cancer. Neurofibromatosis type 1 is caused by loss-of-function mutation in neurofibromin 1 (NF1), however the pathophysiology of NF1 is still understudied in the context of malignancy due to its rare nature. Preliminary results have demonstrated the utility of a ‘phenotype risk score’ (PheRS) algorithm in confirming a significant association of PheRS and carrier status for pathogenic variants in NF1. This project will investigate the clinical and genetic features associated with NF1 mutation in patients with cancer. Harnessing rich longitudinal electronic health records from secondary care and the national cancer registry, results arising from this work could increase our understanding of the clinical trajectories of patients with NF1 mutation and associations with a wide range of prognostic and therapeutic outcomes.
Neurofibromatosis type 1 is an autosomal dominant genetic disorder that may predispose individuals to developing cancer. Neurofibromatosis type 1 is caused by loss-of-function mutation in neurofibromin 1 (NF1), however the pathophysiology of NF1 is still understudied in the context of malignancy due to its rare nature. Preliminary results have demonstrated the utility of a ‘phenotype risk score’ (PheRS) algorithm in confirming a significant association of PheRS and carrier status for pathogenic variants in NF1. This project will investigate the clinical and genetic features associated with NF1 mutation in patients with cancer. Harnessing rich longitudinal electronic health records from secondary care and the national cancer registry, results arising from this work could increase our understanding of the clinical trajectories of patients with NF1 mutation and associations with a wide range of prognostic and therapeutic outcomes.
SMARCA4 Variant Analysis
Project Lead
William Foulkes
Project Date
09/07/2019
Lay Summary
Genetic variants in the gene SMARCA4 can lead to a rare ovarian cancer called Small Cell Carcinoma of the Ovary Hypercalcemic Type (SCCOHT) as well as to a developmental disorder called Coffin-Siris syndrome (CSS). However, not all persons carrying SMARCA4 variants develop these conditions, and some individual variants can be associated with only one or the other, but not both. In order to better help counsel women who carry SMARCA4 variants about their clinical options, we will conduct a comprehensive review of all information linked to SMARCA4 germline variants observed in the Genomics England genomes to improve our understanding of the link between each variant and the conditions associated with this variant, if any.
Genetic variants in the gene SMARCA4 can lead to a rare ovarian cancer called Small Cell Carcinoma of the Ovary Hypercalcemic Type (SCCOHT) as well as to a developmental disorder called Coffin-Siris syndrome (CSS). However, not all persons carrying SMARCA4 variants develop these conditions, and some individual variants can be associated with only one or the other, but not both. In order to better help counsel women who carry SMARCA4 variants about their clinical options, we will conduct a comprehensive review of all information linked to SMARCA4 germline variants observed in the Genomics England genomes to improve our understanding of the link between each variant and the conditions associated with this variant, if any.
Using mutational signatures and functional genomics to classify breast cancer gene variants
Project Lead
William Foulkes
Project Date
17/04/2019
Lay Summary
Genetic screening has become a routine part of medical care for breast cancer patients. The information can be used for cancer prevention in relatives and to guide therapy choices in patients. However, there are still many genetic variants identified via screening for which the impact on the risk of breast cancer is unknown, leaving patients and families with a lot of uncertainty. Our goal is to develop a novel strategy that uses the genetic information contained in the patient’s tumour to determine if a genetic variant is disease-causing or not. This would bypass the need to study each variant using lengthy molecular laboratory tests. We will analyse the genomes of multiple tumours from breast cancer patients who carry variants of unknown significance in several breast cancer predisposition genes. We will study the same variants in a traditional molecular laboratory setting using validated functional assays and compare the results. If successfully implemented, our new classification strategy will resolve the uncertainty for many patients whose genetic tests reported a variant of unknown significance and will improve the efficacy of genetic testing for future breast cancer patients.
Genetic screening has become a routine part of medical care for breast cancer patients. The information can be used for cancer prevention in relatives and to guide therapy choices in patients. However, there are still many genetic variants identified via screening for which the impact on the risk of breast cancer is unknown, leaving patients and families with a lot of uncertainty. Our goal is to develop a novel strategy that uses the genetic information contained in the patient’s tumour to determine if a genetic variant is disease-causing or not. This would bypass the need to study each variant using lengthy molecular laboratory tests. We will analyse the genomes of multiple tumours from breast cancer patients who carry variants of unknown significance in several breast cancer predisposition genes. We will study the same variants in a traditional molecular laboratory setting using validated functional assays and compare the results. If successfully implemented, our new classification strategy will resolve the uncertainty for many patients whose genetic tests reported a variant of unknown significance and will improve the efficacy of genetic testing for future breast cancer patients.
Role of functional non coding variants in the germline contributing to ovarian cancer predisposition
Project Lead
Suzana Ezquina
Project Date
27/03/2019
Lay Summary
Ovarian cancer is the fifth most prevalent gynaecological cancer in the western countries. The most common subtype is high grade serous ovarian cancer, with a late diagnosis and a poor prognosis. The susceptibility is shown to be increased in families with history of ovarian cancer, and having a first degree relative increases the risk by three fold. Some genes have already been associated with increased inherited susceptibility, but little is known about the other regions of the genome. Our research aims to discover novel variants in non-coding and regulatory regions, associated with the inheritance of the susceptibility of ovarian cancer.
Ovarian cancer is the fifth most prevalent gynaecological cancer in the western countries. The most common subtype is high grade serous ovarian cancer, with a late diagnosis and a poor prognosis. The susceptibility is shown to be increased in families with history of ovarian cancer, and having a first degree relative increases the risk by three fold. Some genes have already been associated with increased inherited susceptibility, but little is known about the other regions of the genome. Our research aims to discover novel variants in non-coding and regulatory regions, associated with the inheritance of the susceptibility of ovarian cancer.
Identifying genes and variants that predispose to multiple types of cancer
Project Lead
Ian Tomlinson
Project Date
02/01/2019
Lay Summary
The study of rare inherited cancer syndromes has shown that, in almost all cases, mutation carriers have an increased risk of several cancer types. This is also true of many of the common, lower risk cancer predisposition genes. We plan to look across multiple types of cancer for new cancer predisposition genes. In most cases, these samples will be derived from the paired normal samples within the cancer part of the 100KGP. These searches will complement our disease-specific work in the colorectal and endometrial cancer GeCIPs and our work in the Inherited Cancer Domain. We expect the most likely class of inherited predisposition gene that we shall identify will be relatively uncommon variation with a moderate effect on cancer risk.
The study of rare inherited cancer syndromes has shown that, in almost all cases, mutation carriers have an increased risk of several cancer types. This is also true of many of the common, lower risk cancer predisposition genes. We plan to look across multiple types of cancer for new cancer predisposition genes. In most cases, these samples will be derived from the paired normal samples within the cancer part of the 100KGP. These searches will complement our disease-specific work in the colorectal and endometrial cancer GeCIPs and our work in the Inherited Cancer Domain. We expect the most likely class of inherited predisposition gene that we shall identify will be relatively uncommon variation with a moderate effect on cancer risk.
Genetic Predisposition to renal and neuroendocrine tumours
Project Lead
Eamonn Maher
Project Date
12/10/2018
Lay Summary
Our research looks to uncover what are the genetic factors that make some individuals susceptible to developing kidney and/or neuroendocrine tumours such as phaeochromocytoma or paraganglioma. With this information we will be able to better identify those at risk and develop apropriate cancer prevention strategies
Our research looks to uncover what are the genetic factors that make some individuals susceptible to developing kidney and/or neuroendocrine tumours such as phaeochromocytoma or paraganglioma. With this information we will be able to better identify those at risk and develop apropriate cancer prevention strategies
Genetic presisposition to multiple primary tumours
Project Lead
Eamonn Maher
Project Date
11/10/2018
Lay Summary
Our research aims to uncover why some individuals will develop multiple tumours so that we might be better identify those at risk and so develop cancer prevention strategies
Our research aims to uncover why some individuals will develop multiple tumours so that we might be better identify those at risk and so develop cancer prevention strategies
Exploring the Association between Germline Variants in CBFB and Familial Breast Cancer
Project Lead
Stephanie Greville-Heygate
Project Date
27/09/2018
Lay Summary
We have found a potentially important alteration in a gene called CBFB in a mother and daughter who have both been affected by breast cancer. CBFB is not currently known to be linked to inherited breast cancer. Therefore, we would like to explore more data to see if other families with a history of breast cancer have alterations in CBFB, which may suggest that CBFB gene alterations cause a predisposition to cancer.
We have found a potentially important alteration in a gene called CBFB in a mother and daughter who have both been affected by breast cancer. CBFB is not currently known to be linked to inherited breast cancer. Therefore, we would like to explore more data to see if other families with a history of breast cancer have alterations in CBFB, which may suggest that CBFB gene alterations cause a predisposition to cancer.
Identifying variation-intolerant genomic ‘black holes’ in intronic and exonic regions
Project Lead
Marc Tischkowitz
Project Date
21/08/2018
Lay Summary
The majority of genetic variants identified in humans have no effect on disease predisposition. Identifying those variants which do play a role in disease can prove difficult and often researchers rely on pathogenicity predicting tools to assess their variant of interest. Within protein coding regions (exons), variants are categorised by their effect on the translated protein. However in non-coding regions, variant pathogenicity is harder to ascertain, particularly outside known regulatory regions. By identifying genomic ‘black holes’ carrying little to no genetic variation in large numbers of individuals, intronic and exonic regions can be identified that are invariable and therefore may contain novel genetic elements that are key to cellular processes. This will aid researchers in predicting the pathogenicity of both intronic and exonic variants and may aid in identifying novel disease associations.
The majority of genetic variants identified in humans have no effect on disease predisposition. Identifying those variants which do play a role in disease can prove difficult and often researchers rely on pathogenicity predicting tools to assess their variant of interest. Within protein coding regions (exons), variants are categorised by their effect on the translated protein. However in non-coding regions, variant pathogenicity is harder to ascertain, particularly outside known regulatory regions. By identifying genomic ‘black holes’ carrying little to no genetic variation in large numbers of individuals, intronic and exonic regions can be identified that are invariable and therefore may contain novel genetic elements that are key to cellular processes. This will aid researchers in predicting the pathogenicity of both intronic and exonic variants and may aid in identifying novel disease associations.
Aggregating variants into introns, exons and protein domains to highlight disease associated genomic regions
Project Lead
Marc Tischkowitz
Project Date
20/08/2018
Lay Summary
Understanding how individuals are predisposed to develop rare diseases will help clinicians to identify those at greatest risk and to create personalised disease management strategies. This study aims to identify genomic regions which increase an individuals risk of disease development when mutated. By aggregating variants into small sections, such as exons (protein coding regions), introns (non-coding regions), and protein domains (known functional blocks of proteins), we increase statistical power to detect regions that may be functionally active, and therefore when disrupted may lead to one rare disease phenotype.
Understanding how individuals are predisposed to develop rare diseases will help clinicians to identify those at greatest risk and to create personalised disease management strategies. This study aims to identify genomic regions which increase an individuals risk of disease development when mutated. By aggregating variants into small sections, such as exons (protein coding regions), introns (non-coding regions), and protein domains (known functional blocks of proteins), we increase statistical power to detect regions that may be functionally active, and therefore when disrupted may lead to one rare disease phenotype.
Using Cancer Phenotypes to Improve Cancer Susceptibility Gene Classification
Project Lead
Stephanie Greville-Heygate
Project Date
27/07/2018
Lay Summary
Breast cancer is the most frequently diagnosed cancer amongst women in the UK. Improvements in genetic sequencing technology and a reduction in cost are facilitating access to cancer genetic testing in mainstream breast cancer care. This technology has the potential to benefit patients by identifying individuals that have an increased risk of developing breast cancer. It may also cause harm through the identification of genetic variants where the association with breast cancer risk is less clear. These are called Variants of Uncertain Clinical Significance (VUS). This project aims to determine whether the variants that are present in a breast cancer and also the appearance of that cancer under a microscope can be used to better interpret these VUS.
Breast cancer is the most frequently diagnosed cancer amongst women in the UK. Improvements in genetic sequencing technology and a reduction in cost are facilitating access to cancer genetic testing in mainstream breast cancer care. This technology has the potential to benefit patients by identifying individuals that have an increased risk of developing breast cancer. It may also cause harm through the identification of genetic variants where the association with breast cancer risk is less clear. These are called Variants of Uncertain Clinical Significance (VUS). This project aims to determine whether the variants that are present in a breast cancer and also the appearance of that cancer under a microscope can be used to better interpret these VUS.
Analysis of Fanconi Anaemia genes across 100K
Project Lead
Marc Tischkowitz
Project Date
21/07/2018
Lay Summary
Fanconi Anemia is a rare recessive peadiatric syndome caused by over 20 different genes. Some of the genes such as FANCN/PALB2 also cause cancers in adults who do not have FA but carry a mutation in one gene copy. Very little is known about many of the FA genes, how they cause cancer and congenital anomalies, and what diseases they might predispose to in the adult setting. We would therefore like to look at somatic and germline variants in these genes across 100K
Fanconi Anemia is a rare recessive peadiatric syndome caused by over 20 different genes. Some of the genes such as FANCN/PALB2 also cause cancers in adults who do not have FA but carry a mutation in one gene copy. Very little is known about many of the FA genes, how they cause cancer and congenital anomalies, and what diseases they might predispose to in the adult setting. We would therefore like to look at somatic and germline variants in these genes across 100K
Analysis of CDH1 and related genes across 100K
Project Lead
Marc Tischkowitz
Project Date
20/07/2018
Lay Summary
CDH1 germline pathogenic variants are known to cause gastric cancers and lobular breast cancers. but they may also predispose to other cancer types. Variants have also been linked to cleft palate. We would like to look at CDH1 germline and somatic variants across the whole 100K cohort to identify new associations with this gene
CDH1 germline pathogenic variants are known to cause gastric cancers and lobular breast cancers. but they may also predispose to other cancer types. Variants have also been linked to cleft palate. We would like to look at CDH1 germline and somatic variants across the whole 100K cohort to identify new associations with this gene
Landscape of Pathogenic Germline Variants in Cancer
Project Lead
Ian Tomlinson
Project Date
08/06/2018
Lay Summary
Deciphering the inherited genetic basis of cancer has three key clinical benefits: (i) prevention of cancer by identifying and managing genetically high-risk individuals; (ii) identification of new targets for anticancer therapy and prophylaxis; and (iii) providing a route to better understanding of cancer at a fundamental level.
Deciphering the inherited genetic basis of cancer has three key clinical benefits: (i) prevention of cancer by identifying and managing genetically high-risk individuals; (ii) identification of new targets for anticancer therapy and prophylaxis; and (iii) providing a route to better understanding of cancer at a fundamental level.
Genetic Predisposition to Multiple Primary Cancers
Project Lead
Clare Turnbull
Project Date
07/06/2018
Lay Summary
Individuals affected by multiple different cancers may have underlying genetic factors contributing to their disease. Identifying these potential risk factors, both known and new, will aid the clinical management of these patients.
Individuals affected by multiple different cancers may have underlying genetic factors contributing to their disease. Identifying these potential risk factors, both known and new, will aid the clinical management of these patients.
Characterising predisposition to rhabdomyosarcomas and other DICER1-related childhood tumours
Project Lead
Mae Goldgraben
Project Date
01/06/2018
Lay Summary
Childhood cancers are believed to be more strongly linked to inherited gene alterations compared to adult cancers, where family background explains only a small proportion of patient cases. We will use genomic data available from Genomics England to examine the genetic variations that predispose these children to cancer. This work will help to better understand the causes of cancer in childhood, aid the earlier diagnosis, therapy and possibly even pave the way to a cure for children at the initial stages of developing these cancers.
Childhood cancers are believed to be more strongly linked to inherited gene alterations compared to adult cancers, where family background explains only a small proportion of patient cases. We will use genomic data available from Genomics England to examine the genetic variations that predispose these children to cancer. This work will help to better understand the causes of cancer in childhood, aid the earlier diagnosis, therapy and possibly even pave the way to a cure for children at the initial stages of developing these cancers.
Genomic and chromosomal instability sequence markers in relation to fertility, early pregnancy and cancers of the reproductive tissues.
Project Lead
Anna Mantzouratou
Project Date
07/10/2021
Lay Summary
Infertility has many different causes and a large cohort of couples experience infertility during their reproductive life. It can manifest because of factors influencing males, like poor sperm a parameters, influencing females, like endometriosis or influencing embryo development like the presence of an extra chromosome in Down’s syndrome pregnancies. Couples can experience repeated implantation failure and recurrent miscarriage due to primary or secondary infertility. Because the causes of the condition are so heterogeneous, it is difficult to design and complete studies that involve large populations of participants with similar characteristics. For this reason a targeted approach of smaller, but very highly selected population studies could allow for more detailed examination of the genome of the participants and the different subgroups that exist among them. This study examines and deciphers whole genomes from highly selected patient populations and involves the use of the 100000 genomes project database (Genomics England) as well as genomic data produced by our research group. The aim of the analysis is the identification of specific sets of factors in parental physiology and genetic makeup that can be associated with certain types of infertility and foetal abnormalities. As a more complex picture of a polygenetic risk is arising for human health, the results from these targeted population studies can help in the identification and prediction of genetic risk for heterogeneous conditions and towards a personalised approach to reproductive healthcare.
Infertility has many different causes and a large cohort of couples experience infertility during their reproductive life. It can manifest because of factors influencing males, like poor sperm a parameters, influencing females, like endometriosis or influencing embryo development like the presence of an extra chromosome in Down’s syndrome pregnancies. Couples can experience repeated implantation failure and recurrent miscarriage due to primary or secondary infertility. Because the causes of the condition are so heterogeneous, it is difficult to design and complete studies that involve large populations of participants with similar characteristics. For this reason a targeted approach of smaller, but very highly selected population studies could allow for more detailed examination of the genome of the participants and the different subgroups that exist among them. This study examines and deciphers whole genomes from highly selected patient populations and involves the use of the 100000 genomes project database (Genomics England) as well as genomic data produced by our research group. The aim of the analysis is the identification of specific sets of factors in parental physiology and genetic makeup that can be associated with certain types of infertility and foetal abnormalities. As a more complex picture of a polygenetic risk is arising for human health, the results from these targeted population studies can help in the identification and prediction of genetic risk for heterogeneous conditions and towards a personalised approach to reproductive healthcare.
Inherited cancer predisposition research plan
Full details of the research proposed by this domain
