Dataset Information

A study comparing cancer patients randomly assigned to be offered either genetic testing ‘at home’ or in hospital

ABSTRACT: Background and study aims Patients who are diagnosed with womb, bowel, or ovarian cancer that fulfill NHS genetic testing criteria are recommended to have genetic testing to see if their cancer was related to an inherited gene alteration. Identifying carriers of alterations allows novel personalised cancer treatments, prevention of second cancers, and testing of family members for cancer screening and prevention. Genetic testing requires pre-test counselling to ensure patients are informed about the impact of having a genetic test and managing the result. This ‘genetic counselling’ has traditionally been provided by genetics services. However, it is now routinely being offered by cancer-treating teams in an approach called “mainstreaming”. Currently, the demand for genetic counselling and testing is swiftly increasing and capacity constraints requires the development of new scalable cost and resource-efficient implementation models. This study will assess if pre-test counselling and genetic testing can be done using a direct-to-patient model. Participants will receive genetic testing information on a smartphone app or website that they can access at home along with counselling support through a study telephone helpline. Those who agree to testing can consent via the app and perform testing at home with a saliva genetic testing kit delivered and returned by post. In the study this direct-to-patient approach is directly compared to the standard mainstreaming approach. Who can participate? Patients aged 18 years and over diagnosed with bowel, womb, or ovarian cancer who are eligible for NHS genetic testing What does the study involve? This study compares and evaluates the uptake of genetic testing using both approaches. The researchers also assess patient satisfaction, quality-of-life, and psychological outcomes following testing, using standardized or customized questionnaires over 1 year of follow-up. Clinician opinions will be elicited. Some patients will also be interviewed to assess attitudes, experiences, and impact on emotional wellbeing. An economic analysis will be undertaken to assess the cost-effectiveness of this approach for the NHS.

DISEASE(S): Endometrial,Patients Diagnosed With Colorectal,Or Ovarian Cancer Eligible For Genetic Testing For Cancer Susceptibility Gene Variants

PROVIDER: 72075 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Type 2 diabetes (T2D) is among the leading causes of death in the U.S. Ethnic differences in T2D prevalence are evident, including especially for Native Hawaiians (NHs) who remain disproportionately affected by it. This difference in T2D susceptibility involves an interplay between genetic and environmental factors, of which epigenetic mechanisms, including DNA methylation (DNAm) provide a novel approach to investigating gene-environment interactions of health and disease. Monocytes, an innate immune cell intrinsic to the inflammatory response, are a fundamental immune cell component that likely underlies T2D pathogenesis, given their involvement in inflammation and inflammation-associated insulin resistance and metabolic dysfunction. From participants enrolled into the Multiethnic Cohort Study (MEC), who self-identified as NH (n=152), Japanese American (JA; n=119), or White (n=121), we investigated monocyte-specific DNAm patterns in participants at a baseline visit, when free of T2D, using the HumanMethylation850K (850K) to determine whether monocytes harbor an ethnic-specific epigenetic signature of T2D risk that precedes T2D diagnosis. Using an epigenome-wide association study (EWAS), we found 904 significantly (q < 0.01) differentially methylated loci (DML) at a 5% difference in DNAm between participants who remained T2D free at a 15-year follow-up (i.e., controls) and those that would be diagnosed with T2D by follow-up (i.e., incident T2D) after adjusted for age, sex, and education level. These methylation differences were enriched at regulatory regions of the genome, including intergenic and intragenic regions. Notably, these DML were able to distinctly stratify NHs by T2D risk groups, however, this signature was inapparent in Whites and JAs. Likewise, NHs in the incident T2D group displayed a higher degree of DNAm variability. Sensitivity analysis with traditional risk factors (fasting glucose and body mass index [BMI]) and neighborhood socioeconomic status (nSES) found these risk factors had minimal effect on T2D risk-associated DML. Next, using a similar approach we found ethnic-specific DML in monocytes that was able to uniquely stratify NHs, JAs, and Whites, however, in NHs this epigenetic landscape displayed a higher degree of DNAm variability. Similarly, these DML were enriched at regulatory regions of the genome. In both cases, we found genes associated with biological functions and pathways relevant to monocyte functionality, including immune activation and cellular metabolism. Due to the higher degree of epigenetic variability in NHs, including especially NHs with T2D risk, we investigated differentially variable CpGs associated with T2D risk and ethnic-differences. We found differentially variable CpGs between T2D risk groups were able to stratify NHs with and without T2D risk, whereas it was unresolvable in JAs and Whites. Ethnic-specific DNAm variability clustered each ethnic population distinctly, and NH controls were further partitioned from NHs with T2D risk. Our findings suggest monocytes harbor a unique DNAm signature associated with T2D risk, which may be related to ethnic differences that underlie DNAm variability in monocytes. The increased epigenetic variability in monocytes from NHs may underlie epigenetic plasticity that could allow these cells to readily respond to adverse environmental conditions throughout the life course that may underlie long-term disease risk, whereas in other less susceptible populations with similar environmental exposure, this epigenetic plasticity may not be apparent in monocytes.

Project description:In the past years several protocols for the proteomic profiling of plasma membrane proteins have been described. Nevertheless, comparative analyses have mainly focused on different variations of one approach [1-3]. To pave the way to high-performance differential plasma membrane proteomics, we compared sulfo-NHS-SS-biotinylation, aminooxy-biotinylation and surface coating with silica beads to isolate plasma membrane proteins for subsequent analysis by one-dimensional gel-free liquid chromatography mass spectrometry. Absolute and relative numbers of plasma membrane proteins and reproducibility parameters on a qualitative and quantitative level were assessed. Sulfo-NHS-SS-biotinylation outperformed aminooxy-biotinylation and surface coating using silica beads for most of the monitored criteria. We further simplified this procedure by introducing a competitive biotin elution strategy, for which the average plasma membrane annotated protein fraction amounted to 54 % (347 proteins). Moreover, purified non-plasma membrane annotated proteins and plasma membrane annotated proteins displayed similarly high reproducibility suggesting specific co-purification. In fact, the non-plasma membrane annotated data was extremely enriched for direct interactors of purified plasma membrane proteins. Computational analysis using additional databases and prediction tools revealed that in total over 90 % of the purified proteins were associated with the plasma membrane. The modified sulfo-NHS-SS-biotinylation protocol was validated by tracking changes in the plasma membrane proteome composition induced by genetic alteration and drug treatment. GPI-anchored proteins were depleted in plasma membrane purifications from cells deficient in the GPI transamidase component PIGS; and treatment of cells with tunicamycin significantly reduced the abundance of N-glycoproteins in surface purifications. Altogether, this study introduces an improved, filter-free sulfo-NHS-SS-biotinylation protocol and demonstrates it to be a specific, effective and reproducible method to isolate proteins associated with the plasma membrane, thus enabling future large-scale comparative cell surface mappings.

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A study comparing cancer patients randomly assigned to be offered either genetic testing ‘at home’ or in hospital

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