Clinical Interpretation and Applications of Genomic Findings in Solid Tumours and Haematological Malignancy

Details

Title

Clinical Interpretation and Applications of Genomic Findings in Solid Tumours and Haematological Malignancy

Type

Stage Two

Module code

HBI117

Requirement

Compulsory

Module objective

By the end of this module Clinical Scientists in HSST will be able to analyse, synthesise, critically evaluate and apply knowledge of methods for clinical interpretation of genomic findings, including the range of methods used, to interpret genomic test results for a range of solid tumours and haematological malignancies. They will select and apply the appropriate methods to analyse data and interpret genomic findings, demonstrating the attitudes and behaviours necessary for overcoming the complexities and uncertainties that can surround interpretation. Although CCSs in Bioinformatics are unlikely to have a diagnostic caseload in the same way as a Clinical Scientist in Molecular Pathology, they will be expected to appreciate the diagnostic workflow and understand the process so they are able to apply their domain expertise in an appropriate manner. They will contribute to the reporting of diagnostic test results, and therefore the diagnosis of patients, through application of their skills and by taking part in activities such as MDTs. They will also understand the impact of diagnostic reports on patients, family members and for future clinical management.

Knowledge and understanding

By the end of this module the Clinical Scientist in HSST will be able to analyse, synthesise, evaluate and critically apply their expert knowledge to clinical diagnostic interpretation, including:

Clinical presentation of acquired cancers, for example:

• Chronic myeloid leukaemia (CML), acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML).
• Sporadic colorectal cancer and lung cancer.

The role of laboratory diagnostics, including genomics, in achieving a diagnosis Cancer as a complex disease of the genome

• Molecular classifications: nucleotide substitutions, small insertions and deletions, copy number, chromosomal rearrangements.
• Driver and passenger mutations; evolution and diversification of the cancer over time; metastatic cancer.
• Molecular characterisation of tumours, including clonal heterogeneity in a variety of sporadic cancers, e.g. sporadic colorectal cancer, sporadic breast cancer, melanoma, chronic lymphocytic leukaemia (CLL), AML.

Personalised medicine and use of clinically actionable biomarkers in the management and treatment of cancer

• Companion diagnostics or treatment with diagnostic-dependent drug.
• Current approaches for a range of cancers: detection of hot spot mutations; NGS panels for multiple cancer genes.
• Awareness of FFPE artefacts and associated issues and algorithmic solutions.
• Clinical trials.

Genetic diagnosis

• The purpose of genetic/genomic testing in a variety of scenarios and clinical pathways, including national initiatives (e.g. 100,000 Genomes Project).
• The process by which genetic/genomic findings are interpreted, discussed at the appropriate MDT and collated into the integrated report.

Treatment monitoring

• Utility of genetic and genomic testing in monitoring efficacy of treatment in cancer and named leukaemic types.
• Principles underlying quantitation of minimal residual disease.

Patient perspective

• The ethical, legal and social implications of genomic testing on patients, and the impact on family members.
• The impact of genomic findings on the patient and patient care.
• How to provide meaningful genomics information.

Evidence-based interpretation of findings

• The major tools used for automated annotation of genetic findings and limitations of their annotation sources.
• All major genomic and cancer databases used for clinical interpretation of genetic findings, including population, disease, locus-specific and general sequence databases.
• The consequences of applying control population variant frequency thresholds and demonstrate selection of appropriate thresholds for different clinical situations.
• The utility of functional studies to determine effects of variants
• RNA (or protein) studies for elucidating splice, non-coding and deep intronic variants, including importance of tissue type and alternative transcripts.
• The availability (or lack) of validated, appropriate functional assays for performing functional studies.
• How phenotype-genotype associations can be derived and how they can be proven.
• How to evaluate relevant software tools/algorithms used for prediction of variant pathogenicity, including those making predictions at nucleotide, protein and functional network levels, predictions of effects on splicing, and conservation.
• The role (including limitations) of predictive tools and previously detected variants in clinical interpretation of genetic findings.
• Awareness of inherited cancer and modes of inheritance.

Data collection and sharing

• The requirement for, and utility of, maintaining internal databases of findings, their clinical interpretation and resulting genotype–phenotype associations.
• The requirement for and utility of data sharing between clinical laboratories at national and international levels.

Best practice and accreditation

• Reporting guidelines for genetic testing in cancer, including how to describe findings, explain interpretation, recommend follow-up testing’
• The role of best practice and standards in clinical diagnostics using the examples of existing national and international guidelines.
• The role of International Standardization Organisation accreditation in this context.
• The role of risk management in the delivery of a safe, high-quality service.

Technical and clinical skills

By the end of this module Clinical Scientists in HSST will have a critical understanding of current evidence and its application to the performance and mastery of a range of technical skills. In addition, they will be able to identify suboptimal areas of practice and recommend improvements, and will:

• Ensure genomics services are delivered in clean and safe environments that are fit forpurpose, based on national best practice.
• Ensure delivery of the highest standards of health and safety in the working environment
• Use a range of major tools for automated annotation of genetic findings and know the limitations of their annotation sources.
• Somatic variant calling and tumour normal subtractions.
• Use a range of major genomic databases for clinical interpretation of genetic findings, including population, disease, locus-specific and general sequence
• Evaluate relevant software tools/algorithms used for prediction of variant pathogenicity, including those making predictions at nucleotide, protein and functional network levels, predictions of effects on splicing, and consrvation.
• Implement and evaluate a variant annotation pipeline that is appropriate to a specific genetic test, including a document describing the design, assumptions and limitations, according to best available practice.
• Compile a comprehensive casebook of variants that details the interpretational workflow that leads to the reported result, including recommendations for and examples of results of follow-up testing and family studies. The casebook should cover a wide range of tests, findings and results, and be representative of the spectrum of clinical service.

By the end of this module the Clinical Scientist in HSST will be expected to critically reflect and apply in practice a range of clinical and communication skills with respect to clinical interpretation. They will communicate effectively with the public, patients, carers, clinicians, academics and other healthcare professionals, and will:

• Contribute to the discussion of selected cases at a MDT meeting, including a defence of the bioinformatics approaches used for the interpretation of
• Describe in language that is accessible to Clinical Scientists in other specialisms, the clinical consequences of a genetic finding and then summarise and justify the evidence from bioinformatics analyses used to inform that
• Describe in language that is accessible to clinicians, the clinical consequences of a genetic finding and then summarise and justify the evidence from bioinformatics analyses used to inform that
• Draft 10 full diagnostic reports detailing a genetic finding, provide interpretation, recommend follow-up and further family
• Discuss functional validation of a genetic finding with relevant stakeholders (such as the lab delivering the functional test).
• Critically evaluate analytical results from complex
• Synthesise very complex information and relay it in a way that can outline the decision-making process to trainees, other staff and the MDT for reflection and
• Take responsibility for the legal and practical requirement for accurate and contemporaneous record keeping, ensuring compliance with national standards and provide scientific advice as required.
• Work within professional boundaries and understand the limitations and need to refer appropriately to other members of the MDT.