Genetics/Genomics: role of genes in diagnosis and/risk and in personalised medicine

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1 Genetics/Genomics: role of genes in diagnosis and/risk and in personalised medicine Lynn Greenhalgh, Macmillan Cancer and General Clinical Geneticist

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7 Cancer Genetics Service Cancer is common 1 in 3 of us will get cancer at some point in our life

8 Cancer Genetics Service Inherited cancers are rare 5-10% of all cancers

9 New Referrals to the Cancer Genetics Service Number of new referrals

10 New referrals to the cancer genetics service

11 Cancer Genetics Service - traditional Low risk families counselled at primary care Moderate risk counselled at local hospital High risk families counselled by a specialised cancer genetics service and genetic testing offered if appropriate as well as offering advice on risk reducing strategies

12 Cancer Genetics Service moving forwards Low risk families counselled at primary care Moderate and some high risk counselled at local hospital and more simple genetic testing offered in specific situations High risk families counselled by a specialised cancer genetics service and both simple genetic and more complex genomic testing offered where appropriate as well as offering advice on risk reducing strategies

13 Breast/Ovarian Cancer Referrals Majority of the referrals Family history clinics GPs Gynaecologists Mostly high risk but some moderate Assessment for ovarian screening

14 Bowel cancer referrals GPs, colorectal services FAP HNPCC Peutz Jeghers Moderate risk

15 Other referrals Von Hippel Lindau Li Fraumeni Cowden syndrome Retinoblastoma Other cancer predisposition syndromes Complex family histories

16 Familial breast cancer Classification and care of people at risk of familial breast cancer and management of breast cancer and related risks in people with a family history of breast cancer Issued: June 2013 NICE clinical guideline 164

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18 Management decisions - based on genetic test results for ladies affected by cancer who are BRCA carriers Surgical options for ladies with breast cancer Maintenance therapy options (lynparza) for ladies with ovarian cancer

19 Management decisions - based on genetic test results for female relatives of BRCA carriers Risk reducing breast surgery Risk reducing BSO Chemoprevention

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21 Potential impact of NICE guidance Still being assessed Who will organise and pay for testing What is the proposed patient pathway This is good news for patients impact on cancer treatment This is good news for their families screening programmes

22 Genetic testing Genetic testing is available to people at lower risk Genetic testing is available to unaffected people There are potentially more genes to test Genetic testing can potentially be offered by non geneticists

23 Genetic testing for a small number of genes Diagnostic Searching an entire gene looking for a coding error Lengthy (several months but TAT decreasing) Expensive (~ but decreasing) Test results Mutation Uninformative Unclassified variant Predicitve Looking for 1 particular gene change already identified within the family Quicker turnaround (4 weeks) Cheaper (~ 150) Test results Yes No

24 Overall contribution of different genes to the genetic causes of inherited predisposition to cancer

25 Panel Gene Testing not yet for cancer predisposition in Liverpool

26 Is there a role for whole genome sequencing?

27 Main difference between genetics and genomics genetics scrutinises the functioning and composition of the gene(s) genomics addresses all genes and their inter relationships in order to identify their combined influence on the growth and development of the organism Genetics is just one part of Genomics NW Coast Genomic Medicine Centre

28 Whole genome sequencing will give us new insights 10,000,000,000 1,000,000, ,000,000 Panels <10m bases Subset of exons 10,000,000 1,000, ,000 Genotyping Exome 10m bases Exons only Whole genome 3.3bn bases Both exons and introns 10, Data Type Large-scale Structural Changes Balanced Translocations Distant Consanguinity Uniparental Disomy Novel / Known Coding Variants Novel / Known Noncoding Variants Targeted gene sequencing SNP + arrays Array CGH* Exome Whole Genome + Single Nucleotide Polymorphism * Comparative Genomic Hybridisation

29 Transforming medicine through functional genomics Functional genomics: a structured analysis of the relationship between genotype and phenotype, typically using high throughput methods to look at the various steps of the transcription process Presents us with more detail of the nature of disease cause and progression Allows more accurate diagnosis of disease and targeted treatment DNA RNA Proteins Metabolites Genomics Analysis of the full DNA sequence (of which single exomes are <1%) Transcriptomics Study of all the RNA forms in the body >30k measures expression of genes Proteomics Study of the proteins produced in the body (>100k products) Metabolomics Study of the >6500 metabolites produced by the body Epigenetics believed to have an important role in onset and development of many cancers & a role in obesity Proteomic biomarkers are being developed to diagnose and specify ovarian cancer Metabolomic biomarkers are being used to inform treatment strategies for Type 2 Diabetes

30 100,000 Genome Project

31 100,000 Genome Project April 2015: Rare Disease recruitment started in 13 centres Feb 2016: Cancer Main Programme went live in 12 centres, with phased roll-out of Cancer types NW Coast Genomic Medicine Centre

32 Aims of the project are we doing this? Increased discovery of pathogenic variants leading to new treatments, devices and diagnostics Major legacies for patients, the NHS and the UK economy by 2017 Accelerate uptake with advanced genomic medicine practice integrated into the NHS Increase public understanding and support for genomic medicine Stimulate and advance UK life sciences industry and commercial activity in genomics

33 A co-ordinated response across health and care Using genomic knowledge for prevention and health protection Coordinating genomic knowledge to make the UK a world leader Sequencing 100,000 genomes to advance genomic knowledge Ensuring the NHS Workforce is skilled and able to deliver for patient benefit Turning genomic knowledge into health interventions NW Coast Genomic Medicine Centre

34 What is a Rare Disease?

35 Facts About Rare Disease A rare disease is defined by the European Union as one that affects less than 5 in 10,000 of the general population.

36 Facts About Rare Disease There are between 6,000 and 8,000 known rare diseases Five new rare diseases are described in medical literature each week. 1 in 17 people, or 7% of the population, will be affected by a rare disease at some point in their lives. This equates to approximately 3.5 million people in the UK and 30 million people across Europe.

37 Facts About Rare Disease In the UK, a single rare disease may affect up to about 30,000 people. The vast majority of rare diseases will affect far fewer than this Some will affect only a handful, or even a single person in the whole of the UK.

38 Facts About Rare Disease 80% of rare diseases have a genetic component. Often rare diseases are chronic and life-threatening. Rare diseases can be single gene, multifactorial, chromosomal or nongenetic.

39 What is a Cancer?

40 A Cancer Cancer is when abnormal cells divide in an uncontrolled way. Some cancers may eventually spread into other tissues.

41 A Cancer There are more than 200 different types of cancer

42 Cancer Cell division and therefore growth is regulated by gene products Alterations within these genes has the potential for a cancer to form and also defines how that cancer behaves By understanding the genetic alterations we can understand what is driving tumour behaviour and therefore target treatments more effectively e.g KRAS in colon cancer, EGFR in lung cancer NW Coast Genomic Medicine Centre

43 The genomic difference driving precision medicine One size fits all treatments & intervention Individuallytailored approach Increasingly precision interventions based upon carefully identified subgroups within the broader population NW Coast Genomic Medicine Centre

44 HEE Genomics Education Programme Strategy and Aims Embed genomics into education: current & future healthcare workforce Integrate whole-genome sequencing (WGS) & functional genomics into mainstream care - benefit patients & the public Build capacity & capability - world-leading response to the genomic medicine revolution Legacy of the 100,000 Genomes Project embedded in the healthcare system & wider economic contribution NW Coast Genomic Medicine Centre

45 Supporting workforce transformation at every level across the NHS Highly Specialised workforce Specialist clinical workforce General workforce clinical and laboratory genetics, molecular pathology, molecular haematology, bioinformatics Eg cancer surgery & medicine,cardiovascular, diabetes, neurology and other specialist teams general practice, all healthcare professionals Wider awareness raising including managers & commissioners, patients and public NW Coast Genomic Medicine Centre

46 NW Coast Genomic Medicine Centre

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48 Genomics Education in Primary Care Primary Care Genomics Education Strategy (HEE) Dr Jude Heywood (GP) We need your input If you are happy to contribute to a survey please leave your details with me NW Coast Genomic Medicine Centre