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Download Medical genetic testing - Festival of Genomics London
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Genomic medicine: are we answering the right questions? Nazneen Rahman Head of Cancer Genetics ICR and RMH @rahman_nazneen #genomicsfest Genomes sequenced Sequencing REBYHINEIHESTTOTE Sequencing Analysis Interpretation THE BOY IS IN THE TREE HE MIGHT BE STUCK - GET A LADDER Patient Sample Sequencing Analysis Interpretation Clinical Actions Patient Sample Sequencing Analysis Interpretation Clinical Actions Patient Sample Sequencing Analysis Interpretation Clinical Actions Q: How do we upscale clinical pathways to accommodate the extraordinary advance in genome sequencing? Q: How do we create radical innovative clinical pathways to complement the extraordinary advance in genome sequencing? OLD DNA SEQUENCING = NEW DNA SEQUENCING = Patient Sample Sequencing Analysis Interpretation Clinical Actions Patient Sample Sequencing Analysis Interpretation Clinical Actions Current variant interpretation Class 5 4 3 2 1 Description Definitely Pathogenic Likely Pathogenic Uncertain Likely Not Pathogenic Not Pathogenic Probability of being Pathogenic >0.99 0.95–0.99 0.05–0.949 0.001–0.049 <0.001 Plon et al Hum Mutat 2008 29:1282-91 Problems: Variant-centric: doesn’t use gene-based, phenotype-based data Largely arbitrary and based on many assumptions. Very laborious, low-throughput, non-scalable. 5 variant classes but never 5 clinical management classes. Current variant interpretation V6 Definitely pathogenic >0.99 Likely pathogenic 0.95-0.99 tool1 V1 tool2 V6 V7 tool3 V2 V5 V1 tool4 V10 V8 V3 tool5 V9 V4 V8 V5 V2 V3 Uncertain 0.05-0.949 (VUS) ?? V7 V10 tool6 V4 V9 Likely not pathogenic 0.001-0.049 Not pathogenic <0.001 Clinical Action Interpretation requirements 1. High-throughput + large volume 2. Fast turnaround 3. Intelligible and usable by non-expert/patients Current variant interpretation V6 Definitely pathogenic >0.99 Likely pathogenic 0.95-0.99 tool1 V1 tool2 V6 V7 tool3 V2 V5 V1 tool4 V10 V8 V3 tool5 V9 V4 V8 V5 V2 V3 Uncertain 0.05-0.949 (VUS) ?? V7 V10 tool6 V4 V9 Likely not pathogenic 0.001-0.049 Not pathogenic <0.001 Clinical Action We urgently need innovative approaches for delivering variant interpretation for the clinic V6 V7 V2 V5 V1 V10 V8 V3 V9 V4 Clinical Action Clinical variant management Action 3 Action 2 Action 1 Manage as not clinically relevant Clinical variant management Action 3 Action 2 V1 V8 V5 V2 Action 1 V3 V10 V9 V6 V7 V4 Manage as not clinically relevant Clinical variant management Action 3 V8 Action 2 Fulfil explicit criteria V1 V5 V2 Action 1 V3 V10 V9 V6 V7 V4 Manage as not clinically relevant Frequency of phenotype Mechanism of pathogenicity Population variation Variability of gene Gene structure/function Variant Phenotype Inheritance pattern Attribution of gene for phenotype Penetrance of gene for phenotype How does it work in practice? BRCA1 and BRCA2 Cancer predisposition genes. Mutations confer increased risks of breast and ovarian cancer. Rare BRCA variants are common! • 1000 UK population controls • 4 pathogenic BRCA mutations (all truncating) All BRCA variants Nonsynonymous BRCA variants >5% freq 100% >5% freq 100% up to 5% freq 44% up to 5% freq 37% up to 1% freq 27% up to 1% freq 18% up to 0.1% freq 13% up to 0.1% freq 9% 10% of healthy population have a rare BRCA variant (VUS) Clinical management of BRCA VUS • Should be managed as a negative BRCA test: – Not used in cancer management. – Not used for cancer risk prediction in relatives. • Actually managed very inconsistently: – Often predictive testing + cancer surveillance in relatives. – Risk reducing surgery (30%). Very significant harms at patient and societal level. Which BRCA variants are pathogenic? Evidence from the last 20 years have shown: • >95% of pathogenic BRCA mutations are truncating. • >95% of truncating mutations are pathogenic. • >95% of non-truncating variants are not pathogenic. Pathogenic non- truncating BRCA mutations are very rare and in key domains RING BRCA1 BRCT 1863 aa DBD BRCA2 3418 aa BRCA clinical variant management Pathogenic Mutation Manage as clinically relevant (16%) Variant requiring evaluation (<0.2%) Variant Manage as not clinically relevant (74%) • Fast, consistent • Automated interpretation for >95% variants >95% automatic Every variant has to be triaged into a clinical management category <5% expert hand curation - Ongoing iteration essential Q: Is the variant pathogenic or nonpathogenic? Q: What is the potential human impact of the variant? Genotype-phenotype is very complex 1. A specific BRCA mutation can confer different risks of different cancers. 2. Different BRCA mutations can confer different risks of a particular cancer. 3. A specific BRCA mutation can confer different risks of a particular cancer in different contexts. Cancers other than breast and ovarian are prob not causally related to the BRCA mutation 30 20 • Only breast and ovarian cancer types contain a significant number of pathogenic mutations in BRCA 15 10 5 P = 0.05 0 OV BR LUSC CESC THCA UCEC BLCA HNSC STAD COAD ESCA GBM LIHC PAAD PRAD READ SARC SKCM KIRP LUAD PCPG ACC DLBC KICH KIRC LAML LGG UCS -log10(Fisher-exact P-value) -1log10(P value) 25 ACC BLCA BR CESC COAD DLBC ESCA GBM HNSC KICH KIRC KIRP LAML LGG LIHC LUAD LUSC OV PAAD PCPG PRAD READ SARC SKCM STAD THCA UCEC UCS Adrenocortical Bladder Breast Cervical Colon Diffuse Large B-cell Esophageal Glioblastoma Head and Neck Kidney Chromophobe Kidney renal clear cell Kidney renal papillary cell Acute Myeloid Leukemia Brain Lower Grade Glioma Liver Lung adenocarcinoma Lung squamous Ovarian Pancreatic Pheochromocytoma or Paraganglioma Prostate Rectum Sarcoma Melanoma Stomach Thyroid Uterine Corpus Endometrioid Uterine BRCA mutations have context-dep risks Familial BC Ford D, Easton E et al, Am.J.Hum.Genet 1998 BRCA mutations have context-dep risks Familial BC Unselected BC ??Population risk Antoniou A, Pharoah PD et al, Am.J.Hum.Genet 2003 Q: Should we tell people about incidental findings? Q: Have we sorted out the pertinent findings? Q: What can we tell people about incidental findings? Patient Sample Sequencing Analysis Interpretation Clinical Actions Q: How can we provide genetic counselling to everyone having a gene test? Q: How do we provide the information people need to consent to and understand their gene test? Medical genetic testing in people with disease is different from Predictive genetic testing in healthy individuals How does it work in practice? Mainstream Model Medical testing (i.e. in cancer patients) through ‘trained’ cancer team. All test results interpreted by Genetics Mutation – all sent Genetics appointment No Mutation – likely no extra Genetics input needed. Testing in unaffecteds done through Genetics. cha the next few years www.mcgprogamme.com Angela George Helen Hanson Simple training for non-geneticists • Takes ~20 mins 4 short e-learning modules on Read documentation Complete checklist • Receive certificate. www.mcgprogramme.com/BRCAtesting Feedback Patient feedback • 100% pleased had test. • 100% happy to have test at oncology appt. • 98% understood may have implications for themselves and their families. Clinician feedback • 100%: I welcome the opportunity to carry out BRCA gene testing for cancer patients through oncology appointments. • 100%: I feel confident to consent a patient for a BRCA gene test; and inform patients of their results. Effective and Efficient Effective and Efficient Save NHS £2M per year on genetic consultations alone Take home The revolutionary change in sequencing requires us to look with fresh eyes at all aspects of genomic medicine. We need to be equally creative and proactive in building paradigm-shifting innovations to clinical processes to maximise benefits and minimise harms. Acknowledgements ICR Genetic Susceptibility Team MCG Programme & TGLclinical Elise Ruark, Shazia Mahamadallie, Angela George, Ann Strydom, Sheila Seal, Shawn Yost, Tara Mills, Anthony Renwick, Daniel Riddell, Imran Uddin, Vicky Cloke, Rachel Linger, Emma Ramsay, Harriet Wylie, Anna Elliot, Helen Hanson, Zoe Kemp, Ingrid Slade, WTCHG - Gerton Lunter, Márton Münz, Anna Fowler, RM Genetics, Gynae and Breast Units UK Cancer Genetics services
