AGBT13 – Thu 2/21 Evening (Genomic Medicine) session

Concurrent Session: Genomic Medicine
George Grills, Cornell University, Chair

7:30 p.m. – 7:50 p.m.
* Olivier Elemento, Weill Cornell Medical College
“Clonal Architecture and Tumor Evolution in Diffuse Large B Cell Lymphomas”

– DLBCL – 25k patients / yr in US; treated with immunochemotherapy (60% cured, 40% relapse)
– HTS (PCR + MiSeq) of VDJ junctions could reveal clonal architecture of DLBCL and tumor evolution
– Studied 18 diagnosis-relapse pairs – 90% of relapse tumors are clonally related to primary original tumor (same VDJ junctions)
– 2 major evolutionary scenarios

  • linear evolution of relapse disease through major diagnosis clone – 65% cases
  • single, small, divergent, chemoresistant clone at diagnosis gives rise to the relapse tumor – 25% cases

– VDJ seq + WES reveals founder mutations and relapse-specific mutations, some clincally actionable

7:50 p.m. – 8:10 p.m.
* Gustavo Glusman, Institute for Systems Biology
“Multi-genome Analysis: a Crucial Tool for Clinical Genomics”
– Example of their Miller syndrome family of 4 with affected kids and unaffected parents
– Complete Genomics WGS on 600+ individuals – custom workflows + Ingenuity
– HaploScribe for variant phasing, autozygosity for IBD analysis and use Kaviar, FAVA, CMS
– discovery of disease-causing variants
– Dataset for modeling systematic failures and biases in technology, eg.

  • Median coverage profiles – normalization/scaling for CNV analysis
  • 30k commonly mutated segments available in FAVA (includes regions from black-listed genes like titin, mucins, etc)

8:10 p.m. – 8:30 p.m.
* Malachi Griffith, Washington University School of Medicine
“Clinical Cancer Sequencing and Integrated Analysis of Whole Genomes, Exomes and Transcriptomes”

– DNA + RNA-seq for tumor + matched normal of 16 cancers (1 ALL, 4 AML, 6 breast, 1 lung, 4 pancreatic)
– timeline 4 weeks (1wk – tumor/blood isolation, 1wk QC/sequencing, 1wk analysis, 1wk++ all other analysis)
– 30-60x WG coverage, 150x exome coverage for tumor/normal
– All info from these applications complements each other, eg. pancreatic exomes provide much more info because of impure samples and need for really high coverage – not possible with genomes
– Combining WES & WGS = higher sensitivity of clincally relevant tumor associated mutations – in sub-clones and low-purity tumors
– Clin-Seq pipeline & Drug-gene interaction database (DGIdb)
– bimodal non-reference read proportion curve => simple clonal burst history

8:30 p.m. – 8:50 p.m.
* Alexander Hoischen, Radboud University Medical Centre Nijmegen, Department of Human Genetics
“De novo Mutations in Embryonic Development and Early Lethality”

– importance of de novo mutations for rare & common sporadic disorders by the direct detection of de novo mutations WES
– genetics of congenital malformations, intellectual disability, and clinically defined syndromes
– early lethality may lead to mis-detection of mendelian disease genes
– 14 fetuses with hypoplastic left heart (HLH), 14 fetuses with neural tube defect and Arnold-Chiari malformation and 10 fetuses with multiple malformations
– 80x coverage, 200 private (non-syn) variants per case

8:50 p.m. – 9:10 p.m.
* Dagan Wells, University of Oxford
“Rapid Genetic Analysis of Single Cells using a Next Generation Sequencing Method: Application to Human Embryos Reveals Aneuploidy and Mutations of the Nuclear and Mitochondrial Genomes”

– In vitro fertilization (IVF) is very inefficient (30%) – choose from several embryo – subjective choice on morphological grounds
– 85% transferred embryos do not implant; increasing age implies higher chance of aneuploidy (20% at 30yr, 75% at 40yr)
– aneuploidy in embryo – principal cause of a range of clinical problems (congenital abnormalities, mental retardation and miscarriage)
– pre-implantation diagnosis/screening (PGD/PGS)
– whole genome amplification followed by next generation sequencing (Ion Torrent) – custom analysis pipeline
– 52k-110k 200bp reads/sample; variable # of reads per chr, but reproducible; so easy to normalize using normals
– correctly diagnosed abnormalities in 10/10 cells from aneuploid cell lines and in 45/45 embryos donated for research – aCGH validataion
– also identified cystic fibrosis in 5/5 single cells from an affected individual and a heteroplasmic mitochondrial DNA mutation

9:10 p.m. – 9:30 p.m.
* Leonard Lipovich, Wayne State University
“Beyond ENCODE: Primate-specific Long Non-coding RNA Genes are Functional in Human Brain and Cancer”

— had to get to drinks, so over n out!!


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