1. Lecture I: Genomic Pathology: An Introduction
Richard L. Haspel, MD, PhD
March 2012
TRIG Curriculum: Lecture 1

2. TRIG Curriculum: Lecture 1
$2,700,000,
The cost and speed of sequencing has changed dramatically in the last decade. It took 13 years and 2.7 billion dollars for the human genome project to be completed. Now time for a whole-genome sequence is measured in hours and thousands of dollars.
March 2012
TRIG Curriculum: Lecture 1

3. TRIG Curriculum: Lecture 1
What do I get for $999?
You get access to your raw data of 50 million DNA bases at high quality (80X coverage). You will have access to new tools and content as they are developed, to take full advantage of your exome sequence data. Most excitingly, you'll be a trailblazer, one of the first people on the planet to know their personal exome sequence!
As an example, one direct-to-consumer genotyping company is offering a whole-exome sequence for $999.
March 2012
TRIG Curriculum: Lecture 1

4. Coming to a clinic near you…
Based on personal experience at Stanford University Hospital & Clinics…patients have already begun to arrive at their physician's office with 23andMe reports in hand seeking expert medical advice.
This article excerpt illustrates patients are already bringing direct-to-consumer testing results to their physicians for interpretation.
Salari K. PLoS Medicine. 2009; 6:e
March 2012
TRIG Curriculum: Lecture 1

5. Coming to a clinic near you…
Aside from direct-to-consumer companies in which clinical utility is questionable, there are more and more papers showing genomic technology can positively affect patient care. Several of these papers will be discussed during these lectures.
March 2012
TRIG Curriculum: Lecture 1

6. TRIG Curriculum: Lecture 1
Definitions
What is a human genome?
A “whole genome” consists of ~3 gigabytes (3 billion “base pairs”) of DNA distributed unequally among 46 chromosomes (diploid genome).
Approximately 98% of the this DNA is “intergenic” (literally “between genes”), does not encode proteins and is of unknown medical relevance.
What is a human exome?
Exome refers to the 2% subset of the whole genome that encompasses our ~22,000 pairs of genes.
Because each gene, on average, is composed of 8 protein-encoding segments (“exons”), an exome corresponds to 8 x 22,000 = 176,000 segments of DNA.
What is a human transcriptome (a.k.a. gene expression profile)?
Transcriptome refers collectively to all of the “expressed” RNA “transcripts” of genes based on the “central dogma” of molecular biology, i.e. DNA -> RNA -> protein.
A transcriptome reflects what a cell is doing at a particular point in time (molecular phenotype) as opposed to what it is capable of doing (genotype).
This slide gives some important definitions. For these lectures, genomic testing refers to testing the entire genome, exome or transcriptome at once as opposed to smaller segments.
March 2012
TRIG Curriculum: Lecture 1

7. Genomic Testing as a Universal Diagnostic
Natural history of disease,
response to therapy
Medical genetics,
preventive medicine
Surgical pathology
Pharmacogenomics
Genomic testing will likely affect many areas of importance to both anatomic pathologists (e.g., sequencing of tumors) and clinical pathologists (e.g., sequencing of microbes).
Medical
Microbiology
Molecular mechanisms of disease
Kahvejian A,.et al. Nat Biotechnol. 2008; 26:
March 2012
TRIG Curriculum: Lecture 1

8. Why Pathologists? We have access, we know testing
Personalized
Risk
Prediction,
Medication
Dosing,
Diagnosis/
Prognosis
Pathologists
Perhaps most important, if it involves testing, it should involve pathologists. As with all testing, we will need to collaborate with other medical professionals. In particular for genomic medicine, we will need to work with genetic counselors and medical geneticists.
Physician sends
sample to
Pathology
(blood/tissue)
Access to patient’s
genome
Genetic Counselors
Medical Geneticists
March 2012
TRIG Curriculum: Lecture 1

9. “[a patient’s genome] is just another lab value.”
-- D.P. Dimmock
ACMG, Vancouver
18 March 2011
Dr. Dimmock was involved in using genomic techniques to determine the cause of inflammatory bowel disease in a pediatric patient (see reference). The genomic tests described in these lectures are in many ways “just another test.” Pathologists know how to provide accurate testing and the image below shows the problems that can arise if not done with proper oversight (e.g., 23andMe is a direct-to-consumer genotyping company that had a mix-up and gave individuals the wrong results).
Sample swaps at 23andMe: a cautionary tale
By Daniel MacArthur | June 7, | 6:00 a.m. 
Worthey EA, et al. Genetics in Medicine. 2011;13:255
March 2012
TRIG Curriculum: Lecture 1

10. Pathologists in Familiar Role?*
As with all testing, pathologists help translate information for other clinicians. In the case of genomic testing, there is evidence that most physicians are not prepared for these new methods and only familiar with old tools (analogy of the image of Laennec and first stethoscope). It is up to pathologists to provide and help other clinicians understand these modern tools (analogy of images of stethoscope and advanced cardiac imaging).
Pathologists
March 2012
TRIG Curriculum: Lecture 1

11. Already considering workflow
The bottom line is that genomic methods will be entering clinical practice and pathologists need to start thinking about models for applying these new methods. A group from Michigan has already piloted a possible workflow for tumor samples (note it involves colleagues in genetic counseling).
Roychowdhury S, et al. Sci Transl Med. 2011; 3: 111ra121
March 2012
TRIG Curriculum: Lecture 1

12. What will be the pathology report of the future?
Ethical issues
Informed consent
Integrated data interpretation
Pathologists use reports to convey data (breast biopsy report on left (AP) and BRCA report on right (CP)). As an example of new models, what will the pathology report of the future look like? It may need increased integration of both AP (histology) and CP (genetic testing) components and may also need to include ethical concerns. To create the best possible reports, we need to understand more about patient-doctor and doctor-doctor communication and the issues that can arise.
March 2012
TRIG Curriculum: Lecture 1

13. Multidisciplinary Teams Needed
Modern medical technology and practice requires a multidisciplinary approach to medical practice.
Greater interaction needed between Pathologists, Genetic Counselors and Medical Geneticists
A key point is that the genomic testing necessitates an even greater need for a multidisciplinary approach particularly in regard to translating the sequence data into an actionable clinical interpretation for the ordering physician and their patient. (The image is from the Michigan group.)
Roychowdhury S, et al. Sci Transl Med. 2011; 3: 111ra121
March 2012
TRIG Curriculum: Lecture 1

14. Training Residents in Genomics (TRIG) Working Group
Recognizing the need for a collaborative approach, the Training Residents in Genomics (TRIG) Working Group of the Pathology Residency Directors Section (PRODS) of the Association of Pathology Chairs (APC) was formed. The TRIG Working Group is made up of experts in molecular pathology, genetic counseling and medical education. These lectures were created by the TRIG Working Group.
March 2012
TRIG Curriculum: Lecture 1

15. What we will cover today:
Review present and future of genomic testing:
Methods
Single gene
Gene chips
Whole-genome/exome/ transcriptome seqeuncing
Clinical utility
Prognosis/diagnosis
Risk prediction
Communicating with the patient
Genomic testing
This lecture will cover three areas: genomic testing methods; interpreting genomic information for clinical care; and communicating genomic testing results to patients. For each area, current testing (indicated by stethoscope) and future testing (indicated by advance cardiac imaging) will be discussed.
March 2012
TRIG Curriculum: Lecture 1