This presentation introduces and discussesthe concept of ‘morphologomics’ that is omics approaches critically reimagined and reappraised from the viewpoint of classic morphology. It was delivered by Dr. Anthony Gill at the Pathology Horizons 2017 conference in Cairns, Australia. introduce and discuss the concept of ‘morphologomics’ that is omics approaches critically reimagined and reappraised from the viewpoint of classic morphology.

1. “Morphologomics”
Anthony J Gill MD FRCPA
Royal North Shore Hospital
Professor of Surgical Pathology
University of Sydney
@CaDxPath
Is there room enough for good old surgical pathology in this brave new world?

2. What are “-omics” technologies?

3. What are “-omics” technologies?
• “-omics” has become the buzzword in
medical research
• “-omics” can be defined as the study of all
of something, eg: genomics, proteomics,
transcriptomics, metabolomics

4. What are “-omics” technologies?
Perhaps “-omics” can be better defined as
the study of all of something if:
1.Provides a lot of data

5. What are “-omics” technologies?
Perhaps “-omics” can be better defined as
the study of all of something if:
1.Provides a lot of data
2.It is so impressive it deserves massive
funding from government agencies and
private benefactors

6. What is “morphologomics”?

7. What is “morphologomics”?
“Morphologomics” can be defined as:
. . . assessing the morphology of everything we
see both macroscopically and under the
microscopic
. . . then integrating into a simplified format
. . . appropriate to be translated into clinical

8. Microscope

9. Morphologomoscope

10. Why the interest in “-omics” now?

11. Ref: “The promise of cheap genome sequencing” The economist April 16th
2009

13. Ref: Collins FS, et al First FDA Authorization for Next-Generation Sequencer N Engl J Med 2013; 369:2369-2371

14. Why the interest in genomics in
cancer diagnosis?
• For the first time massive parallel, whole
exome and whole genome sequencing
of tumours is within clinical reach.

15. What is the value of advanced molecular
testing in routine cancer diagnosis?

16. What is the value of advanced molecular
testing in routine cancer diagnosis?
• There is no good peer reviewed evidence
of either the yield or cost effectiveness

17. FOUNDATION ONE

18. FoundationOne $5800US
FoundationOne HEME $7000
FoundationACT $5800US

19. Value of second opinion in surgical
pathology

20. Value of second opinion in surgical
pathology
Rates of discordance range from 2.3% to 22%
1 Manion E et al, Mandatory second opinion in surgical pathology referral material: clinical consequences of major disagreements
Am J Surg Pathol 2008;32:732-737
2 Zhu et al Oral Oncology 2016; 53:36-41

21. Value of second opinion in surgical
pathology
Rates of discordance range from 2.3% to 22%
Item 72859 ($370) second opinion
1 Manion E et al, Mandatory second opinion in surgical pathology referral material: clinical consequences of major disagreements
Am J Surg Pathol 2008;32:732-737
2 Zhu et al Oral Oncology 2016; 53:36-41

22. Why the interest in genomics?
• For the first time whole genome
sequencing of tumours is within clinical
reach.
• Facilitates personalized medicine

23. We have always had personalized
medicine for cancer

24. Colonel Sir George Beatson
1848-1933
Lancet 1896
“Targeted” therapy of Breast
Cancer

25. “Targeted” therapy of Breast Cancer

26. “Targeted” therapy now means any treatment that requires a molecular test
Personalized medicine now means using a molecular test

27. Everyone talks about personalized medicine with
genomics but applying it in the real world is difficult . . .
Chantrill LA et al Precision Medicine for Advanced Pancreas Cancer: The Individualized Molecular Pancreatic Cancer
Therapy (IMPaCT) Trial et al Whole genomes redefine the mutational landscape of pancreatic cancer Clinical Cancer
Research Clinical Cancer Research 2015; 21:2029-37

28. Directly Targeting
Actionable Molecular Phenotypes
Novel strategies with drugs available for human use:
Phase IV Novel Indication Seeking
Rescuing
Repurposing
Early Development
eg: PTEN, MET, LKB1, c-KIT, PDGFR … …

29. The original IMPaCT trial schema.
Lorraine A. Chantrill et al. Clin Cancer Res 2015;21:2029-
2037
©2015 by American Association for Cancer Research

30. An overview of the number of cases successfully screened for eligibility for the IMPaCT trial.
Lorraine A. Chantrill et al. Clin Cancer Res 2015;21:2029-
2037
©2015 by American Association for Cancer Research

31. Barriers to enrollment.
Lorraine A. Chantrill et al. Clin Cancer Res 2015;21:2029-
2037
©2015 by American Association for Cancer Research

32. The original IMPaCT trial schema.
Lorraine A. Chantrill et al. Clin Cancer Res 2015;21:2029-
2037
©2015 by American Association for Cancer Research

33. Why the interest in genomics?
• For the first time whole genome
sequencing of tumours is within clinical
reach.
• Facilitates personalized medicine
• Opportunity to create a legacy resource
which will last for generations.

35. Australian Pancreatic Cancer Genome Initiative
(Australian Pancreatic Cancer Network)
~ 400 cases
Amber Johns and Team

36. APGI Progress by Site
N=366

37. Biankin et al Nature 2012; 491:399-405

38. Waddell et al Whole genomes redefine the mutational landscape of pancreatic cancer Nature 2015; 518:495-5015

39. )
Bailey et al Nature 2016 ;531:47–52

40. Scarpa et al Nature 2017 ; 543:65–71

41. Genome wide mutation rate in PDAC
LB Alexandrov, S Nik-Zainal, DC Wedge, et al Signatures of mutational processes in human cancer Nature 2013; 500:415-421

42. LB Alexandrov, S Nik-Zainal, DC Wedge, et al Signatures of mutational processes in human cancer Nature 2013; 500:415-421

43. APOBEC
Deamination
BRCA pathway
defective
Possibly age related
signature
Genes ?
Microsatellite
instability
Defects in DNA
mismatch repair
Genes: MLH1, MLH3, MSH2,
MSH6, PMS1
Defects in dsb DNA
repair
Genes: BRCA1, BRCA2,
ATM?, PALB2?, RAD51?
DNA de-aminating
enzymes involved in
viral defense
Genes: APOBEC3 implicated
Mining mutagenic signatures in PDAC
LB Alexandrov, S Nik-Zainal, DC Wedge, et al Signatures of mutational processes in human cancer Nature 2013; 500:415-421

45. Garvan:
Andrew Biankin
Rob Sutherland
Liz Musgrove
Roger Daly
James Kench
Marc Jones
Jianmin Wu
Anthony Gill
Page Tobelman
Jeremy Humphris
Mark Pinese
Angela Chou
David Chang*
Mark Cowley*
Chris Scarlett*
& APGI collaborators
(John Fawcett, O’Rourke, Barbour,
Henry, Kelly Slater)
Amber Johns
Scott Mead
Michelle Thomas
Chris Toon
Mary-Anne Brancato
Cathy Axford
Emily Colvin
Amanda Mawson
Johana Susanto
Marina Pajic
Mona Martyn-Smith
Lorraine Chantrill
Adnan Nagrial
Venessa Chin

53. 8 Different types of Pancreatic
adenocarcinoma
1.Adenosquamous
2.Colloid
3.Hepatoid
4.Medullary
5.Signet ring
6.Tubular (ductal)
7.Undifferentiated
8.Undifferentiated carcinoma
with osteoclast-like giant cells

54. 8 Different types of Pancreatic
adenocarcinoma
1.Adenosquamous
2.Colloid
3.Hepatoid
4.Medullary
5.Signet ring
6.Tubular (ductal)
7.Undifferentiated
8.Undifferentiated carcinoma
with osteoclast-like giant cells

55. 8 Different types of Pancreatic
adenocarcinoma
1.Adenosquamous
2.Colloid
3.Hepatoid
4.Medullary
5.Signet ring
6.Tubular (ductal)
7.Undifferentiated
8.Undifferentiated carcinoma
with osteoclast-like giant cells
$27million government funded
project misses half of all pancreas
cancers

56. 8 Different types of Pancreatic
adenocarcinoma
1.Adenosquamous
2.Colloid
3.Hepatoid
4.Medullary
5.Signet ring
6.Tubular (ductal)
7.Undifferentiated
8.Undifferentiated carcinoma
with osteoclast-like giant cells
$27million government funded
project misses half of all pancreas
cancers
and there was only 8 of them to begin with . . .

59. APGI Timeline
Sites Initiated-
first patient
recruited
First 100 pts-
National sites
grow- SA, QLD
First 150 genomes
sequenced
50 genomes in
DCC
Hit target of
350 eligible 597
Patients
June 2009 July 2010 March 2011 February 2012 October 2012
May 2013
Collections hit
200
All national sites
active
2009 2011 2012 2013
250
Sequenced
Nature
publication- Global
landscape of PC

60. APGI Timeline
Sites Initiated-
first patient
recruited
First 100 pts-
National sites
grow- SA, QLD
First 150 genomes
sequenced
50 genomes in
DCC
Hit target of
350 eligible 597
Patients
June 2009 July 2010 March 2011 February 2012 October 2012
May 2013
Collections hit
200
All national sites
active
2009 2011 2012 2013
250
Sequenced
Nature
publication- Global
landscape of PC

62. What else can be done with all
this genomics?
Direct to consumer genomic industry
The concept of recreational pathology
testing?
How this effects pathologists

63. Back in the olden days . . .

64. Back in the olden days . . .

65. But now . . .Home blood
pressure monitoring

66. Home blood pressure monitoring works
Hypertensive patients achieve better control
with home blood pressure
Cost effective
Widespread uptake
Ref:
Margolis KL et al Effect of Home Blood Pressure Telemonitoring and Pharmacist Management on Blood Pressure Control A Cluster Randomized Clinical
Trial JAMA. 2013;310(1):46-56
Billups SJ et al Cost-effectiveness Evaluation of a Home Blood Pressure Monitoring Program Am J Manag Care. 2014;20(9):e380-e387
http://www.strategyr.com/MarketResearch/Blood_Pressure_BP_Monitoring_and_Measurement_Instruments_Market_Trends.asp
Global market predicted to exceed US$2.6 billion by 2020

67. Home blood glucose testing
First home blood sugar tests late 60s
1981 glucometer
Now standard of care
Market projected to reach US$12.1 billion dollars by 2020
http://www.strategyr.com/MarketResearch/Blood_Glucose_Blood_Sugar_Monitoring_Devices_Market_Trends.asp

68. Home pregnancy tests
1977 – Home pregnancy test introduced
By 2020, market size predicted to reach USD$1.41 billion
http://www.marketdataforecast.com/market-reports/global-pregnancy-testing-market-201/

69. Recreational Health Care
Testing
Personal high tech wearables

70. Fitbit
FitbitTM
accounts for 25% of market

71. Fitbit
FitbitTM
accounts for 25% of market
6.5 million devices in the last quarter 2016

74. FDA approval status
weight management
physical fitness
relaxation
stress management
mental acuity
self-esteem
sleep management
sexual function
Currently, the FDA draft guidance for low risk devices advises that personal
health wearables are general wellness products if they only collect data on:

76. The grey zone between
recreational pathology testing and
pathology
in the genomic era

78. 1983 – Founded (ancestry publishing)
1990-2001 – one billion records
Costs $29.99 per month

81. 1983 – Founded (Ancestry publishing, Utah)
1990-2001 – one billion records
2002 – DNA testing introduced (Y & mitochondrial)
2013 – Autosomal testing
2015 – One million people tested
2016 – Two million people tested
Jan 2017 – Three million people tested
Current cost $149 -> Saliva

82. AncestryDNA does not sequence DNA
Uses microarray technology to search for 700,000 polymorphism
SNP (single nucleotide polymorphisms)
About 10 million SNPs in human genome
Every SNP has a different ID number
RSID (reference SNP cluster ID)
SNPs are characterized by online databases

83. Most SNPs are in introns
rs816948

84. Some SNPs are in exons
rs36053993

85. AncestryDNA does not sequence DNA
Uses microarray technology to
Search for 700,000 polymorphisms
SNP (single nucleotide polymorphisms)
About 10 million SNPs in human genome
Every SNP has a different ID number
RSID (reference SNP cluster ID)
SNPs are characterized by online databases

91. November thanksgiving weekend – 560,000 DNA KITs (‘cyber Monday’)
Sold more than 1.4 million kits in the last quarter of 2016. Now has 3 million kits sold
About 15% of DNA users subscribe to Ancestry.com
Revenue $850 million
Current cost $149 -> Saliva

92. November thanksgiving weekend – 560,000 DNA KITs (‘cyber Monday’)
Sold more than 1.4 million kits in the last quarter of 2016. No has 3 million kits sold
About 15% of DNA users subscribe to Ancestry.com
April 2016 -> company valued at $2.6billion
Current cost $149 -> Saliva

93. November thanksgiving weekend – 560,000 DNA KITs (‘cyber Monday’)
Sold more than 1.4 million kits in the last quarter of 2016. No has 3 million kits sold
About 15% of DNA users subscribe to Ancestry.com
April 2016 -> company valued at $2.6billion
Tim Sullivan, president and CEO -> focus is on genealogy
Current cost $149 -> Saliva

94. Raw SNP data available for download
(17.2Mb)

95. Founded in 2006 by Linda Avey, Paul Cusenza and Anne Wojcicki
2007 – Google and others invested $3,900,000
Time magazine invention of the year in 2008
Has not turned a profit since October 2015
Considered a Silicon Valley ‘Unicorn’ – market capital > $1Billion

96. 23andme specs
Illumina HumanOmniExpress-24 format
• 2007 - 576,000 SNPs
• 2008 - 597,000 SNPs
• 2010 - 992,000 SNPs
• 2013 - 611,000 SNPs

97. 23andme
Three products
1.Ancestry/genealogical
2.Health Edition
3.Complete Edition

100. 23andme

101. 23andme experience

109. FDA approval
2013 - FDA ordered 23andMe to stop marketing its Saliva Collection Kit and
Personal Genome Service (PGS) on the basis that the test is a ‘medical device’

111. FDA approval
2013 - FDA ordered 23andMe to stop marketing its Saliva Collection Kit and
Personal Genome Service (PGS) on the basis that the test is a ‘medical device’

114. April 2017 – FDA approval
Celiac disease
Hereditary Thrombophilia
Alpha-1 Antitrypsin Deficiency
Glucose-6-Phosphate Dehydrogenase deficiency
Early onset of Dystonia
Factor XI deficiency
Gaucher’s Disease type 1
Hereditary Haemochromatosis
Late-Onset Alzheimer’s Disease
Parkinson’s Disease

122. The business model of 23andme
Sequence 3000 genomes from patients with Parkinson’s

123. The business model of 23andme
$10 million upfront payment
$50 million milestone payment
Sequence 3000 genomes from patients with Parkinson’s

126. Nat Genet. 2016;48(9):1031-6
75,607 depressed
231,747 controls
Replicated
45,773 depressed
106,354 controls
Identified 17 different SNPs from 15 regions associated with depression

127. The business model
is more akin to a social
media company

128. The business model
is more akin to a social
media company

129. The business model
is more akin to a social
media company