Professor Cris PrintBiomedical Scientist

Director

Genomics Into Medicine Initiative

Auckland

11:00 - 11:55 WS #84: An Open Discussion on Genomics in Medicine: When, Where, and How

12:05 - 13:00 WS #95: An Open Discussion on Genomics in Medicine: When, Where, and How

(Repeated)

Dr Justin O'SullivanAssociate Director

Research

Laboratory Head

University of Auckland · Liggins Institute,

Auckland

An Open Discussion on

Genomics in Medicine:

When, Where, and How

Justin O’Sullivan and Cris Print

August 2018

Plan

• …

How are GPs most likely

to be involved?

Points for discussion

In what areas are GPs most likely

to use genomics in the near future?

• Cancer – germline (~5% cancer attributable to single

gene highly penetrant variants) and somatic (directing

treatment) (discussed yesterday by Cris Print)

• Rare disease including disorders of biochemical

pathways - 80% of diseases affecting 5% of individuals

are genetic in origin – can avoid protracted diagnostic

odysseys, phenotype-driven (discussed yesterday by Patrick Yap)

• Risk stratification for complex diseases using genomic

data and lifestyle factors (discussed yesterday by Tony Merriman)

• In prenatal diagnosis (discussed yesterday by Dean Morbeck)

• Direct to consumer testing interpretation and occasional

use (discussed yesterday by Stephen Robertson)

How much ‘genomics’ will GPs need to know?

• The RCGP identifies three roles for genetics in primary

care:

o identifying patients with, or at risk of, a genetic condition

o clinical management of genetic conditions

o communicating genetic information

• Current knowledge and skills of GPs are transferable to

genomics – “GPs will not require substantial additional

expertise or an in-depth knowledge of genomic variants”.

• However GPs may require an understanding of

terminology and principles underpinning genomics

Royal College of General Practitioners. RCGP Curriculum 3 02 Genetics in primary care

New science of genomics that is

rapidly entering the clinic

• The relevance of the 3-dimensional genome structure - a

“SNP” may promote disease by affecting a physically

distant gene (discussed yesterday by Justin O’Sullivan)

• Somatic stem cell mutations accumulate throughout life,

altering immune responses, and promoting disease

• New technologies such as point of care DNA sequencing

machines and sequencing of cancer mutations in the

blood of cancer patients

Schierding et al. Front Genet. 2014;5:39

We can determine population based risk

100 trillion cells, 20 % have DNA, 2 m long

= 266 Astronomical units.

133 X’s

Territories exist in

human Go fibroblast cells

DNA is structured

within cells.

Bolzer et al. 2005 PLoS Biology 3(5):e157

Territories exist in exponentially yeast cells.

Gehlen et al. 2012 Nucleus 3(4):1-15

Our heritable information is encoded in

more than the DNA sequence

We are a tale of many

genomes

Yassour et al. 2016; DOI: 10.1126/scitranslmed.aad0917

There are common features of the human microbiome

Dynamic

Sensitive: to birth mode,

predominant nutrition

antibiotic use

Transition to solids

High diversity

Resilience to

change

Billy Apple®

Ethics: The University of Auckland Human Participants Ethics Committee

Ref: 017841 and 2008/157

Excretory Wipings (1971, Apple, 161 West 23rd St, New York), censored in From

Barrie Bates to Billy Apple 1960-1974 (1974, Serpentine Gallery, London)

What happens over one individual’s lifetime?n=Billy Apple®

Billy was healthy in 1970

Billy’s 2016 flora is not what it used to be in 1970

Faith, J. et al. (2013) Science,

341(6141)

~50% of the microbial population structure is predicted to be stable over 50 years.

The active flora is different in children born very preterm

Serum cholesterol,

high hepatic TAG, less

glycogen & glucose

metabolism

increased in protein rich diets

And what these bacteria are actually doing is very different

Arginine biosynthesis

Histidine biosynthesis

New science that is transforming our

understanding of some diseases:

somatic stem cell mutations

• Clonal haematopoiesis is an expanded blood-cell

“clone” carrying a somatic mutation in patients with no

other hematologic abnormality

• Accumulates with age (found in >10% of people >70

years)

• Case–control analyses showed that CH individuals

have 1.9 x elevated risk of coronary artery disease

Jaiswal et al., N Engl J Med vol 377 pp 111-121

Case–control analyses showed that

CH individuals have significantly elevated

risk of coronary artery atherosclerosis

• Exome sequencing of endometriosis identified somatic mutations

in ~80% of lesions

• These mutations are in known cancer driver genes such as

ARID1A, PIK3CA, KRAS, or PPP2R1A

• This does not mean that endometriosis is a neoplastic disease,

however identical mutations are found in endometriosis and

ovarian cancer of the same woman

New diagnostic

techniques

Chromosomal Microarray

(a digital Karyotype)

• Detects Copy number variants “CNVs deletions or

duplications of DNA

• 15-20% diagnostic yield compared with 5% with conventional

karyotype

• Now first line investigation for intellectual disability and congenital

anomalies

• Should be offered to persons with significant intellectual disability

without a diagnosis where a diagnostic re-evaluation would improve

clinical care, and who have previously only had a karyotype

Duplication

Deletion

Next generation Sequencing

• Particularly applicable to clinically and genetically heterogeneous

disorders e.g. >200 genes for neuromuscular disorders

• Whole genome sequencing (WGS) – all 3 billion base pairs of the

human genome, low relative yield, expensive (~$20,000), a clinical

provider in Sydney

• Whole exome sequencing (WES) – ~3% of the human genome,

~30% diagnostic yield, price falling (<$3,000) and is cost effective

• Targeted panels (or filtered exome sequencing) cost effective

• Point of care sequencing, e.g. “Minion”, in trials for microbiology

https://nanoporetech.com

NZ ‘exome’ Sequencing

McKeown et. al., A pilot study of exome sequencing in a diverse New Zealand cohort with undiagnosed disorders and cancer.

Journal of the Royal Society of New Zealand, 2018 DOI: 10.1080/03036758.2018.1464033

Direct to Consumer

Genetics

The direct to consumer testing

landscape

(discussed yesterday by Prof Stephen Robertson)

• Test companies regulated as consumer products

• Patients controls and manage their data

• Patient often chooses a third party to interpret the data,

which is often done online

• Test quality and interpretation quality usually unregulated

• Even within a company’s test there are mixed (Analytic

validity, Clinical validity, Clinical utility and Personal utility)

for different genes and SNPs

CME resources

https://www.primarycaregenetics.org/?page_id=109&lang=en

https://www.eviq.org.au