18. Future of Genetics

Question 1

integration into clinical care is severely challenged by …

Answer 1

a lack of accurate interpretations of the vast amount of human genetic variation known to exist

Question 2

challenges to single gene testing

Answer 2

locus heterogeneity: a mutation in one of several genes may lead to a clinically similar disease

Question 3

incidental results

Answer 3

genetic variants uncovered during testing that are unrelated to the primary disease under investigation, but of potential clinical significance

Question 4

why are most cancers not screened for

Answer 4

because their prevalence in the general population is too low to justify screening programmes on an individual cancer basis

Question 5

in what situation could you screen for cancer tests

Answer 5

should multiple cancers be effectively screened for in a single test this would alter this calculation

Question 6

what is the essential to this proposed cancer screening

Answer 6

the success of this approach is the sensitivity and specificity of the classifier which determines whether the test result is normal (non cancer) or abnormal

Question 7

what is the best biological matrix to look for early signs of cancer

Answer 7

• tumours can secrete small fragments of DNA called circulating tumour DNA (ctDNA), into circulation where they are found in plasma
• because all cells in the body have access to the circulatory system, blood is an attractive analyte for a cancer test
• a “liquid biopsy” using blood samples obtained from cancer patients could detect the characteristics of ctDNA that may have prognostic and/or therapeutic implications

Question 8

problem with the biological matrix to look for early signs of cancer

Answer 8

with mutations found in ctDNA, circulating in the blood it is difficult to say where the mutation comes from (tissue of origin)

Question 9

how may epigenetics offer a solution to this problem

Answer 9

each tissue has a characteristic epigenetic pattern

Question 10

how does preparing DNA methylation help determine the tissue of origin of a cancer signature in the blood

Answer 10

• each tissue has a different pattern of fingerprint of DNA methylation
• alterations in DNA methylation are common in a variety of tumors are considered to be among the earliest and most comprehensive genomic aberrations occurring during carcinogenesis

Question 11

DNA methylation’s relation to cancer

Answer 11

DNA methylation has long been regarded as a hallmark of cancer and holds great promises for early-stage cancer detection

Question 12

comparing methylation patterns from an individual blood sample …

Answer 12

has the potential to be used to screen for early signs of a variety of different cancers

Question 13

is early screening ready for clinic

Answer 13

• Grail a sequencing company is pioneering the use of ctDNA in blood for the early detection of 50 different types of cancer
• the NHS is set to initiate the trial of Galleri blood test
• the pilot will enroll over 150,000 participates to examine the tests clinical utility

Question 14

Variant of Unknown significance (VUS)

Answer 14

a genetic alteration whose association with disease risk or health impact is not clearly established

Question 15

Clinvar

Answer 15

a database containing genetic variations classified for diseases and drug responses, with supporting evidence

Question 16

where do the submissions in ClinVar come from

Answer 16

over 90% come from clinical labs and represent a glimpse of the state of variation being observed in patients

Question 17

how can the biological and clinical impact of genetic variants be predicted at scale

Answer 17

• computational predictive modeling
• bioinformatics tools
• database comparisons

Question 18

explain bioinformatics tools

Answer 18

use of software that predicts the impact of genetic variants on protein structure and function

Question 19

explain database comparisons

Answer 19

compare the variant against databases that catalog known disease-associated and benign variants

Question 20

what is the biggest challenge VUS predicts

Answer 20

many of these VUS arise due to missense variants
- missense variant results in the sibstitution of one amino acid for another in the protein
- this change can affect the protein’s structure and function, depending on where the change occurs and what amino acids are involved

Question 21

why might you combine genetic data with other types of data

Answer 21

when genetics isn’t enough

by integrating genetic information with various other data types - such as clinical, environmental and lifestyle factors: genetic data can contribute to a comprehensive overview of an individual’s health status and potential future health trajectories

Question 22

GMAI

Answer 22

Generalist Medical AI
- broad and comprehensive AI system designed to perform a variety of tasks across the medical and healthcare fields
- GMAI model aims to be more versatile and wide-ranging in its capabilites

Question 23

GMAI features

Answer 23

1. multi functionality
2. decision support
3. patient interaction (through chat boxes or virtual health assistants)
4. training and education (provide simulation-based learning environments)

Question 24

what does NGS based Genomic testing offer

Answer 24

increased diagnostic reach over single gene testing and allows for translational research and new discoveries

Question 25

what can cell free DNA offer

Answer 25

great potential for the early detection of cancer