Highlights in Pathology: Medical Genetics and Genomics (August 2020)

Dr. Elaine Goh, Trillium Health Partners

The following highlights have been chosen to represent different aspects of Medical Genetics and Genomics encompassing infectious disease characterization, cancer genetics, prenatal genetics and data privacy.  

1. Genomic characterization and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

Lu R, Zhao X, Li J et al. Lancet. 2020 395:565-574

COVID-19 has dominated much of the news and discussions in 2020. Genetics has had a role to play in understanding the virus.

The paper by Lu et al. was first published online on January 29, 2020 to describe the 2019 novel coronavirus.

The authors collected 10 total samples taken from nine inpatients with viral pneumonia in China.

These patients were found to be negative for the common respiratory pathogens.

Eight of the patients visited the Huanan seafood market and one stayed in a hotel near the market.

Bronchoalveolar lavage fluids or throat swabs were inoculated into pathogen-free human airway epithelial (HAE) cells and the apical samples were then collected for next-generation genomic sequencing. Phylogenetic analysis was done to compare against other coronaviruses to help postulate the origin and the evolutionary history of the virus.

The results showed that the sequence identity among the patient samples were 99.98% and the virus was a new betacoronavirus.

The suggested original host was the bat, given the close relation to two bat-derived coronavirus strains. However, there was less than 90% sequence identity between the novel coronavirus and these bat strains meaning that bats were not the direct ancestors.

Factors including bats hibernating around the time of the outbreak, no bats being sold in the seafood market and intermediary host animals playing a role in SARS-CoV and MERS-CoV suggest that there is an unknown intermediate animal from the market that may have transmitted to human hosts.

Finally, using molecular modelling to look at receptor-binding domains, the authors suggest that the 2019 novel coronavirus could use the angiotensin-converting enzyme 2 (ACE2) as a cell receptor similar to SARS-CoV, although there were several residues that were different, thus requiring further study.

The next major genetic contribution to the COVID-19 pandemic will be to sequence individuals who have been infected with COVID-19 and determine the role of host genetic factors to susceptibility and severity of COVID-19 disease (The COVID-19 Host Genetics Initiative, 2020).

2. Ontario Health Technology Assessment Series – Cell-Free Circulating Tumour DNA Blood Testing to Detect EGFR T790M Mutation in People With Advanced Non-Small Cell Lung Cancer: a Health Technology Assessment

Ontario Health Technology Assessment Series; Vol. 20: No. 5, pp. 1-176, March 2020 (PDF)

When individuals affected with lung cancer have a lung biopsy and are found to have a pathogenic variant in the epidermal growth factor receptor (EGFR), EGFR tyrosine kinase inhibitors can be given as treatment. However, 60% will develop resistance to the drug due to a resistance variant known as T790M.

The Ontario Genetics Advisory Committee (OGAC), which is a subcommittee of the Ontario Health Technology Advisory Committee, was asked to provide guidance for a recommendation about whether to publicly fund cell-free circulating tumour DNA blood testing (i.e. a liquid biopsy) to detect this T790M resistance variant in those with non-small cell lung cancer who had disease progression after EGFR tyrosine kinase inhibitor treatment.

A Health Technology Assessment was completed by the Quality business unit at Ontario Health. This included:

  • a systematic literature search of available clinical evidence
  • systematic economic literature search
  • primary economic evaluation of cost-effectiveness and cost-utility comparing liquid biopsy as a triage test, liquid biopsy alone and tissue biopsy alone
  • budget impact analysis
  • patient engagement

It was found that liquid biopsy had a positive predictive value of 89%, negative predictive value of 61%, sensitivity of 68% and specificity of 86%.

Liquid biopsy was estimated to cost $700 compared to a tissue biopsy which cost $2,500.

When compared to tissue biopsy alone, using liquid biopsy as a triage test was less costly and did not lead to as many tissue biopsies. It also resulted in the greatest number of people on the tyrosine kinase inhibitor and lead to the most correct treatment decisions.

Patients who had lung cancer suggested it was more acceptable to use a liquid biopsy test as there would be less pain and anxiety as compared to a tissue biopsy.

The budget impact for funding liquid biopsy for this indication would range from $60,000 to $3 million yearly, which includes non-testing related costs such as costs of treatment and end of life care.

Cost-savings from using liquid biopsy as a triage test and decreasing the number of tissue biopsies would be $2 million to $4 million yearly.

The recommendation of the Quality business unit at Ontario Health was to fund liquid biopsy as a triage test to detect EGFR T790M mutation in people with non-small cell lung cancer whose disease has progressed following EGFR tyrosine kinase inhibitor treatment.  

3. Genetic ancestry analysis on >93,000 individuals undergoing expanded carrier screening reveals limitations of ethnicity-based medical guidelines

Kaseniit KE, Haque IS, Goldberg JD, et al. Genetics in Medicine. Published online 29 June 2020 

In the practice of prenatal genetics, family history and ethnicity are asked of patients to determine if they may be at a higher risk to be a carrier for an autosomal recessive condition. If so, it may be important to screen them for certain genetic conditions based on ethnicity.

The conditions to be screened are based on guidelines by the Canadian College of Medical Geneticists (Wilson et al. Journal of Obstetrics and Gynaecology of Canada).

As expanded carrier screening has become more accessible due to next-generation sequencing and commercial expanded carrier panels, more data has accumulated about the utility of ethnicity-based screening.

Kaseniit et al. performed a 96-gene expanded carrier screen (ECS) in 93,419 individuals.

They collected data on carrier status, dual-component genetic ancestry and self-reported ethnicity.

The authors defined the major genetic ancestry of the individual as >50% of the genetic ancestry lineage based on the sequencing data.

The results showed that in 9% of individuals, the self-reported ethnicity did not match the major genetic ancestry, thus indicating that self-reported ethnicity may not be consistent with sequencing data. Therefore, carrier risks may be missed based on self-reported ethnicity.

Compared to pan-ethnic ECS, ethnicity-based guidelines would have only found 23% of the carriers identified in the study. Thus the authors advocate for pan-ethnic expanded carrier screening with the knowledge that limitations such as acceptance by medical societies, lack of insurance funding and health care utilization for determining partner carrier status and interpretation of variants of uncertain significance remain challenges to this approach.

4. Privacy challenges and research opportunities for genomic data sharing

Bonomi L, Huang Y, Ohno-Machado L., Nature Genetics. July 2020. 52:646-654

Genetic data not only has the ability to identify an individual and predict their genetic traits but may also have implication for family members. Therefore, the data generated from genetic testing has significant privacy challenges.

Bonomi et al. present a review of privacy challenges in their paper, by highlighting two main types of “privacy attacks”:

  1. “Identification”, which is the ability of the attacker to use techniques like data linkage, DNA phenotyping and pedigree or genealogy information to identify an unknown individual.
  2. “Phenotype Inference” where the aim is to find a genetic diagnosis or understand one’s genetic characteristics when the individual person is known. This can be done through inference from different data sources.

Given the availability of public, research and private direct-to-consumer companies with databases of genomic data, the paper reviews data security and data anonymization techniques to protect privacy.

The paper ends by suggesting research directions that may help to provide more security of data.

This paper is especially timely as there was a recent appeal from the Quebec Court of Appeal saying the Genetic Non-Discrimination Act signed into law in 2017 was “unconstitutional”, stating that Parliament did not have power to affect a decision that should be under provincial legislature.

On July 10, 2020, the Supreme Court of Canada upheld the Genetic Non-Discrimination Act saying that it is a crime “to force someone to get that (genetic) testing, or share their results, to sign a contract or buy something” (Supreme Court of Canada 2020). Therefore, under the Genetic Non-Discrimination Act, it is illegal to compel an individual to test or release the results of their genetic testing in order to gain a service.

However, privacy concerns are still present and need to be addressed once the testing has been completed.

Additional references

Supreme Court of Canada. Case in Brief: Reference re: Genetic Non-Discrimination Act. July 10, 2020. 2020 SCC 17 

The COVID-19 Host Genetics Initiative. The COVID-19 Host Genetics Initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARS-CoV-2 virus pandemic. European Journal of Human Genetics. 2020 28:715-718.

Wilson RD, De Bie I, Armour CM et al. Joint SOGC-CCMG Opinion for Reproductive Genetic Carrier Screening: An Update for All Canadian Providers of Maternity and Reproductive Healthcare in the Era of Direct-to-Consumer Testing. 2016 Aug; 38(8):742-762.