Revolutionising Early Cancer Diagnosis – PanSeer & GALLERI

By Sreenidhi Venkatesh

The development of cancer diagnostics and treatments is a leading sector of biomedical research with over $5 billion and £455 million being invested in cancer research by the National Cancer Institute US and Cancer Research UK, respectively (CRUK, 2020; National Cancer Research, 2021). Screening and diagnosis of cancers forms an important facet of the various areas of research. Statistics from the CRUK estimate that thousands of lives can be saved by increased screening for cancers (Bowel, Breast, Cervical etc.), thereby decreasing the high mortality rates of the disease. Early cancer detection is a sector which could revolutionise the prognosis of patients. Improving detection techniques since the 1970s in the UK has improved survival (CRUK, 2016; CRUK, 2020; Crosby et al., 2020). 

Amidst the multitude of cancer diagnostics are simple blood-tests, two of which are PanSeer and GALLERI. While they are still novel and require further optimisation and clinical trials, they do show promise in bettering early diagnosis. The tests focus on identifying circulating tumour DNA (ctDNA). Due to the limited presence of ctDNA in the early stages of cancer, previous diagnostics have been unable to effectively identify them and have been error prone. ctDNA is a form of cfDNA – cell-free DNA which is released when a cell dies. ctDNAs are unique because of certain markers the possess which includes single nucleotide variants (SNVs), insertion-deletion mutations (indels), and copy number alterations (CNAs) (Chen et al., 2020).

The PanSeer assay, developed by Kun Zhang – a bioengineer at University of California, is a blood-based test that can detect potential cancers of the oesophagus, lungs, liver, stomach, colon, and rectum. It was developed and tested as a part of the Taizhou Longitudinal Study (TLS) where over 100,000 healthy people donated plasma samples and were monitored over time. PanSeer does not indicate that patients will develop cancer in the future, but rather highlights the existence of tumour cells under asymptomatic conditions. Cancer diagnostics tend to identify ‘cancer-specific methylation signatures’. This assay focuses on recognising common abnormal methylation seen in a range of cancers and it does not focus on the tissue of origin. Across 477 genomic sites, 10613 CpG sites are methylated (Nuwer, 2020). 

The ability of this assay to conduct early diagnosis of cancer lies in the modified protocol used in comparison to standard diagnostic techniques which rely on bisulphate conversion. Bisulphate conversion leads to a high amount of DNA loss, and to circumvent this PanSeer uses semi-targeted PCR. This means that only a single ligation and single PCR primer per amplicon is necessary. This has a greater recovery rate of molecules, thereby preventing DNA loss and increasing sensitivity (Chen et al., 2020). 

The PanSeer assay had the ability to detect the 5 specific types of cancer in 95% of asymptomatic patients who received a cancer diagnosis up to 4 years later (Chen et al., 2020). It therefore forms the cornerstone to effective early cancer diagnostics for these specific forms of cancer. 

The GALLERI test, developed by the company GRAIL, is newer compared to PanSeer, and it operates on the same mechanisms. The assay focuses on analysing cfDNA like PanSeer. By combining genome-wide cfDNA sequencing and machine learning, not only does this test have the capability of indicating the presence of cancer, but it also helps tissue of origin identification (Liu et al., 2020). Funded by GRAIL, a circulating cell-free genome atlas (CCGA) study was performed to develop the assay (GALLERI, 2020; GRAIL, 2020). 

While PanSeer opted out of performing bisulphate conversion, in the GALLERI assay, whole genome bisulphate sequencing (WGBS) was used to analyse cfDNA. No further details of the protocol had been published. By combining data from around fifteen-thousand patients, a signature of fragment-level methylation was determined. This data was then used to determine genomic regions which played a significant role in indicating the signatures of cancer and its tissue of origin. With increasing severity of cancer, the accuracy of tissue specific origin identification seemed to improve in the assay. Through this study performed, GALLERI had the ability to detect up to 50 types of cancer with tissue specific origin accurately predicted in 93% of samples (n = 344) (Liu et al., 2020).

The study GALLERI was based on was predominantly focused on developing the assay while the PanSeer test, conducted over nearly a decade ago, indicated that it was able to identify potential cancer diagnosis up to 4 years earlier. Therefore, it is possible that GALLERI will have a profound positive impact on cancer diagnostics, however, before it reaches that stage it is essential that optimisation and long-term studies are performed. Similarly, while the PanSeer test did conduct long-term follow up with patients, it was focused on individuals from a certain region predominantly of Chinese ethnicity. It is vital that such a study be performed in multiple regions across the globe as it seemed to have the potential to improve early diagnostics. The GALLERI test did indicate particularly that while they were able to detect a multitude of cancers, the sample size for some of these was small in relation to others, thus conclusions cannot be made about the test’s ability to identify all 50+ cancers.

Since the studies for each of the assays, the developments for both have varied. According to CRUK, there is a likelihood of the NHS to begin a pilot-study of more than 140 thousand people (CRUK, 2020). Following the release of PanSeer’s positive results in July 2020, the company with its ownership, Singlera Genomics, are raising funds for further cohort studies and clinical trials and has raised $150 million for the commercialisation of PanSeer (Singlera Genomics, 2020). 

Over the next few decades, the further optimisation and development of these tests is going to be of immense benefit in improving cancer therapeutic success and survival rates. In the past, insufficient funds, high costs, and under prioritisation of this sector have withheld it from progressing. However, companies like Singlera Genomics and GRAIL are hopeful to integrate their potentially effective and affordable diagnostic assays across the globe.

References:

National Cancer Institute. (2021) Funding for Research Areas. Available from: https://www.cancer.gov/about-nci/budget/fact-book/data/research-funding [Accessed 17th May 2021]

Cancer Research UK. (2020) Facts and Figures about our Research Funding. Available from: https://www.cancerresearchuk.org/funding-for-researchers/facts-and-figures-about-our-research-funding-0 [Accessed 17th May 2021]

Cancer Research UK. (2016) Cancer Screening and Diagnostics. Available from: https://www.cancerresearchuk.org/health-professional/cancer-screening-and-diagnosis-statistics#heading-Eight [Accessed 17th May 2021]

Cancer Research UK. (2020) Cancer Incidence Statistics. Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics/incidence#heading-Zero [Accessed 17th May 2021]

Crosby, D., Lyons, N., Greenwood, E., Harrison, S., Hiom, S., Moffatt, J., Quallo, T., Samuel, E. & Walker, I. (2020) A Roadmap for the Early Detection and Diagnosis of Cancer. The Lancet Oncology. 21 (11), 1397-1399. Available from: https://doi.org/10.1016/S1470-2045(20)30593-3 [Accessed 17th May 2021]

Chen, X., Gole, J., Gore, A., He, Q., Lu, M., Min, J., Yuan, Z., Yang, X., Jiang, Y., Zhang, T., Suo, C., Li, X., Cheng, L., Zhang, Z., Niu, H., Li, Z., Xie, Z., Shi, H., Zhang, X., Fan, M., Wang, X., Yang, Y., Dang, J., McConnell, C., Zhang, J., Wang, J., Yu, S., Ye, W., Gao, Y., Zhang, K., Liu, R. & Jin, L. (2020) Non-invasive early detection of cancer four years before conventional diagnosis using a blood test. Nature Communications. 11 (3475). Available from: https://doi.org/10.1038/s41467-020-17316-z [Accessed 17th May 2021]

Nuwer, R. (2020) Experimental Blood Test Detects Cancer upto Four Years before Symptoms Appear. Available from: https://www.scientificamerican.com/article/experimental-blood-test-detects-cancer-up-to-four-years-before-symptoms-appear/#:~:text=Zhang%20and%20his%20colleagues%20focused,DNA%20to%20alter%20genetic%20activity. [Accessed 17th May 2021]

GALLERI. Early Cancer Detection. Available from: https://www.galleri.com/hcp/early-cancer-detection [Accessed 17th May 2021]

Liu, M. C., Oxnard, G. R., Klein, E. A., Swanton, C. & Seiden, M. V. (2020) Sensitive and Specific Multi-Cancer Detection and Localisation using Methylation Signatures in Cell-Free DNA. Annals of Oncology. 31 (6), 745-759. Available from: https://doi.org/10.1016/j.annonc.2020.02.011 [Accessed 17th May 2021]

GRAIL. (2020) Science. Available from: https://grail.com/science/ [Accessed 17th May 2021]

GRAIL. (2020) GALLERI. Available from: https://grail.com/galleri/ [Accessed 17th May 2021]

Cancer Research UK. (2020) What is the GALLERI Blood Test. Available from: https://www.cancerresearchuk.org/about-cancer/cancer-in-general/tests/blood-tests/Galleri-blood-test [Accessed 17th May 2021]

Singlera Genomics. (2020) Publications. Available from: https://singleraoncology.com/publications/ [Accessed 17th May 2021]

 

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