Cancer Likelihood in Plasma

Cancer Likelihood in Plasma (CLiP) refers to a set of ensemble learning methods for integrating various genomic features useful for the noninvasive detection of early cancers from blood plasma.[1] An application of this technique for early detection of lung cancer (Lung-CLiP) was originally described by Chabon et al (2020)[2] from the labs of Ash Alizadeh and Max Diehn at Stanford.[3][4]

This method relies on several improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)[5] for analysis of circulating tumor DNA (ctDNA). The CLiP technique integrates multiple distinctive genomic features of a cancer of interest findings within a machine-learning framework for cancer detection. For example, studies have shown that the majority of somatic mutations found in cell-free DNA (cfDNA) are not tumor derived, but instead reflect clonal hematopoeisis (also known as CHIP).[2][6] Even though CHIP tends to target specific genes, it also involves many generally non-recurrent mutations that can be shed from leukocytes and detected in cfDNA, regardless of whether profiling patients with cancer and healthy adults.[2] However, genuine tumor derived ctDNA mutations can be distinguished from CHIP-derived mutations. This is because unlike tumor-derived mutations, CHIP-derived mutations that are shed from leukocytes into plasma tend to occur on longer cfDNA fragments, and to lack specific mutational signatures such as those associated with tobacco smoking in lung cancer that are also found in tumor derived ctDNA molecules. CLiP integrates these features within hierarchical ensemble machine learning models that consider somatic mutations and copy number alternations, among other features.[2] While the CLiP method is unique in relying exclusively on mutations and copy number alterations, it is related to a variety of other liquid biopsy methods being commercially developed for early cancer detection using ctDNA and proteins (e.g., CancerSEEK / DETECT-A [7]), cfDNA fragmentation patterns (e.g., DELFI),[8][9] and DNA methylation (e.g., cfMeDIP-Seq,[10] GRAIL[11]).

While the CLiP method has not yet been broadly applied for population-based cancer screening, it has been shown to distinguish discriminate early-stage lung cancers from risk-matched controls across multiple cohorts of patients enrolled across the US.[12]

## References

1. ↑ Polikar, Robi (2009-01-11). "Ensemble learning" (in en). Scholarpedia 4 (1): 2776. doi:10.4249/scholarpedia.2776. ISSN 1941-6016. Bibcode: 2009SchpJ...4.2776P. http://www.scholarpedia.org/article/Ensemble_learning.
2. ↑ 2.0 2.1 2.2 2.3 Chabon, Jacob J.; Hamilton, Emily G.; Kurtz, David M.; Esfahani, Mohammad S.; Moding, Everett J.; Stehr, Henning; Schroers-Martin, Joseph; Nabet, Barzin Y. et al. (April 2020). "Integrating genomic features for non-invasive early lung cancer detection" (in en). Nature 580 (7802): 245–251. doi:10.1038/s41586-020-2140-0. ISSN 1476-4687. PMID 32269342. https://www.nature.com/articles/s41586-020-2140-0.
3. ↑ "CLiP". https://clip.stanford.edu/.
4. ↑ "Stanford Team Debuts New Liquid Biopsy Lung Cancer Screening Method" (in en-us). https://www.genomeweb.com/cancer/stanford-team-debuts-new-liquid-biopsy-lung-cancer-screening-method.
5. ↑ Newman, Aaron M.; Bratman, Scott V.; To, Jacqueline; Wynne, Jacob F.; Eclov, Neville C. W.; Modlin, Leslie A.; Liu, Chih Long; Neal, Joel W. et al. (May 2014). "An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage" (in en). Nature Medicine 20 (5): 548–554. doi:10.1038/nm.3519. ISSN 1546-170X. PMID 24705333.
6. ↑ Razavi, Pedram; Li, Bob T.; Brown, David N.; Jung, Byoungsok; Hubbell, Earl; Shen, Ronglai; Abida, Wassim; Juluru, Krishna et al. (December 2019). "High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants" (in en). Nature Medicine 25 (12): 1928–1937. doi:10.1038/s41591-019-0652-7. ISSN 1546-170X. PMID 31768066. PMC 7061455. https://www.nature.com/articles/s41591-019-0652-7.
7. ↑ KaiserApr. 28, Jocelyn; 2020; Pm, 1:40 (2020-04-28). "DNA blood test spots cancers in seemingly cancer-free women, but also produces false alarms" (in en). https://www.sciencemag.org/news/2020/04/blood-tests-spot-cancers-symptoms-appear-also-produce-false-positives.
8. ↑ "New blood test uses DNA 'packaging' patterns to detect multiple cancer types" (in en). https://www.sciencedaily.com/releases/2019/05/190529131206.htm.
9. ↑ "Delfi Diagnostics – Early Detection of Cancer – Baltimore, MD" (in en-US). https://delfidiagnostics.com/.
10. ↑ Shen, Shu Yi; Burgener, Justin M.; Bratman, Scott V.; De Carvalho, Daniel D. (October 2019). "Preparation of cfMeDIP-seq libraries for methylome profiling of plasma cell-free DNA" (in en). Nature Protocols 14 (10): 2749–2780. doi:10.1038/s41596-019-0202-2. ISSN 1750-2799. https://www.nature.com/articles/s41596-019-0202-2.
11. ↑ "PATHFINDER Study" (in en-US). 2020-02-18. https://grail.com/clinical-studies/pathfinder-study/.
12. ↑ editor, Ian Sample Science (2020-03-25). "AI program could check blood for signs of lung cancer" (in en-GB). The Guardian. ISSN 0261-3077. https://www.theguardian.com/society/2020/mar/25/ai-program-could-check-blood-for-signs-of-lung-cancer.

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