Microsatellite instability
Also known as MSI
A "microsatellite" is a small segment of DNA where a short pattern of DNA bases is repeated several times (Albert de la Chapelle, 2003). "Microsatellite instability" is when the repeated sequences get longer. Microsatellite instability occurs in several diseases, including some cancers, and neurological diseases like Huntington's disease. In cancer, microsatellite instability happens if the DNA mismatch repair (MMR) genes are broken (Russell Bonneville et al, 2017).
How is MSI measured?
MSI status can be measured through either genomic sequencing or polymerase chain reaction (PCR, C R Boland et al, 1998). MSI is reported as being either "stable" or "high" (unstable). Some tests will also report an "MSI-Low" or "MSI-Indeterminate" category.
Since errors in the MMR genes cause microsatellite instability, "MMR deficiency" will be used as an equivalent to "MSI-high".
How is MSI measured with PCR?
While PCR is a significantly older method for detecting MSI than genomic sequencing, it is still widely used. PCR is a commonly available lab technique that uses a carefully controlled biological reaction to find and amplify specific DNA sequences (Lilit Garibyan and Nidhi Avashia, 2013). These DNA sequences can be put through a gel, which allows a lab technician to identify the length of the DNA sequences.
The standard method for assessing MSI with PCR looks at 5 microsatellites that are frequently enlarged in cancer (C R Boland et al, 1998). The PCR test needs both "normal" (non-tumor) and tumor tissue from a patient. When the tumor and normal DNA fragment goes through the gel, the lengths of the fragments are compared. If the length of a microsatellite is changed, then that microsatellite is considered instable. A patient is considered to be MSI-high if 2 or more of the 5 microsatellites are unstable.
How is MSI measured with sequencing?
Clinical sequencing tests typically include multiple microsatellites. For instance, the Guardant360 panel includes 99 microsatellites (Jason Willis et al, 2019), while FoundationOne includes 1,880 microsatellites (Sally E. Trabucco et al, 2019). When the microsatellites are sequenced, a computer algorithm is used to identify whether the sizes of the microsatellites have changed.
The large number of microsatellites included in clinical sequencing panels addresses the major limitation of the standard PCR test for MSI. Since the PCR test only looks at 5 microsatellites, it may miss MSI-high cases that genomic sequencing could identify. In a study of prostate cancer patients by Jennifer A. Hempelmann et al, 2018, they found that NGS-based methods correctly identified 93% of MSI-high patients, while PCR only identified 72% of MSI-high patients.
What is the typical MSI status for prostate cancer patients?
High microsatellite instability is uncommon in prostate cancer. Several real world studies have estimated that 2-5% of prostate cancer patients have high microsatellite instability.
| When was the study published? | What data did it use? | How many patients were included? | What % of patients were MSI-High? | References |
|---|---|---|---|---|
| 2019 | Patients sequenced at Memorial Sloan Kettering as part of a clinical trial | 15,045 (all cancers), 1,048 (prostate cancer) | 5.1% (54 of 1,048, included MSI-I) | Alicia Latham et al, 2019 |
| 2019 | Prostate cancer patients sequenced at Memorial Sloan Kettering | 1,346 | 3.1% (32 of 1,033) | Wassim Abida et al, 2019 |
| 2019 | Prostate cancer patients sequenced with FoundationOne | 3,476 | 2.7% (87 of 3,326) | Jon H. Chung et al, 2019 |
| 2021 | Advanced prostate cancer patients sequenced with Guardant360 | 460 | 3.7% (15 of 405) | Pedro Barata et al, 2021 |
| 2024 | Prostate cancer patients sequenced at Tempus | 5,538 | 2.5% (138 of 4,438) | Qiyuan Hu et al, 2024 |
In prostate cancer, there is some evidence that high microsatellite instability is correlated with high tumor mutational burden (Jon H. Chung et al, 2019, Ryon P. Graf et al, 2022).
How does MSI impact my treatment options?
For a patient with metastatic castration resistant prostate cancer, getting your MSI assessed may give you additional treatment options. The FDA has granted accelerated approvals to two medications that can be used to treat any metastatic/recurrent MSI-high solid tumors that lack other treatment options:
References
- Albert de la Chapelle. (2003) 'Microsatellite Instability', New England Journal of Medicine.
See abstract at PubMed Central See article at publisher's site - Russell Bonneville, Melanie A. Krook, Esko A. Kautto, Jharna Miya, Michele R. Wing, Hui-Zi Chen, Julie W. Reeser, Lianbo Yu, Sameek Roychowdhury. (2017) 'Landscape of Microsatellite Instability Across 39 Cancer Types', JCO Precision Oncology.
See article at PubMed Central See article at publisher's site - C R Boland, S N Thibodeau, S R Hamilton, D Sidransky, J R Eshleman, R W Burt, S J Meltzer, M A Rodriguez-Bigas, R Fodde, G N Ranzani, S Srivastava. (1998) 'A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer', Cancer Research.
See abstract at PubMed Central See article at publisher's site - Lilit Garibyan, Nidhi Avashia. (2013) 'Research Techniques Made Simple: Polymerase Chain Reaction (PCR)', Journal of Investigative Dermatology.
See article at PubMed Central See article at publisher's site - C R Boland, S N Thibodeau, S R Hamilton, D Sidransky, J R Eshleman, R W Burt, S J Meltzer, M A Rodriguez-Bigas, R Fodde, G N Ranzani, S Srivastava. (1998) 'A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer', Cancer Research.
See abstract at PubMed Central See article at publisher's site - Jason Willis, Martina I Lefterova, Alexander Artyomenko, Pashtoon Murtaza Kasi, Yoshiaki Nakamura, Kabir Mody, Daniel V T Catenacci, Marwan Fakih, Catalin Barbacioru, Jing Zhao, Marcin Sikora, Stephen R Fairclough, Hyuk Lee, Kyoung-Mee Kim 10 , Seung Tae Kim, Jinchul Kim, Danielle Gavino, Manuel Benavides, Nir Peled, Timmy Nguyen, Mike Cusnir, Ramez N Eskander, Georges Azzi, Takayuki Yoshino, Kimberly C Banks, Victoria M Raymond, Richard B Lanman, Darya I Chudova, AmirAli Talasaz, Scott Kopetz, Jeeyun Lee, Justin I Odegaard. (2019) 'Validation of Microsatellite Instability Detection Using a Comprehensive Plasma-Based Genotyping Panel', Clinical cancer research.
See abstract at PubMed Central See article at publisher's site - Sally E. Trabucco, Kyle Gowen, Sophia L. Maund, Eric Sanford, David A. Fabrizio, Michael J. Hall, Evgeny Yakirevich, Jeffrey P. Gregg, Phil J. Stephens, Garrett M. Frampton, Priti S. Hegde, Vincent A. Miller, Jeffrey S. Ross, Ryan J. Hartmaier, Shih-Min A. Huang, James X. Sun. (2019) 'A Novel Next-Generation Sequencing Approach to Detecting Microsatellite Instability and Pan-Tumor Characterization of 1000 Microsatellite Instability–High Cases in 67,000 Patient Samples', The Journal of Molecular Diagnostics.
See article at PubMed Central See article at publisher's site - Jennifer A. Hempelmann, Christina M. Lockwood, Eric Q. Konnick, Michael T. Schweizer, Emmanuel S. Antonarakis, Tamara L. Lotan, Bruce Montgomery, Peter S. Nelson, Nola Klemfuss, Stephen J. Salipante, Colin C. Pritchard. (2018) 'Microsatellite instability in prostate cancer by PCR or next-generation sequencing', Journal for ImmunoTherapy of Cancer.
See article at PubMed Central See article at publisher's site - Alicia Latham, Preethi Srinivasan, Yelena Kemel, Jinru Shia, Chaitanya Bandlamudi, Diana Mandelker, Sumit Middha, Jaclyn Hechtman, Ahmet Zehir, Marianne Dubard-Gault, Christina Tran, Carolyn Stewart, Margaret Sheehan, Alexander Penson, Deborah DeLair, Rona Yaeger, Joseph Vijai, Semanti Mukherjee, Jesse Galle, Mark A Dickson, Yelena Janjigian, Eileen M O'Reilly, Neil Segal, Leonard B Saltz, Diane Reidy-Lagunes, Anna M Varghese, Dean Bajorin, Maria I Carlo, Karen Cadoo, Michael F Walsh, Martin Weiser, Julio Garcia Aguilar, David S Klimstra, Luis A Diaz Jr, Jose Baselga, Liying Zhang, Marc Ladanyi, David M Hyman, David B Solit, Mark E Robson, Barry S Taylor, Kenneth Offit, Michael F Berger, Zsofia K Stadler. (2019) 'Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer', Journal of Clinical Oncology.
See article at PubMed Central See article at publisher's site - Wassim Abida, Michael L Cheng, Joshua Armenia, Sumit Middha, Karen A Autio, Hebert Alberto Vargas, Dana Rathkopf, Michael J Morris, Daniel C Danila, Susan F Slovin, Emily Carbone, Ethan S Barnett, Melanie Hullings, Jaclyn F Hechtman, Ahmet Zehir, Jinru Shia, Philip Jonsson, Zsofia K Stadler, Preethi Srinivasan, Vincent P Laudone, Victor Reuter, Jedd D Wolchok, Nicholas D Socci, Barry S Taylor, Michael F Berger, Philip W Kantoff, Charles L Sawyers, Nikolaus Schultz, David B Solit, Anuradha Gopalan, Howard I Scher. (2019) 'Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade', JAMA Oncology.
See article at PubMed Central See article at publisher's site - Jon H. Chung, Ninad Dewal, Ethan Sokol, Paul Mathew, Robert Whitehead, Sherri Z. Millis, Garrett M. Frampton, Gennady Bratslavsky, Sumanta K. Pal, Richard J. Lee, Andrea Necchi, Jeffrey P. Gregg, Primo Lara, Emmanuel S. Antonarakis, Vincent A. Miller, Jeffrey S. Ross, Siraj M. Ali, Neeraj Agarwal. (2019) 'Prospective Comprehensive Genomic Profiling of Primary and Metastatic Prostate Tumors', JCO Precision Oncology.
See article at PubMed Central See article at publisher's site - Pedro Barata, Neeraj Agarwal, Roberto Nussenzveig, Benjamin Gerendash, Ellen Jaeger, Whitley Hatton, Elisa Ledet, Brian Lewis, Jodi Layton, Hani Babiker, Alan Bryce, Rohan Garje, Cy Stein, Lesli Kiedrowski, Philip Saylor, Oliver Sartor. (2021) 'Clinical activity of pembrolizumab in metastatic prostate cancer with microsatellite instability high (MSI-H) detected by circulating tumor DNA', Journal for ImmunoTherapy of Cancer.
See article at PubMed Central See article at publisher's site - Qiyuan Hu, Abbas A. Rizvi, Geoffery Schau, Kshitij Ingale, Yoni Muller, Rachel Baits, Sebastian Pretzer, Aïcha BenTaieb, Abigail Gordhamer, Roberto Nussenzveig, Adam Cole, Matthew O. Leavitt, Ryan D. Jones, Rohan P. Joshi, Nike Beaubier, Martin C. Stumpe, Kunal Nagpal. (2024) 'Development and validation of a deep learning-based microsatellite instability predictor from prostate cancer whole-slide images.', npj Precision Oncology.
See article at publisher's site - Jon H. Chung, Ninad Dewal, Ethan Sokol, Paul Mathew, Robert Whitehead, Sherri Z. Millis, Garrett M. Frampton, Gennady Bratslavsky, Sumanta K. Pal, Richard J. Lee, Andrea Necchi, Jeffrey P. Gregg, Primo Lara, Emmanuel S. Antonarakis, Vincent A. Miller, Jeffrey S. Ross, Siraj M. Ali, Neeraj Agarwal. (2019) 'Prospective Comprehensive Genomic Profiling of Primary and Metastatic Prostate Tumors', JCO Precision Oncology.
See article at PubMed Central See article at publisher's site - Ryon P. Graf, Virginia Fisher, Janick Weberpals, Ole Gjoerup, Marni B. Tierno, Richard S. P. Huang, Nicolas Sayegh, Douglas I. Lin, Kira Raskina, Alexa B. Schrock, Eric Severson, James F. Haberberger, Jeffrey S. Ross, James Creeden, Mia A. Levy, Brian M. Alexander, Geoffrey R. Oxnard, Neeraj Agarwal. (2022) 'Comparative Effectiveness of Immune Checkpoint Inhibitors vs Chemotherapy by Tumor Mutational Burden in Metastatic Castration-Resistant Prostate Cancer', JAMA Network Open.
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