BRAFV600E immunohistochemistry facilitates universal screening of colorectal cancers for lynch syndrome
Open accessAbstract
BRAFV600E mutation in microsatellite-unstable (MSI) colorectal carcinomas (CRCs) virtually excludes Lynch syndrome (LS). In microsatellite-stable (MSS) CRCs it predicts poor prognosis. We propose a universal CRC LS screening algorithm using concurrent reflex immunohistochemistry (IHC) for BRAFV600E and mismatch-repair (MMR) proteins. We compared BRAFV600E IHC with multiplex polymerase chain reaction (PCR) and matrix-assisted laser desorption/ionization-time of flight mass spectrometry in 216 consecutive CRCs from 2011. Discordant cases were resolved with real-time PCR. BRAFV600E IHC was performed on 51 CRCs from the Australasian Colorectal Cancer Family Registry (ACCFR), which were fully characterized for BRAF mutation by allele-specific PCR, MMR status (MMR IHC and MSI), MLH1 promoter methylation, and germline MLH1 mutation. We then assessed MMR and BRAFV600E IHC on 1403 consecutive CRCs. By matrix-assisted laser desorption/ionization-time of flight mass spectrometry 15 cases did not yield a BRAF result, whereas 38/201 (19%) were positive. By IHC 45/216 (20%) were positive. Of the 7 discordant cases, real-time PCR confirmed the IHC result in 6. In the 51 CRCs from the ACCFR, IHC was concordant with allele-specific PCR in 50 cases. BRAFV600E and MSI IHC on 1403 CRCs demonstrated the following phenotypes: BRAF/MSS (1029 cases, 73%), BRAF/MSS (98, 7%), BRAF/MSI (183, 13%), and BRAF/MSI (93, 7%). All 11/1403 cancers associated with proven LS were BRAF/MSI. We conclude that BRAF IHC is highly concordant with 2 commonly used PCR-based BRAFV600E assays; it performed well in identifying MLH1 mutation carriers from the ACCFR and identified all cases of proven LS among the 1403 CRCs. Reflex BRAFV600E and MMR IHC are simple cheap tests that facilitate universal LS screening and identify the poor prognosis of the BRAFV600E-mutant MSS CRC phenotype.
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dMMR/BRAFV600E-negative tumors exhibit improved overall survival compared to dMMR/BRAFV600E-positive and proficient MMR/BRAFV600E-negative or proficient MMR/BRAFV600E-positive tumors.
“Despite growing evidence indicating that dMMR/BRAFV600E(−) tumors exhibit improved overall survival (OS) compared to dMMR/BRAFV600E(+) and proficient MMR (pMMR)/BRAFV600E(−) or pMMR/BRAFV600E(+) tumors [49,51]”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [51]
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- Authors
- Toon, C. W., Walsh, M. D., Chou, A., Capper, D., Clarkson, A., Sioson, L., Clarke, S., Mead, S., Walters, R. J., Clendenning, M., Rosty, C., Young, J. P., Win, A. K., Hopper, J. L., Crook, A., von Deimling, A., Jenkins, M. A., Buchanan, D. D., & Gill, A. J.
- Affiliations
- The University of Sydney (AU)
- The University of Queensland (AU)
- UNSW Sydney (AU)
- Heidelberg University (DE)
- QIMR Berghofer Medical Research Institute (AU)
- St Vincent's Hospital Sydney (AU)
- Royal North Shore Hospital (AU)
- Corresponding author
- Toon, Christopher W.
- Capper, David
- Clarkson, Adele
- Sioson, Loretta
- Gill, Anthony J.
- ORCID
- Venue
- American Journal of Surgical Pathology
- Published
- 2013-10
- Volume
- 37
- Issue
- 10
- Pages
- 1592-1602
- ISSN
- 0147-5185 (ISSN-L)
- PMC
- PMC3773060
- OpenAlex
- W1983162753
- Cited by
- 136
- References
- 39
- Citations by year
- 2025: 5 · 2024: 14 · 2023: 3 · 2022: 5 · 2021: 14 · 2020: 5 · 2019: 10 · 2018: 9 · 2017: 13 · 2016: 16 · 2015: 16 · 2014: 20 · 2013: 6
- FWCI
- 14.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- The American Journal of Surgical Pathology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Funders
- National Comprehensive Cancer Network
- National Cancer Institute (UM1CA167551, U24CA097735, # CA-95-011, U01CA097735)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Keywords
- BRAF V600E mutation, Lynch syndrome, colorectal cancer, microsatellite instability, mismatch repair proteins, universal screening, MLH1 promoter methylation
- MeSH terms
- Algorithms, Colorectal Neoplasms, Hereditary Nonpolyposis, Female, Humans, Immunohistochemistry, Male, Mass Screening, Mutation, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Tissue Array Analysis, Proto-Oncogene Proteins B-raf, Microsatellite Instability, DNA Mismatch Repair, Multiplex Polymerase Chain Reaction
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