Single-cell AI-based detection and prognostic and predictive value of DNA mismatch repair deficiency in colorectal cancer
Testing for DNA mismatch repair deficiency (MMRd) is recommended for all colorectal cancers (CRCs). Automating this would enable precision medicine, particularly if providing information on etiology not captured by deep learning (DL) methods. We present AIMMeR, an AI-based method for determination of mismatch repair (MMR) protein expression at a single-cell level in routine pathology samples. AIMMeR shows an area under the receiver-operator curve (AUROC) of 0.98, and specificity of ≥75% at 98% sensitivity against pathologist ground truth in stage II/III in two trial cohorts, with positive predictive value of ≥98% for the commonest pattern of somatic MMRd. Lower agreement with microsatellite instability (MSI) testing (AUROC 0.86) reflects discordance between MMR and MSI PCR rather than AIMMeR misclassification. Analysis of the SCOT trial confirms MMRd prognostic value in oxaliplatin-treated patients; while MMRd does not predict differential benefit of chemotherapy duration, it correlates with difference in relapse by regimen (P<sub>Interaction</sub> = 0.04). AIMMeR may help reduce pathologist workload and streamline diagnostics in CRC.
Authors
- Ann‐Katrin Rodewald
- Rachel Kerr (ORCID: https://orcid.org/0000-0002-7240-3269)
- Marta Nowak (ORCID: https://orcid.org/0000-0002-8398-2171)
- Faiz Jabbar (ORCID: https://orcid.org/0000-0001-6304-3874)
- Luciana Gneo (ORCID: https://orcid.org/0000-0002-1890-2665)
- Andrea Harkin (ORCID: https://orcid.org/0000-0002-8831-7381)
- David Kerr (ORCID: https://orcid.org/0000-0001-7811-6722)
- Francesco Pezzella (ORCID: https://orcid.org/0000-0003-1505-7854)
- Mark Saunders (ORCID: https://orcid.org/0000-0002-7195-4712)
- Timothy Iveson (ORCID: https://orcid.org/0000-0002-4681-2712)
- Caroline Kelly (ORCID: https://orcid.org/0000-0002-5330-7888)
- Owen J. Sansom (ORCID: https://orcid.org/0000-0001-9540-3010)
- Joanne Edwards (ORCID: https://orcid.org/0000-0002-7192-6906)
- Jennifer Hay (ORCID: https://orcid.org/0000-0001-9973-4992)
- Noori Maka
- Alistair Easton (ORCID: https://orcid.org/0000-0001-8148-5406)
- Enric Domingo (ORCID: https://orcid.org/0000-0003-4390-8767)
- Karin Oein
- Tijana Tomasevic
- Ian Tomlinson
Institutions
- Centre for Human Genetics (GB)
- University of Zurich (CH)
- University of Oxford (GB)
- Life Science Zurich (CH)
- Center for Pediatric Endocrinology Zurich (CH)
- The Christie NHS Foundation Trust (GB)
- Cancer Research UK Scotland Institute (GB)
- Oxford BioMedica (United Kingdom) (GB)
- Queen Elizabeth University Hospital (GB)
- University of Southampton (GB)
- University of Glasgow (GB)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-09-01
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101727
- Citations
- 7
- Primary Topic
- Genetic factors in colorectal cancer
- Type
- article
- Field-Weighted Citation Impact
- 2.97
Funders
- Cancer Research UK
- National Institute for Health and Care Research
- University of Glasgow
- Promedica Stiftung
- NIHR Oxford Biomedical Research Centre