Mutational Signatures in Colorectal Cancer: Translational Insights, Clinical Applications, and Limitations
Abstract
:Simple Summary
Abstract
1. Introduction: Historical Perspective on Mutational Signature
2. Mutational Signature Characterizing Colorectal Cancer Tumors
2.1. Specific Signatures of MSI/MMRd CRC
- SBS6 is associated with MMRd cells and is commonly found in cancers with MMR deficiency, including those associated with Lynch syndrome. It demonstrates a markedly elevated incidence of C>T transitions at NpCpG trinucleotides.
- SBS14 is linked to MMR deficiency and is often associated with tumors exhibiting high microsatellite instability.
- SBS15 is associated with MMR deficiency and UV light exposure and is characterized by a high number of C>T transitions at dipyrimidines.
- SBS20 has been linked to defective DNA mismatch repair, though it is less prevalent and is often found in MSI-high cancers.
- SBS21 is also linked to MMR deficiency, though its relationship with this process is less well understood than that of other MMR-related signatures.
- SBS26 is specifically associated with defective mismatch repair, which is characterized by a high level of C>A and C>T mutations. It could be related to the high consumption of alcohol.
- SBS44 is associated with defective DNA mismatch repair and often found in combination with other MMR-related signatures or with a co-occurrence of colibactin-related SBS88.
2.2. Specific Signature of MSS/MMRp POLE-Mutant CRC
- SBS10A: This variant is characterized by a high number of T>G mutations and is linked to mutations in the exonuclease domain of POLE.
- SBS10B is analogous to SBS10A, yet it may exhibit disparate mutation contexts and slightly variant mutation spectra. Nevertheless, it remains associated with POLE mutations.
2.3. Specific Signature of MSS/MMRp POLE wt CRC
- SBS1 is frequently linked to the spontaneous deamination of 5-methylcytosine, which results in C>T transitions. It has been identified as exhibiting a clock-like pattern, whereby the number of mutations in most cancers and normal cells can be correlated with the age of the individual or the tumor. Furthermore, SBS1 has been observed in colon adenomas.
- SBS5 is a similar clock-like signature with an unknown etiology that has been observed in numerous cancer types.
- SBS17A has been linked to oxidative damage and has been associated with gastric cancers. However, it has also been identified in CRC.
- SBS17B: This is similar to SBS17A and may be linked to oxidative damage, and some studies associated SBS17b with fluorouracil (5FU) chemotherapy.
- SBS18 is distinguished by C>A transversions, which may be associated with reactive oxygen species.
- SBS23 is a rare and poorly understood phenomenon that has been observed on occasion in CRC.
- SBS28 is a rare phenomenon with an unclear etiology. In some cases, it was found related to the emergence of SBS10a, SBS10b, and SBS17b signatures.
- SBS37 is less prevalent and the mechanisms underlying its occurrence remain unclear. It has been observed in a range of cancers, albeit infrequently.
- SBS40 is a ubiquitous signature with an unknown etiology, present in a multitude of cancer types (until COSMIC version 3.3) and was superseded by SBS40a, SBS40b, and SBS40c in COSMIC version 3.4.
- SBS44 has been previously associated with defective mismatch repair. Additionally, it can manifest in microsatellite-stable (MSS) tumors, albeit to a lesser extent. It can co-occur with SBS88.
- SBS93 is frequently found in MSS primary tumors but almost absent in MSI; it has been associated with esophageal and gastric cancers and could be related to diet or smoking but these data should be confirmed in further studies.
2.4. Additional Mutational Signatures Found in All CRCs
3. Perspective on Clinical Applications and Benefits of Mutational Signature Analysis in Colorectal Cancer
3.1. Improving Minimal Residual Disease Tests in Stage II (High-Risk) and Stage III CRC after Surgery
3.2. CRC Stratification Based on the Effect of Genetic and Epigenetic Changes
3.3. Identification of Potential Vulnerabilities by Mutational Signatures Analysis
3.4. Evaluation of Drug Effects and Guiding the Therapy
4. Limitations of Mutational Signature Analysis
5. Conclusions
Funding
Acknowledgments
Conflicts of Interest
References
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Crisafulli, G. Mutational Signatures in Colorectal Cancer: Translational Insights, Clinical Applications, and Limitations. Cancers 2024, 16, 2956. https://doi.org/10.3390/cancers16172956
Crisafulli G. Mutational Signatures in Colorectal Cancer: Translational Insights, Clinical Applications, and Limitations. Cancers. 2024; 16(17):2956. https://doi.org/10.3390/cancers16172956
Chicago/Turabian StyleCrisafulli, Giovanni. 2024. "Mutational Signatures in Colorectal Cancer: Translational Insights, Clinical Applications, and Limitations" Cancers 16, no. 17: 2956. https://doi.org/10.3390/cancers16172956