OESOPHAGEAL cancer (OAC) is the seventh most common cancer in the world. Patients with this cancer are commonly treated with neoadjuvant chemotherapy, radiotherapy, or surgery. Unfortunately, over half of tumours are resistant to neoadjuvant therapy and survival rates are poor. A novel study, shared at the UEG Week Virtual, aimed to understand the genetic and transcriptomic changes in OAC.
Melissa Schmidt, Centre for Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, UK, and her team investigated treatment response using a multi-omics study to evaluate the genetic and transcriptomic changes caused by neoadjuvant treatment in patients with OAC. Samples were taken from patients with OAC who responded to chemotherapy and from individuals who did not respond to chemotherapy at different stages of treatment (before, during, and after neoadjuvant therapy). Individuals who responded to chemotherapy were given platinum-based chemotherapy whereas patients who did not respond to chemotherapy were given radiochemotherapy instead.
The exons of the genome were sequenced from a total of 65 samples. Forty-two samples were taken from 13 chemotherapy-responding individuals and 23 samples were taken from nine non-responding individuals. In addition, blood samples were drawn and sequenced as a control. Finally, the researchers conducted RNA sequencing on an additional 78 samples: 17 samples from patients responding to chemotherapy and 25 samples from patients who did not respond to chemotherapy.
Fascinatingly, the scientists discovered significant changes in the cell signalling and immune pathways at the transcriptome level in neoadjuvant treatment. Samples taken after treatment showed there was significant enhancements in numerous signalling pathways, including the mitogen-activate protein kinase, phosphoinositide 3–protein kinase B, RAS, Wingless-related integration site, and Hedgehog signalling cascades, all of which are important in cancer development.
Furthermore, there were substantial changes in mutation signatures after a patient underwent neoadjuvant chemotherapy with FOLFOX (folinic acid, fluorouracil, and oxaliplatin). There were also key changes in single nucleotide variant profile, which indicated loss of subclones and spatial heterogeneity. Additionally, the phylogenetic tree analysis revealed there was plasticity in phenotypes due to resistance in treatment. Other insights included the revelation of non-silent mutations, namely, KMT2D, SMARCA4, AXIN1, EGFR, and FAT1–4. All these mutations were new in patients undergoing neoadjuvant treatment.
This novel study showed that major altering genetic and transcriptomic changes were caused in mutation signatures by chemotherapy and radiochemotherapy. Future research could involve studying how these genetic changes occur during neoadjuvant therapy and modifying patient treatments accordingly.
