Mutated DNA Damage Repair Pathways Are Prognostic and Chemosensitivity Markers for Resected Colorectal Cancer Liver Metastases

Abstract

Deficiency of the DNA damage repair (DDR) signaling pathways is potentially responsible for genetic instability and oncogenesis in tumors, including colorectal cancer. However, the correlations of mutated DDR signaling pathways to the prognosis of colorectal cancer liver metastasis (CRLM) after resection and other clinical applications have not been fully investigated. Here, to test the potential correlation of mutated DDR pathways with survival and pre-operative chemotherapy responses, tumor tissues from 146 patients with CRLM were collected for next-generation sequencing with a 620-gene panel, including 68 genes in 7 DDR pathways, and clinical data were collected accordingly. The analyses revealed that 137 of 146 (93.8%) patients had at least one mutation in the DDR pathways. Mutations in BER, FA, HRR and MMR pathways were significantly correlated with worse overall survival than the wild-types (P < 0.05), and co-mutated DDR pathways showed even more significant correlations (P < 0.01). The number of mutated DDR pathways was also proved an independent stratifying factor of overall survival by Cox multivariable analysis with other clinical factors and biomarkers (hazard ratio = 9.14; 95% confidence interval, 1.21–68.9; P = 0.032). Additionally, mutated FA and MMR pathways were positively and negatively correlated with the response of oxaliplatin-based pre-operative chemotherapy (P = 0.0095 and 0.048, respectively). Mutated DDR signaling pathways can predict pre-operative chemotherapy response and post-operative survival in CRLM patients.

Prognosis of resectable colorectal liver metastases after surgery associated with pathological features of primary tumor

“…In the genomic analysis of 137 CRLM patients’ tumor tissues by Wang Kun et al. ( 16 ), defects in DNA damage repair signaling pathways such as MMR were found to have a significant negative impact on the overall survival of patients. dMMR in particular was found to be a significant indicator for OS in patients with colorectal cancer after surgical treatment in the study of Wen-Yue Yan et al.…”

“…However, complete or partial expression of MMR protein is more likely to cause intrahepatic recurrence (15). In the genomic analysis of 137 CRLM patients' tumor tissues by Wang Kun et al (16), defects in DNA damage repair signaling pathways such as MMR were found to have a significant negative impact on the overall survival of patients. dMMR in particular was found to be a significant indicator for OS in patients with colorectal cancer after surgical treatment in the study of Wen-Yue Yan et al (17), who found that patients with dMMR also had longer PFS and OS compared to those with pMMR.…”

Colorectal Cancer Immunotherapy: State of the Art and Future Directions

“… 34 A further implication of the impact of genomic instability on antitumor immunity in CRC is that many chemotherapeutic treatments currently in clinical use to treat CRC, such as the FOLFOX or FOLFIRI regimens, induce DNA damage that can activate the cGAS/STING pathway. 35 – 38 This implies that combinatorial treatments of chemotherapeutic regimens or radiotherapy with immune checkpoint inhibitors (ICIs) could potentially improve the prognosis of many CRC patients. 39 …”