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.
Highlights
Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related deaths [1]
According to the World Health Organization criteria, the response to chemotherapy was classified, which agrees with the Response Evaluation Criteria in Solid Tumors (RECIST)
Regular functions of DNA damage repair (DDR) are essential to regular replication and metabolism for cells
Summary
Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related deaths [1]. 50% of patients diagnosed with colorectal cancer will develop liver metastases during their disease. Surgical resection of colorectal liver metastases (CRLM) remains the only potentially curative therapy, with 5-year survival rates exceeding 50% in many series. Of patients who undergo liver resection, 50% to 75% will develop disease recurrence within 2 years after resection [2, 3]. Accurate prognostic markers are needed for risk stratification and optimization of patient selection for hepatic resection. The prognostic landscape for predicting long-term outcomes in patients undergoing CRLM resection is changing [4,5,6,7,8]. The molecular and genetic determinants of metastatic colorectal cancer’s outcomes continue to expand, the importance of these molecular biomarkers in the personalized management of CRLM will only continue to increase
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