上尿路尿路上皮癌中同源重组修复（HRR）相关基因的突变模式

Homologous recombination (HR) repair (HRR) has been indicated to be a biomarker for immunotherapy, chemotherapy, and poly-ADP ribose polymerase inhibitors inhibitors (PARPis). Nonetheless, their molecular correlates in upper tract urothelial carcinoma (UTUC) have not been well studied. This study aimed to explore the molecular mechanism and tumor immune profile of HRR genes and the relevance of their prognostic value in patients with UTUC.

One hundred and ninety-seven tumors and matched blood samples from Chinese UTUC were subjected to next-generation sequencing. A total of 186 patients from The Cancer Genome Atlas were included. Comprehensive analysis was performed.

In Chinese patients with UTUC, 5.01% harbored germline HRR gene mutations, and 1.01% had Lynch syndrome-related genes. A total of 37.6% (74/197) of patients carried somatic or germline HRR gene mutations. There was marked discrepancy in the mutation landscapes, genetic interactions, and driver genes between the HRR-mut cohorts and HRR-wt cohorts. Aristolochic acid signatures and defective DNA mismatch repair signatures only existed in individuals in the HRR-mut cohorts. Inversely, the unknown signature (signature A) and signature SBS55 only existed in patients in the HRR-wt cohorts. HRR gene mutations regulated immune activities by NKT cells, plasmacytoid dendritic cells, hematopoietic stem cell, and M1 macrophages. In patients with local recurrence, patients with HRR gene mutations had poorer DFS rates than patients with wild-type HRR genes.

Our results imply that the detection of HRR gene mutations can predict recurrence in patients with UC. In addition, this study provides a path to explore the role of HRR-directed therapies, including PARPis, chemotherapy, and immunotherapy.