TP53-specific mutations serve as a potential biomarker for homologous recombination deficiency in breast cancer:a clinical next-generation sequencing study

Background:TP53 mutations and homologous recombination deficiency(HRD)occur frequently in breast cancer.However,the characteristics of TP53 pathogenic mutations in breast cancer patients with/without HRD are not clear.Methods:Clinical next-generation sequencing(NGS)of both tumor and paired blood DNA from 119 breast cancer patients(BRCA-119 cohort)was performed with a 520-gene panel.Mutations,tumor mutation burden(TMB),and genomic HRD scores were assessed from NGS data.NGS data from 47 breast cancer patients in the HRD test cohort were analyzed for further verification.Results:All TP53 pathogenic mutations in patients had somatic origin,which was associated with the protein expression of estrogen receptor and progestogen receptor.Compared to patients without TP53 pathologic mutations,patients with TP53 pathologic mutations had higher levels of HRD scores and different genomic alterations.The frequency of TP53 pathologic mutation was higher in the HRDhigh group(HRD score≥42)relative to that in the HRD-low group(HRD score<42).TP53 has different mutational characteristics between the HRD-low and HRD-high groups.TP53-specific mutation subgroups had diverse genomic features and TMB.Notably,TP53 pathogenic mutations predicted the HRD status of breast cancer patients with an area under the curve(AUC)of 0.61.TP53-specific mutations,namely HRD-low mutation,HRD-high mutation,and HRD common mutation,predicted the HRD status of breast cancer patients with AUC values of 0.32,0.72,and 0.58,respectively.Interestingly,TP53 HRD-high mutation and HRD common mutation combinations showed the highest AUC values(0.80)in predicting HRD status.Conclusions:TP53-specific mutation combinations predict the HRD status of patients,indicating that TP53 pathogenic mutations could serve as a potential biomarker for poly-ADP-ribose polymerase(PARP)inhibitors in breast cancer patients.

Epidermal growth factor receptor stabilizes programmed death ligand 1 by glycosylation in colorectal cancer with microstatellite instability status

Programmed death ligand-1(PD-L1)is involved in inhibiting of T lymphocyte proliferation,producing cytokine,cytolytic activity,and suppressing of the immune response.Genes with molecular alterations involved in DNA mismatch repair promote cancer initiation and tumor progression.Clinical studies show that colorectal cancer(CRC)patients harboring microsatellite instability(MSI)have a higher anti-programmed cell death protein 1/PD-L1 immunotherapy response ratio compared with microsatellite stable subgroup patients.The underlying mechanism has however remained unclear.Here,we found that compared with microsatellite stable samples,PD-L1 was glycosylated and highly expressed both in MSI CRC cell lines and tissue samples.Specifically,PD-L1 was Nglycosylated at its N35,N192,N200,and N219 sites,and the four glycosylation sites were all responsible for PD-L1 degradation.Additionally,non-glycosylated PD-L1 underwent rapid degradation compared with glycosylated PD-L1 through the 26S proteasome pathway.The faster degradation of the non-glycosylated PD-L1 was ascribed to its binding to glycogen synthase kinase 3b via ubiquitination.This degradation phenotype was,however,not observed for glycosylated PD-L1.Significantly,glycosylated PD-L1 was up-regulated by activated epidermal growth factor receptor in MSI CRC cells.Together,our results indicate that epidermal growth factor receptor stabilized PD-L1 via glycosylation in MSI CRC cells,uncovering a novel role of PD-L1 in MSI CRC immunosuppression and disease progression.The study was approved by the Clinical Ethics Review Committee at the Six Affiliated Hospital of Sun Yat-sen University,China(Approval No.2019ZSLYEC-005).