Low AGR was a strong independent predictor of long-term cancer-specific survival among colorectal cancer patients. Additionally, among the patients with normal albumin (>3.5 g/dl), patients with lower globulins but higher albumin and AGR levels had better survival.

T cell receptors (TCRs) enable T cells to specifically recognize mutations in cancer cells1–3. Here we developed a clinical-grade approach based on CRISPR–Cas9 non-viral precision genome-editing to simultaneously knockout the two endogenous TCR genes TRAC (which encodes TCRα) and TRBC (which encodes TCRβ). We also inserted into the TRAC locus two chains of a neoantigen-specific TCR (neoTCR) isolated from circulating T cells of patients. The neoTCRs were isolated using a personalized library of soluble predicted neoantigen–HLA capture reagents. Sixteen patients with different refractory solid cancers received up to three distinct neoTCR transgenic cell products. Each product expressed a patient-specific neoTCR and was administered in a cell-dose-escalation, first-in-human phase I clinical trial (NCT03970382). One patient had grade 1 cytokine release syndrome and one patient had grade 3 encephalitis. All participants had the expected side effects from the lymphodepleting chemotherapy. Five patients had stable disease and the other eleven had disease progression as the best response on the therapy. neoTCR transgenic T cells were detected in tumour biopsy samples after infusion at frequencies higher than the native TCRs before infusion. This study demonstrates the feasibility of isolating and cloning multiple TCRs that recognize mutational neoantigens. Moreover, simultaneous knockout of the endogenous TCR and knock-in of neoTCRs using single-step, non-viral precision genome-editing are achieved. The manufacture of neoTCR engineered T cells at clinical grade, the safety of infusing up to three gene-edited neoTCR T cell products and the ability of the transgenic T cells to traffic to the tumours of patients are also demonstrated.

Variation in DNA repair capacity, which is believed to be largely determined by genetic traits, is linked to risk of certain cancers. The Asp312Asn and Lys751Gln polymorphisms in the xeroderma pigmentosum complementary group D (XPD) gene may alter DNA repair capacity. We thus examined the hypothesis that these 2 XPD polymorphisms are associated with risk of lung cancer via a large hospital-based, case-control study among Chinese. The study subjects consisted of 1,006 patients with primary lung cancer and 1,020 age-and sex-matched population controls. XPD genotypes were determined using PCR-RFLP techniques, and the associations between genotypes and risk of lung cancer were estimated by odds ratios (ORs) and their 95% confidence intervals (CIs) calculated by unconditional logistic regression. The DNA repair system plays an important role in protecting against mutagenesis and carcinogenesis. It has been documented that the defect in DNA repair causes several hereditary cancer syndromes 1 and the development of some common sporadic cancers may also associated with reduced DNA repair capacity. [2][3][4] Accumulating evidence indicates that variation in DNA repair capacity is likely to be largely determined by genetic traits. The defect of DNA repair often results from gene mutations. However, single nucleotide polymorphisms (SNPs), when located within the coding and/or regulating regions of the gene, can also spoil DNA repair capacity due to the amino acid substitution or diminished protein expression. XPD (xeroderma pigmentosum complementary group D), an important DNA repair protein, encodes an evolutionarily conserved ATP-dependent helicase that participates in both nucleotide excision repair and basal transcription as part of the transcription factor TFIIH. 5 Mutations at different sites in XPD that destroy XPD protein function cause 3 severe syndromes: Cockayne's syndrome, trichotiodystrophy and xeroderma pigmentosum, which exhibits a Ͼ1,000-fold incidence of sun-induced skin cancer and elevated risk of internal cancers. 6,7 Several SNPs have also been identified in the XPD locus. Among them, a G-to-A transition in codon 312 of exon 10 results in an Asp3 Asn substitution in an evolutionarily conserved region, and another transversion, A-to-C in codon 751 of exon 23, produces a Lys3 Gln substitution. 8 The 2 sites are reported to be in linkage disequilibrium and appear to have phenotypic significance, although contradictory results exist regarding which allele is associated with impaired DNA repair capacity. 4,9 -14 Since XDP is one of the important components in the nucleotide excision repair (NER) and NER is the most flexible pathway that has the ability to remove a broad range of DNA damage such as BPDE-DNA adducts induced by benzo(a)pyrene, 15,16 a major constituent of tobacco smoking, the impact of these 2 genetic variations in XPD on risk of cancer in addition to skin cancer has been attracting research interest. Some case-control studies have been conducted in different ethnic populations to investigate ...

Esophageal squamous cell carcinoma (ESCC), which is prevalent in China, is believed to be induced by environmental carcinogens. Accumulating evidence has shown that individual variation in DNA repair capacity resulting from genetic polymorphism influences risk of environmental carcinogenesis. We therefore investigated the associations between genetic polymorphisms in the DNA repair genes XRCC1 (Arg194Trp and Arg399Gln) and XPD (Asp312Asn and Lys751Gln) and risk of ESCC in an at-risk Chinese population. Genotypes were determined by a PCR-based approach in 433 patients with ESCC and 524 frequency-matched normal controls. We found that individuals with Trp/Trp genotype at XRCC1 Arg194Trp site had a 2-fold increased risk of this disease compared to Arg/Arg genotype (adjusted OR ‫؍‬ 1.98; 95% CI 1.26 -3.12). Furthermore, when compared to Arg/Arg and Arg/Trp genotype combined, homozygote for Trp/Trp genotype significantly increased the risk of developing ESCC, with the adjusted OR being 2.07 (95% CI 1.34 -3.20). However, the XRCC1 Arg399Gln polymorphism was not significantly associated with risk of ESCC, with the adjusted OR being 0.87 (95% CI 0.55-1.37). Neither Asp312Asn nor Lys751Gln polymorphisms in the XPD gene influenced risk of ESCC in our study. These findings suggest that DNA repair gene XRCC1 but not XPD might play a role in esophageal carcinogenesis and might represent a genetic determinant in the development of the cancer.

Aberrant elevation of JARID1B and histone H3 lysine 4 trimethylation (H3K4me3) is frequently observed in many diseases including prostate cancer (PCa), yet the mechanisms on the regulation of JARID1B and H3K4me3 through epigenetic alterations still remain poorly understood. Here we report that Skp2 modulates JARID1B and H3K4me3 levels in vitro in cultured cells and in vivo in mouse models. We demonstrated that Skp2 inactivation decreased H3K4me3 levels, along with a reduction of cell growth, cell migration and malignant transformation of Pten/Trp53 double null MEFs, and further restrained prostate tumorigenesis of Pten/Trp53 mutant mice. Mechanistically, Skp2 decreased the K63-linked ubiquitination of JARID1B by E3 ubiquitin ligase TRAF6, thus decreasing JARID1B demethylase activity and in turn increasing H3K4me3. In agreement, Skp2 deficiency resulted in an increase of JARID1B ubiquitination and in turn a reduction of H3K4me3, and induced senescence through JARID1B accumulation in nucleoli of PCa cells and prostate tumors of mice. Furthermore, we showed that the elevations of Skp2 and H3K4me3 contributed to castration-resistant prostate cancer (CRPC) in mice, and were positively correlated in human PCa specimens. Taken together, our findings reveal a novel network of SKP2- JARID1B, and targeting SKP2 and JARID1B may be a potential strategy for PCa control.