Immunogenetic polymorphisms predict therapeutic efficacy and survival outcomes in tumor patients receiving PD-1/PD-L1 blockade.

BACKGROUND: While immune checkpoint inhibitors (ICIs) demonstrate remarkable clinical responses, only a small subset of patients obtains benefits. Genes linked to the tumor immune system are confirmed to be critical for the treatment of ICIs, and their polymorphisms can contribute to ICI efficacy. Here, we examined the potential of immunogenetic variations to predict the efficacy and survival of the PD-1/PD-L1 blockade. METHODS: Cancerous patients receiving PD-1/PD-L1 blockade were recruited and followed up. Pivotal genes related to tumor-immunity were filtered through a protein-protein interaction network and the degree algorithm in Cytoscape. Finally, 39 genetic variants were genotyped through multiplex genotyping assays. Association analyses between variants and ICI efficacy and progression-free survival (PFS) were performed. RESULTS: Overall, 318 patients were ultimately enrolled. Hence, three immunogenetic variants were identified as predictors of PD-1/PD-L1 blockade response. Mutant alleles from ATG7 rs7625881, CD274 rs2297136, and TLR4 rs1927911 were all at increased risk of tumor progression following ICI therapy (OR: 1.475, 1.641, 1.462, respectively; P value: 0.028, 0.017, 0.027, respectively). Significant immunogenetic variants also attained similar trends in the PD-1 blockade, lung cancer, or lung cancer using PD-1 blockade subgroups. Furthermore, the mutant genotypes of CD274 rs2297136 (GG as the reference: HR: 0.50 (95%CI: 0.29-0.88), P value: 0.015) and TLR4 rs1927911 (AA as the reference: HR: 0.65 (95%CI: 0.47-0.91), P value: 0.012) indicated poorer PFS and were both independent prognostic factors. CONCLUSION: Immunogenetic polymorphisms, including ATG7 rs7625881, CD274 rs2297136, and TLR4 rs1927911, were first identified as potential predictors of response to PD-1/PD-L1 blockade in tumor patients.

Allele frequency and proportion defined by circulating tumor DNA profiling predict tyrosine kinase inhibitors' therapeutic outcomes for non-small cell lung cancer.

PURPOSE: Circulating tumor DNA is more and more accessible for patients who cannot undergo biopsy. No consistent conclusion has been reached on whether frequency and proportion of mutations defined by ctDNA profiling can predict therapeutic outcomes. METHODS: One hundred patients with non-small cell lung cancer harboring activating EGFR mutations (exon 19 deletion, L858R and T790M mutation) were collected in West China hospital from December 18, 2017 to December 31, 2019. We retrospectively analyzed the frequency and proportion distribution of ctDNA mutations and its relationship with tyrosine kinase inhibitors therapeutic outcomes. RESULTS: Patients with lower frequency of sensitizing EGFR mutations (< 3%) had a longer progression-free survival (PFS) time than those with higher frequency (15 months vs. 10 months, p = 0.028). Moreover, patients with the lower ratio of T790M mutation frequency and the maximum-somatic-allele-frequency (T790M/MSAF < 30%) had a less prolonged PFS than those with higher T790M/MSAF (7 months vs. 15 months, p = 0.013). CONCLUSION: The frequency and proportion of ctDNA mutations are worth clinical attention in the prediction of therapeutic outcomes.

IKBKE and BANK1 Polymorphisms and Clinical Characteristics in Chinese Women with Systemic Lupus Erythematosus.

BACKGROUND: Defects in apoptotic cell clearance is a pathogenic factor in systemic lupus erythematosus (SLE). This study screened potential pathogenic single nucleotide polymorphisms (SNPs) related to anti-apoptosis from an SLE family and explored their contribution to SLE susceptibility in Chinese women. METHODS: Four SNPs (IKBKE rs15672, BANK1 rs12640056, BANK1 rs6842661, and NFKBIA rs1957106) with potential SLE susceptibility were analyzed for clinical characteristics between 567 patients with SLE and 345 healthy control subjects. RESULTS: IKBKE rs15672 G/A and BANK1 rs12640056C/T polymorphisms were associated with SLE susceptibility (rs15672 A vs G, P = 0.028, OR = 1.25, 95% CI = 1.02-1.52; rs12640056 T vs C, P = 0.015, OR = 0.78, 95% CI = 0.64-0.95, respectively). In addition, patients with AA+GA genotypes of IKBKE rs15672 had higher positive rates of anti-SSB antibodies (q = 0.008) and lower positive rates of anti-RIB antibodies (q = 0.024) than those with the GG genotype. There were no significant differences in BANK1 rs12640056 between different genotypes and clinical characteristics. CONCLUSION: IKBKE rs15672 G/A and BANK1 rs12640056C/T polymorphisms are associated with susceptibility to SLE in Chinese women. This highlights the important role of these two SNPs in this disease and suggests that multiple genes from these pathways are candidates for functional studies and therapeutic targets.

Analysis of WDFY4 rs7097397 and PHLDB1 rs7389 polymorphisms in Chinese patients with systemic lupus erythematosus.

OBJECTIVES: To explore the relationship among patient-specific SNPs from one SLE family, lupus susceptibility, and laboratory indicators in a western Chinese population. METHODS: We previously performed whole exome sequencing in one SLE family and screened 5 SLE candidate SNPs. In this study, we verified them in 634 SLE patients and 400 healthy controls and analyzed the relationship between SNPs and laboratory indicators. RESULTS: Among the 5 candidate SNPs, PHLDB1 rs7389T/G (dominant model, OR = 0.627, 95%CI = 0.480-0.820, P = 0.001) and WDFY4 rs7097397G/A (dominant model, OR = 0.653, 95%CI = 0.438-0.973, P = 0.035) were associated with SLE susceptibility. In addition, the G allele of rs7389 was related to an increased level of TNF-α (q = 0.013). The A allele of rs7097397 was related to reduced levels of IL-1ß (q = 0.033) and IL-6 (q = 0.039) and high positive rate of antinuclear antibodies (q = 0.021). CONCLUSIONS: Our study indicated that both the rs7389T/G and rs7097397G/A polymorphisms were related to SLE susceptibility in western China. rs7389T/G was related to increased TNF-α content, while rs7097397G/A was associated with reduced IL-1ß and IL-6 content and increased antinuclear antibody positive rate. Key Points • The G allele of rs7389 was related to reduced susceptibility to SLE. • The A allele of rs7097397 was associated with reduced susceptibility to SLE. • The G allele of rs7389 was related to increased levels of TNF-α. • The A allele of rs7097397 was related to decreased concentrations of IL-1ß and IL-6, as well as an increased positive rate of antinuclear antibody.

Anti-Golgi Antibody as a Potential Indicator for Rheumatoid Arthritis.

OBJECTIVE: To reveal the relationship between anti-Golgi antibody (AGA) and clinical diseases through retrospective analysis. METHODS: The clinical data of 584 cases testing positive for AGA in the past 11 years were collected and retrospectively analyzed. RESULTS: AGA pattern accounted for .2% of positive ANA results. In total, 35.0% of diagnosed patients had autoimmune diseases (AID), mainly rheumatoid arthritis (RA). High-titer AGA (≧1:1000) was common in AID. In nondiagnosed patients with clinical symptoms, joint pain/muscle pain was the most common. CONCLUSIONS: Positive AGA with high titer was closely related to RA. Joint pain/muscle pain was the most common symptom in patients who tested AGA positive. Therefore, AGA may be a key indicator of RA in the Chinese population.

Clinical application of free/total PSA ratio in the diagnosis of prostate cancer in men over 50 years of age with total PSA levels of 2.0-25.0 ng ml-1 in Western China.

The goal of this study was to investigate the clinical application of free/total prostate-specific antigen (F/T PSA) ratio, considering the new broad serum total PSA (T-PSA) "gray zone" of 2.0-25.0 ng ml-1 in differential diagnosis of prostate cancer (PCa) and benign prostate diseases (BPD) in men over 50 years in Western China. A total of 1655 patients were included, 528 with PCa and 1127 with BPD. Serum T-PSA, free PSA (F-PSA), and F/T PSA ratio were analyzed. Receiver operating characteristic curves were used to assess the efficiency of PSA and F/T PSA ratio. There were 47.4% of cancer patients with T-PSA of 2.0-25.0 ng ml-1. When T-PSA was 2.0-4.0 ng ml-1, 4.0-10.0 ng ml-1, and 10.0-25.0 ng ml-1, the area under the curve (AUC) of F/T PSA ratio was 0.749, 0.769, and 0.761, respectively. The best AUC of F/T PSA ratio was 0.811 when T-PSA was 2.0-25.0 ng ml-1, with a specificity of 0.732, a sensitivity of 0.788, and an optimal cutoff value of 15.5%. The AUC of F/T PSA ratio in different age groups (50-59 years, 60-69 years, 70-79 years, and ≥80 years) was 0.767, 0.806, 0.815, and 0.833, respectively, and the best sensitivity (0.857) and specificity (0.802) were observed in patients over 80 years. The T-PSA trend was in accordance with the Gleason score, tumor node metastasis (TNM) stage, and American Joint Committee on Cancer prognosis group. Therefore, the F/T PSA ratio can facilitate the differential diagnosis of PCa and BPD in the broad T-PSA "gray zone". Serum T-PSA can be a Gleason score and prognostic indicator.

The value of anti-rods and rings antibodies in Western China population: A retrospective study.

The study aimed to retrospectively investigate the clinical significance of anti-rods and rings (anti-RR) antibodies in antinuclear antibodies (ANAs) test samples of western China. Between January 2016 and November 2018, the laboratory data and clinical details of patients with positive anti-RR antibodies were collected and analysed. The results showed that total of 197 227 patients tested, 109 453 patients presented with positive ANAs (55.50%), but only 107 patients with positive anti-RR antibodies (0.10%), including 51 females and 56 males. Diagnose were established in 51 of 107 patients: 25 were hepatopathy (HCV 8/25, HBV 12/25); 13 were autoimmune diseases (AID); and 7 were renal insufficiency; 6 were chronic obstructive pulmonary disease (COPD). We make the conclusions that anti-RR antibodies have a low prevalence, and there is no gender difference. Anti-RR antibodies exist other diseases besides hepatitis C, such as HBV, some autoimmune diseases, renal insufficiency and COPD, which we need further investigation.