Cancer Genomics & Proteomics最新文献

Background/aim: Recently, neoantigen (NA) profiling has been intensively performed for the development of novel immunotherapy. We previously reported a melanoma case with a high tumor mutation burden that achieved complete remission after anti-programmed death-1 therapy. We herein revisited the same case, characterized the NA profiles of other metastatic lesions using in silico algorithms and in vitro CTL assays, and investigated the immunological status, including tumor-infiltrating lymphocytes and the T cell receptor (TCR) repertoire profile, in metastatic sites.

Materials and methods: NA candidates obtained from whole-exome sequencing were applied to the HLA-binding prediction algorithm, NetMHCpan4.1. HLA-A*2402-restricted sequence candidates with a strong binding capacity (<50 nM) and elution affinity (<1%) were selected and evaluated for synthetic peptide candidates. The immunological status in metastatic sites was characterized using gene expression profiling, immunohistochemistry, and a TCR repertoire analysis.

Results: The genomic analysis revealed that all metastatic sites, such as costal, intra-muscular, and brain lesions, had >1,500 SNVs, and 12 driver mutations were common to all sites. New driver mutations were identified in intra-muscular (KMT2C: p.P3292S) and brain (JAK1: p.S404P) metastases and a functional analysis of these mutations revealed that JAK1 mutation exhibited a promoting effect on invasion activity. CTL assays using synthetic NA peptides identified more NA epitopes in brain metastasis.

Conclusion: These results might suggest that the heterogeneity of driver gene mutations is unremarkable, while immunological response is variable in metastatic sites. As a result, the genomic and immunological investigation has provided a very valuable and informative suggestion regarding better cancer therapy decisions.

Background/aim: Despite the excellent prognosis post thyroidectomy and radioiodine therapy, papillary thyroid cancer (PTC) patients still undergo dismal outcomes, especially when tumors undergo de-differentiation and thus progress to radioiodine refractory status. Our knowledge on the pathogenesis mechanisms of PTC and NIS protein (responsible for iodine uptake) activity is still behind satisfaction. To increase our knowledge on these issues, we conducted this study.

Materials and methods: We analyzed microarray data to identify the genes differentially expressed between normal and tumor thyroid tissues. Next, pathway enrichment analysis was conducted to derive candidate genes and pathways involved in PTC oncogenesis and NIS activity. The expression of candidate genes was confirmed by an independent TCGA dataset. Then, we used siRNA to knockdown the MDM2 gene to examine the potential pathogenesis mechanisms of MDM2 and MDM2-P53-NIS axis in cells. Also, we examined whether oncogenic activities, including cell proliferation, colony formation, cell migration and cell invasion, were altered with MDM2 knockdown. Moreover, NIS protein intensity in cell membrane was also investigated.

Results: Through analyzing microarray data, pathway enrichment and correlation analyses, we focused on MDM2 since it could be involved in the MDM2-P53-NIS axis. Knockdown of MDM2 significantly reduced the mRNA levels and protein abundance of MDM2. In addition, P53 protein was also elevated with MDM2 knockdown. With MDM2 knockdown, cell proliferation and colony formation were repressed. And, both cell migration and invasion abilities were interfered. Moreover, MDM2 knockdown also enhanced the intensity of membrane NIS protein.

Conclusion: MDM2 knockdown not only reduced the oncogenic activities of thyroid cancer but also enhanced the intensity of NIS protein responsible for iodine intake in thyroid gland. Therefore, MDM2 could serve as a prognosis indicator in thyroid cancer.

Therapy resistance, including castration-resistance and metastasis, remains a major hurdle in the treatment of prostate cancer. In order to identify novel therapeutic targets and treatment modalities for prostate cancer, we conducted a comprehensive literature search on PubMed to identify de-regulated circular RNAs that influence treatment efficacy in preclinical prostate cancer-related in vivo models. Our analysis identified 49 circular RNAs associated with various processes, including treatment resistance, transmembrane and secreted proteins, transcription factors, signaling cascades, human antigen R, nuclear receptor binding, ubiquitination, metabolism, epigenetics and other target categories. The identified targets and circular RNAs can be further scrutinized through target validation approaches. Down-regulated circular RNAs are candidates for reconstitution therapy, while up-regulated RNAs can be inhibited using small interfering RNA (siRNA), antisense oligonucleotides (ASO) or clustered regularly interspaced short palindromic repeats/CRISPR associated (CRISPR-CAS)-related approaches.

Background/aim: The disialoganglioside GD2 has been shown to promote cell proliferation, migration, tumor and metastasis through specific signaling pathways in tumor cells originating from the neuroectoderm, including melanomas, neuroblastomas, glioblastomas, and breast carcinomas. GD2 has therefore emerged as a potential diagnostic biomarker in early malignancy as evidenced by the high specificity of its expression in tumor cells. Furthermore, recent findings show that GD2 might also act as a novel cancer stem cell (CSC) marker. Our study aimed to investigate the relationship between GD2 and 34 recognized CSC markers in human breast cancer.

Materials and methods: We analyzed the relationship between the mRNA expression profiles of three key enzymes involved in the biosynthesis of GD2 - B4GalT5, B4GALNT1, and ST8SIA1 - and 34 CSC markers in 91 human breast cancer tissue samples.

Results: All three enzymes had positive and statistically significant correlation between each other with p<0.0001. Furthermore, each enzyme was found to have highly significant correlations with 15 CSC markers associated with aggressive cancer behavior: BMI1, CX43, ALCAM (CD166), Podoplanin, CD29, CD24, CD49f, IL8RA, NGFR, hTERT, Nestin, OCT4, CTBP, PSCA and Myc.

Conclusion: These findings lend further support to the growing evidence that GD2 is a potential biomarker of CSCs and epithelial-mesenchymal transition (EMT) in human breast cancer that can be amenable to therapeutic targeting.

Background/aim: Oncogenic processes are delineated by metabolic dysregulation. Drug likeness is pharmacokinetically tested through the CYP450 enzymatic system, whose genetic aberrations under epigenetic stress could shift male organisms into prostate cancer pathways. Our objective was to predict the susceptibility to prostate neoplasia, focused on benign prostatic hyperplasia (BPH) and prostate cancer (PCa), based on the pharmacoepigenetic and the metabolic profile of Caucasians.

Materials and methods: Two independent cohorts of 47,389 individuals in total were assessed to find risk associations of CYP450 genes with prostatic neoplasia. The metabolic profile of the first cohort was statistically evaluated and frequencies of absorption-distribution-metabolism-excretion-toxicity (ADMET) properties were calculated. Prediction of miRNA pharmacoepigenetic targeting was performed.

Results: We found that prostate cancer and benign prostatic hyperplasia patients of the first cohort shared common cardiometabolic trends. Drug classes C08CA, C09AA, C09CA, C10AA, C10AX of the cardiovascular, and G04CA, G04CB of the genitourinary systems, were associated with increased prostate cancer risk, while C03CA and N06AB of the cardiovascular and nervous systems were associated with low-risk for PCa. CYP3A4*1B was the most related pharmacogenetic polymorphism associated with prostate cancer susceptibility. miRNA-200c-3p and miRNA-27b-3p seem to be associated with CYP3A4 targeting and prostate cancer predisposition. Metabolomic analysis indicated that 11β-OHT, 2β-OHT, 15β-OHT, 2α-OHT and 6β-OHT had a high risk, and 16α-OHT, and 16β-OHT had an intermediate disease-risk.

Conclusion: These findings constitute a novel integrated signature for prostate cancer susceptibility. Further studies are required to assess their predictive value more fully.

Background/aim: Comprehensive transcriptome analysis has revealed SPOC Domain Containing 1 (SPOCD1) as a potential biomarker for esophageal squamous cell carcinoma (ESCC). However, the expression and oncological roles of SPOCD1 in ESCC remains underexplored. We aimed to evaluate the role of SPOCD1 in oncogenesis and prognosis of ESCC in vitro and in vivoMaterials and Methods: The Cancer Cell Line Encyclopedia (CCLE) database was utilized to evaluate correlations between SPOCD1 expression and oncogenes in ESCC. mRNA and protein levels were measured by qRT-PCR and Simple Western assays, respectively. siRNA-mediated knockdown and overexpression experiments assessed the effects of SPOCD1 expression on proliferation, migration, and invasion of ESCC cell lines. In vivo, siRNA knockdown effects on tumor growth were tested in mouse xenograft models. SPOCD1 mRNA levels in 164 resected tissues were correlated with clinicopathological parameters and survival, while a cohort of 177 patients was analyzed for protein expression and survival.

Results: SPOCD1 mRNA expression varied widely among ESCC cell lines and correlated with epithelial-mesenchymal transition-related genes. Knockdown significantly suppressed proliferation, migration, and invasion (p<0.001), while overexpression increased proliferation (p<0.001). In vivo, siRNA knockdown reduced tumor growth compared to both si-control (p=0.005) and untransfected groups (p<0.001). High SPOCD1 mRNA expression was linked to poor disease-specific survival (p=0.009, HR=1.965, 95% CI=1.187-3.252) and disease-free survival (p=0.047, HR=1.602, 95% CI=1.007-2.549). Similarly, elevated protein levels were associated with unfavorable disease-specific (p=0.013, HR=1.860, 95% CI=1.137-3.041) and disease-free survival (p=0.032, HR=1.618, 95% CI=1.042-2.513).

Conclusion: SPOCD1 expression correlates with the aggressiveness of ESCC cells, and its expression levels in tumor tissues may serve as a prognostic factor for ESCC patients.

Background/aim: Matrix metalloproteinase-9 (MMP-9) has been associated with the development and progression of breast cancer (BCa). However, the relationship between MMP-9 genetic variants and BCa susceptibility remains contentious and inconclusive. This study aimed to evaluate the association of MMP-9 rs3918242 promoter polymorphisms with BCa, with a particular focus on the risk of triple-negative breast cancer (TNBC).

Materials and methods: A case-control study was conducted involving 1,232 BCa patients and 1,232 healthy controls. The MMP-9 rs3918242 genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis.

Results: The genotype distribution of MMP-9 rs3918242 among the control group adhered to Hardy-Weinberg equilibrium (p=0.3265). No statistically significant differences were observed in the genotype frequencies between BCa cases and controls (p for trend=0.2555). Although the homozygous variant genotype (TT) showed a potential risk-increasing effect, this was not statistically significant [odds ratio (OR)=1.43, 95% confidence interval (CI)=0.88-2.36, p=0.1869]. Similarly, allele frequency analysis indicated no significant association between the variant T allele and overall BCa risk (OR=1.13, 95%CI=0.97-1.33, p=0.1265). Additionally, no interaction was detected between MMP-9 rs3918242 genotypes and the age of BCa onset (both p>0.05). Notably, the TT genotype of MMP-9 rs3918242 was significantly associated with an increased risk of TNBC (OR=2.49, 95%CI=1.32-4.72, p=0.0072).

Conclusion: The MMP-9 rs3918242 TT genotype may serve as a potential predictive biomarker for TNBC in the Taiwanese population.

Background/aim: Methylation in the estrogen receptor alpha (ESRα) promoter is an epigenetic abnormality associated with breast cancer (BCa), whereas hypermethylation results in the loss of ER expression.

Materials and methods: Pyrosequencing was used to investigate a potential link between aberrant methylation in the P0/P1 promoters of ESRα and the risk of progression of benign fibrocystic and fibroadenoma tumors to BCa.

Results: Results showed a significantly elevated level of DNA methylation in ESRα P1 promoter (p=0.0001) in fibroadenoma compared to ER-negative BCa tumors and a two-fold increased ESRα expression in fibrocystic and fibroadenoma benign tissues. In addition, methylation levels of HIN-1 and RASSF1A promoters were elevated in ER-positive compared to ER-negative BCa (p-value<0.04). ANOVA Mixed Model revealed significantly higher methylation levels in the promoter of RASSF1A for fibroadenoma and ER-positive BCa (p=0.004) compared to ER-negative BCa. Tumors with unclassified molecular subtypes (ER-positive, PR-negative, HER2-negative) had elevated levels of methylation (p=0.046) in the P0 promoter compared with luminal B (ER-positive, PR-positive, HER2-positive) tumors. Grade 3 tumors showed a borderline association with ESRα P1 promoter methylation when compared with grade 2 tumors (p=0.056).

Conclusion: ESRα P0 promoter hypermethylation may occur in the early stages of breast carcinogenesis, while P1 promoter methylation appears in later stages with a poor prognosis. Therefore, methylation of the ESRα promoter and other tumor-related genes could serve as a potential biomarker for predicting fibroadenoma progression risk to BCa.

Background/aim: The widespread implementation of cancer genomic profiling (CGP) has led to an increase in the detection of germline TP53 pathogenic variants (gTP53v) in patients who do not meet the classical Li-Fraumeni syndrome (LFS) criteria. The present study aimed to characterize the clinical features and treatment outcomes of gTP53v cases identified through routine CGP testing.

Patients and methods: We conducted a retrospective analysis of 43 patients with gTP53v identified through CGP testing between June 2019 and August 2024. Clinical characteristics, molecular features, and treatment outcomes were analyzed and compared with TP53 wild-type cases from the same database (n=6,515).

Results: The median age at diagnosis was 38 years (range=1-83 years), with 58.1% of cases presenting with non-core LFS tumors. A genomic analysis revealed diverse variant types (missense: 32, frameshift: 8, and nonsense: 3) with variant allele frequencies ranging between 0.10 and 0.696. Among 37 patients who received first-line chemotherapy, the objective response rate was 62%, which was significantly higher than in TP53 wild-type cases (32%, p=0.02). Complete responses were observed in six patients and partial responses in 14.

Conclusion: The present results suggest that gTP53v carriers identified through CGP represent a broader clinical spectrum than classical LFS, while demonstrating potentially favorable treatment outcomes. These results challenge traditional paradigms and emphasize the need for individualized approaches to patient care, particularly in cases with atypical presentations requiring the careful interpretation of mosaicism, de novo mutations, and clonal hematopoiesis.

The Wiskott-Aldrich syndrome protein (WASP) and the WASP family verprolin-homologous protein (WAVE) family are essential molecules that connect GTPases to the actin cytoskeleton, thereby controlling actin polymerisation through the actin-related protein 2/3 complex. This control is crucial for forming actin-based membrane protrusions necessary for cell migration and invasion. The elevated expression of WASP/WAVE proteins in invasive breast cancer cells highlights their significant role in promoting cell motility and invasion. This review summarises the discovery, structural properties, and activation mechanisms of WASP/WAVE proteins, focuses on the contribution of the WASP/WAVE family to breast cancer invasion and migration, particularly synthesises the results of nearly a decade of research in this field since 2015. By exploring promising therapeutic strategies for breast cancer, including small molecule inhibitors and biological agents, this review stresses the potential for developing anticancer drugs that target the WASP/WAVE family and associated pathways, intending to improve the prognosis for patients with metastatic breast cancer.