Cancer Genetics最新文献

Gene fusions involving NUP98 have been reported in several hematologic malignancies yet have been very rarely reported in B-acute lymphoblastic leukemia (B-ALL). Two cases of B-ALL for which chromosome banding analysis (CBA) and fluorescence in situ hybridization (FISH) suggested apparent NUP98 rearrangements were further investigated with next-generation sequencing-based methodologies to verify the findings obtained with traditional cytogenetic methodologies. In the first case, CBA revealed a hyperdiploid karyotype with multiple structural abnormalities including additional material of unknown origin at 11p15; subsequent break-apart probe (BAP) FISH for NUP98 demonstrated 2 intact fusion signals and a single separate 5'NUP98 signal. However, whole-genome sequencing found no evidence of a NUP98 gene fusion. The results obtained with conventional cytogenetic methodologies were in fact attributable to structural variants (SV) with breakpoints not within NUP98 but within the 5'NUP98 BAP probe-binding sequence. In the second case, CBA revealed several structural and numeric abnormalities including a complex translocation between chromosomes 11 (at 11p15.4) and 19 (at 19p13.3) and an insertion of unknown material at 11p15.4. BAP FISH demonstrated a typical FISH signal pattern consistent with an apparent NUP98 rearrangement. However, no evidence of a NUP98 fusion was found on RNA sequencing. In conclusion, the two cases thus presented with clinical false positive NUP98 rearrangements by FISH. In the clinical laboratory, SVs in the vicinity of genes involved in recurrent rearrangements in hematologic malignancies may result in misleading results with conventional chromosome methodologies. This may preclude an accurate definition of the genetic attributes of malignancies with ensuing impacts on risk stratification and management. Higher-resolution testing methodologies such as whole-genome sequencing and RNA sequencing may be helpful in resolving unexpected results with conventional chromosome methodologies and enhancing the accuracy of genetic characterization of hematological malignancies in the clinical laboratory.

Background: Neurofibromatosis type 1 (NF1) is one of the most common genodermatoses. It can affect every organ and is associated with an increased risk of benign and malignant tumors. Most common tumoral locations involve nervous system and soft tissues but a large variety of tumors have been described. So far, hepatoblastoma in a patient with NF1 has been reported twice in the literature.

Case presentation: A liver mass was discovered in a 11 year-old girl with NF1 leading to a diagnosis of epithelial hepatoblastoma with pulmonary metastasis. Targeted analysis on blood revealed a germline NF1 missense variant. Exome sequencing, RNA-seq and methylation analyses performed on tumoral and metastatic samples confirmed the germline NF1 variant and showed classical driver variants for hepatoblastoma.

Conclusions: We present here the third case of hepatoblastoma in a patient with NF1 and discuss the possible link between this rare tumor and this neurocutaneous genetic condition.

Introduction: POT1 tumor predisposition (POT1-TPD) is an autosomal dominant disorder characterized by increased lifetime malignancy risk. Melanoma, angiosarcoma, and chronic lymphocytic leukemia are the most frequently reported malignancies [1]. Protection of telomeres protein 1 (POT1) is part of the shelterin protein complex to maintain/protect telomeres [2]. Proposed mechanisms for oncogenesis with POT1 loss of function include telomere elongation and DNA damage response causing genomic instability [3]. Ependymomas are a heterogeneous group representing one-third of pediatric brain tumors and are locally aggressive with frequent recurrence [4].

Case presentation: A healthy 3-year-old male presented with worsening vertigo, headaches, and emesis. Radiographic studies demonstrated a midline posterior fossa mass in the fourth ventricle. Following a gross total resection, pathology demonstrated a posterior fossa ependymoma, group A. Next generation sequencing (NGS) using our institution's clinically validated panel, "CinCSeq," identified a POT1 splice site variant (c.1164-1G>A; variant allele fraction 46 %). Paired germline testing via the Molecular Characterization Initiative confirmed this variant as heterozygous in the patient. Genetic testing confirmed the POT1 pathogenic variant in his mother, who has a history of multiple nevi. The patient completed treatment with focal proton radiotherapy with no evidence of disease recurrence to date.

Discussion: To our knowledge, this represents the first documented pediatric ependymoma patient with a familial, germline POT1 pathogenic variant. Somatic POT1 mutational frequency, as determined by NGS in over 60,000 solid tumors, is 2.94 %. Among this cohort, 48 cases were ependymomas with one non-benign POT1 mutation [5]. Alterations of telomere maintenance have been reported in intracranial ependymomas previously through increased human telomerase reverse transcriptase (hTERT) expression [6,7]. This case sheds light on a potential new predisposition for ependymoma development and the expanding phenotype of POT1-TPD. We recognize the POT1 pathogenic variant may have been discovered incidentally in this case. Further research is needed to advance our understanding of the association between POT1 genetic alterations and ependymomas.

The transcription factor TWIST1 is a major regulator of Epithelial-Mesenchymal Transition, enhancing cancer cell mobility and invasive potential. Overexpression of TWIST1 is associated with tumor progression and poor prognosis. In our study, we explored the role of TWIST1 as both a prognostic biomarker and a therapeutic target in bladder cancer (BC), as well as the relationship between its promoter methylation and mRNA expression in bladder cancer patients. In cohort of 66 bladder cancer patients, we explored TWIST1 expression levels in tumor samples through RT-qPCR analysis; Our findings revealed a significant correlation between high TWIST1 expression levels and advanced bladder tumor stages, grades, and progression; suggesting its association with aggressive BC phenotypes. Importantly, patients with low TWIST1 expression exhibited significantly prolonged disease-free survival (DFS), indicating its potential as a prognostic marker for stratification and as a therapeutic target in advanced BC. In contrast, there was no direct correlation between TWIST1 promoter methylation status and TWIST1 expression levels in BC tumors. In summary, TWIST1 expression could play an important role as a molecular marker for BC patients' prognosis and overall survival prediction. Moreover, our results suggest that TWIST1 promoter methylation doesn't affect the gene expression in BC. Furthermore, understanding the molecular mechanisms driving TWIST1 dysregulation may uncover novel therapeutic targets to improve the management of BC.

DNA double strand breaks (DSBs) can be generated spontaneously during DNA replication and are repaired primarily by Homologous Recombination (HR). However, efficient repair requires chromatin remodeling to allow the recombination machinery access to the break. TIP60 is a complex conserved from yeast to humans that is required for histone acetylation and modulation of HR activity at DSBs. Two enzymatic activities within the TIP60 complex, KAT5 (a histone acetyltransferase) and RUVBL1 (an AAA+ ATPase) are required for efficient HR repair. Post-translational modification of RUVBL1 by the PRMT5 methyltransferase activates the complex acetyltransferase activity and facilitates error free HR repair. In S. pombe a direct interaction between PRMT5 and the acetyltransferase subunit of the TIP60 complex (KAT5) was also identified. The TIP60 complex has been partially solved experimentally in both humans and S. cerevisiae, but not S. pombe. Here, we used in silico protein structure analysis to investigate structural conservation between S. pombe and human PRMT5 and RUVBL1. We found that there is more similarity in structure conservation between S. pombe and human proteins than between S. cerevisiae and human. Next, we queried the COSMIC database to analyze how mutations occurring in human cancers affect the structure and function of these proteins. Artificial intelligence algorithms that predict how likely mutations are to promote cellular transformation and immortalization show that RUVBL1 mutations should have a more drastic effect than PRMT5. Indeed, in silico protein structural analysis shows that PRMT5 mutations are less likely to destabilize enzyme function. Conversely, most RUVBL1 mutations occur in a region required for interaction with its partner (RUVBL2). These data suggests that cancer mutations could destabilize the TIP60 complex. Sequence conservation analysis between S. pombe and humans shows that the residues identified in cancer cells are highly conserved, suggesting that this may be an essential process in eukaryotic DSB repair. These results shed light on mechanisms of DSB repair and also highlight how S. pombe remains a great model system for analyzing DSB repair processes that are tractable in human cells.

Collision tumors, characterized by the coexistence of two unique neoplasms in close approximation, are rare and pose diagnostic challenges. This is particularly true when the unique neoplasms are of the same histologic type. Here we report such a case where comprehensive tumor profiling by next generation sequencing (NGS) as well as immunohistochemistry revealed two independent adenocarcinomas comprising what was initially diagnosed as a single adenocarcinoma of the gastroesophageal (GEJ) junction. Biopsy of the esophageal portion of the GEJ mass showed a mismatch repair deficient tumor with loss of immunoreactivity for MLH1 and PMS2, while the biopsy taken from the gastric portion of the mass revealed a separate tumor with a discordant, non-overlapping, set of molecular alterations, including an EML4::ALK fusion, as well as intact MMR. This case illustrates one way in which NGS can reveal diagnoses such as collision tumor that are wholly unexpected based on clinical and histological grounds. Such diagnoses can have important implications for patient care, particularly in cases where there is discordance for targetable molecular alterations.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults and has the highest fatality rate. Patients aged 65 and above exhibit the poorest prognosis, with a mere 30 % survival rate within one year. One important issue in optimizing outcomes for AML patients is their limited ability to predict responses to specific therapies, response duration, and likelihood of relapse. Despite rigorous therapeutic interventions, a significant proportion of patients experience relapse. Consequently, there is a pressing need to introduce new targets for therapy. Sequencing and biotechnology have come a long way in the last ten years. This has made it easier for many omics technologies, like genomics, transcriptomics, proteomics, and metabolomics, to study molecular mechanisms of AML. An integrative approach is necessary to understand a complex biological process fully and offers an important opportunity to understand the information underlying diseases. In this review, we studied papers published between 2010 and 2024 employing omics approaches encompassing diagnosis, prognosis, and risk stratification of AML. Finally, we discuss prospects and challenges in applying -omics technologies to the discovery of novel biomarkers and therapy targets. Our review may be helpful for omics researchers who want to study AML from different molecular aspects.

Background: In recent years, concerns have emerged regarding the potential link between Juvenile idiopathic arthritis (JIA) and an elevated risk of developing breast cancer. However, the potential relationship between JIA and breast cancer is currently unclear. The objective of this study is to investigate the mechanism of JIA on cancer risk.

Methods: Use the Bulk-seq data related to JIA, selected from the GEO database, to explore potential candidate genes using methods such as WGCNA and consensus machine learning labeling. Verify using breast cancer Bulk-seq data from TCGA and scRNA-seq analyses.

Results: A total of 2050 genes potentially related to JIA were identified by WGCNA, and after merged with differentially expressed genes, 43 potential candidate genes were found. Subsequently, consensus machine learning label analysis was conducted on the aforementioned genes, and a total of 6 genes closely related to JIA were identified. In breast cancer, we found that PRRG4, NCR3 and CREB5 also had significant differences in TCGA. And it is closely related to prognosis. ScRNA-seq analysis showed that the expression of PRRG4 was different in T cells in JIA, and PRRG4 was mainly expressed in T cells in breast cancer.

Conclusions: The findings of this study support a mechanism between JIA and an increased risk of breast cancer.

Objective: Studies of squamous cell carcinoma of the head and neck (HNSCC) have demonstrated the importance of nuclear receptors and their associated coregulators in the development and treatment of HNSCC. We sought to characterize members of the nuclear receptor super family through interrogation of RNA-Seq and microarray data.

Materials and methods: TCGA RNA-Seq data within the cBioportal platform comparing HNSCC samples (n = 515 patients with RNA-Seq data) to normal tissue (n = 82 patients) was interrogated for significant differences in nuclear receptor expression. Affymetrix microarray analysis of HNSCC tumors relative to normal oral mucosa (41 tumor, 13 normal) was analyzed.

Results: Of the 48 NR genes and 19 NR cofactors examined, 99 % of tumor samples in the TCGA had some form of NR gene 'alteration' compared to normal tissue. These alterations predominantly encompass expression changes. NR genes (PPARG) and (RORC), and the NR cofactor, (NCOA1), were differentially expressed and downregulated in tumors compared to normal tissue.

Conclusion: We have discovered significant decreases in PPARG expression with co-occurring changes in genes involved with lipid metabolism and cell cycle progression in HNSCC. We are targeting PPARγ with thiazolidinediones in a series of clinical trials to restore normal signaling via differentiation to hopefully reverse carcinogenesis. We also observed several receptors with differential expression associated with clinical factors that may become the focus of interest in future targeting efforts. These data provide evidence for nuclear receptors playing a role in the dysregulation of gene expression in HNSCC and illustrate the utility of current bioinformatic tools for interrogating complex, high throughput data sets.

Recurrent translocation t(1;19) (q23;p13) describes a unique cytogenetic group of childhood B-cell acute lymphoblastic leukemia (ALL). Historically, t(1;19)(q23;p13.3) has been associated with poor outcomes. However, recent data suggests that currently intensified treatments have overcome this dismal prognosis. We conducted this study to understand this type of translocation in our population. From January 1999 until May 2020, 44 children with t(1;19) were identified by cytogenetics analysis during charts review. Cytogenetics (CG) testing results (Karyotype and/or FISH) were retrieved from the medical files on 37/44 patients. Of the 37 patients with Cytogenetics results, a total of 12 patients were found to have t(1;19)(q23;p13.3) as the only detectable genetic change, 13 patients were presented with t(1;19)(q23;p13.3) plus further chromosomal rearrangement (Table 1), 12 patients were presented with a variation involving t(1;19)(q23;p13.3) with or without additional chromosomes rearrangement. Patients were treated on different protocols, yet most were derived from the North American guidelines. Among the included subjects, relapse or refractory disease was identified in 15 cases (34 %), and 12 died due to progressive refractory leukemia. At the five-year mark, the estimated overall survival rate stood at 72​​ %. No statistical difference existed between patients treated on the high-risk (HR) protocol and those treated on the standard-risk (SR) protocol. It appeared that t(1,19) standard risk ALL had more relapses on the standard risk protocol. Furthermore, Relapses were mostly earlier and poorly salvageable. As such, treatment intensification for standard risk ALL with t(1,19) is warranted.