Genetic Prognostic Markers Research Articles

Higher tumor mutational burden is associated with inferior outcomes among pediatric patients with neuroblastoma.

Neuroblastoma is a pediatric malignancy with heterogeneous clinical outcomes. Our aim was to identify prognostic genetic markers for patients with neuroblastoma, who were treated with the Taiwan Pediatric Oncology Group (TPOG) neuroblastoma N2002 protocol, to improve risk stratification and inform treatment. Our analysis was based on 53 primary neuroblastoma specimens, diagnosed pre-chemotherapy, and 11 paired tumor relapse specimens. Deep sequencing of 113 target genes was performed using a custom panel. Multiplex ligation-dependent probe amplification was performed to identify clinical outcomes related to copy-number variations. We identified 128 variations associated with survival, with the number of variations being higher in the relapse than that in the diagnostic specimen (p=.03). The risk of event and mortality was higher among patients with a tumor mutational burden ≥10 than that in patients with a lower burden (p<.0001). Multivariate analysis identified tumor mutational burden, MYCN amplification, and chromosome 3p deletion as significant prognostic factors, independent of age at diagnosis, sex, and tumor stage. The 5-year event-free survival and overall survival rate was lower among patients with high tumor burden than in patients with low tumor burden. Furthermore, there was no survival of patients with an ALK F1147L variation at 5 years after diagnosis. Genome sequencing to determine the tumor mutational burden and ALK variations can improve the risk classification of neuroblastoma and inform treatment.

Abstract 4915: Identification and validation of novel prognostic genetic markers in HER2-negative advanced gastric cancer (AGC) by artificial intelligence (AI) deep learning and machine learning algorithm

Abstract Introduction: Despite advances in anticancer treatments, there has been urgent need to identify novel prognostic markers for HER2-negative AGC. We propose AI based deep learning and machine learning pipeline to explore genetic markers that predict patient response to chemotherapy in HER2-negative AGC. Methods: We retrospectively assessed 179 stage IV HER2-negative AGC patients who have been treated with first-line chemotherapy in Yonsei Cancer Center, Korea between 2015 and 2021. In-house targeted sequencing panel data (CancerSCANTM and CancerMaster) were used to identify candidate prognostic markers. DeepSurv was mainly used to analyze the progression-free survival (PFS), which is a deep learning algorithm that can investigate prognostic roles. The SHapley Additive exPlanations (SHAP) method was applied to open the deep learning models’ black-box and calculate the importance ranking of gene features. Machine learning models-random survival forest, elastic-net, and lasso-were also investigated to identify potentially meaningful gene variants. To rank the gene features, we calculated variable importance (VIMP) for random survival forest, and penalized regression coefficients for elastic-net and lasso. All deep learning and machine learning models were trained using 5-folds cross-validation in 1,000 iterations of re-sampling bootstrapping with hyperparameter tuning by grid search. To classify responder or non-responder related genetic markers to chemotherapy, we used the signs of averaged penalize coefficients obtained from elastic-net and lasso. Based on the median linear predictor with candidate gene features, patients were classified into high-risk and low-risk group. Results: A total of 7,824 common variants were analyzed and 20 prognostic genetic markers were identified based on the top average values of SHAP, VIMP, and penalized regression coefficients. The top 10 non-responder genetic markers are included as follows: PARP4(p.S873N), CHUK(p.V268I), BARD1(359_365del), CREBBP(p.Y1125F), BARD1(p.P24S), PHLPP2(p.R1312Q), FAT3(p.Q3375R), CASP5(p.T106A), PHLPP2(p.I544V), and PTCH2(p.T988M). Otherwise, the top 10 responder genetic markers are defined as follows: IL7R(p.I66T), NOTCH4(L16delinsLL), FGFR3, BCL2A1(p.G82D), ZNF217(p.T548I), BRCA1(p.K1183R), FANCA(p.A412V), ADGRA2, CDKN2B, and FANCM(p.S175F). The high-risk group had worse PFS compared with low-risk group (median PFS 4.1 vs. 9.1 months; P-value &amp;lt;0.0001). Conclusion: This study showed the potential of AI deep learning and machine learning pipeline that employs an innovate prognostic genetic markers for HER2-negative AGC. Current ongoing analyses of larger cohort with more comprehensive clinical data will be presented. Citation Format: Sejung Park, Seok-Jae Heo, Choong-Kun Lee, Yaeji Lee, Woo Sun Kwon, Jingmin Che, Minseok Kim, Hyun Cheol Chung, Sun Young Rha. Identification and validation of novel prognostic genetic markers in HER2-negative advanced gastric cancer (AGC) by artificial intelligence (AI) deep learning and machine learning algorithm [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4915.

Frequency and Prognostic Impact of Aberrant Antigens Expression among Egyptian Adult Acute Leukemia.

Aberrant antigen expression was reported to be due to genetic and epigenetic dysregulation. This study aimed to address aberrant antigen expression and its link to poor prognostic genetic markers in acute leukemia patients. This study included 432 newly diagnosed acute leukemia patients (AML, B-ALL). For all included patients blast cells expression for line assignment CD33 CD13 on B-All and CD7 on cytogenetically normal-AML blasts was assessed by flow cytometry in parallel to FLT3 and Philadelphia and philadelphia like chromosome in B-ALL. From the total 432 cases of acute leukemia, the most frequent aberrant antigen expressed in B acute lymphoid leukemia (ALL) was CD33 (23.3%) followed by CD13(16.7%); while the most frequent one in AML was CD7 (16.7%). Aberrant myeloid phenotype in B-ALL was associated with lower mean total leukocytes count (TLC), low platelets count, positive Philadelphia like chromosome, shorter overall survival compared to the B-ALL without. Aberrant lymphoid phenotype (CD7) in AML was associated with a higher platelets count, FLT3 mutation, shorter disease-free and overall survival compared to those patients without. CD7 aberrant antigen expression is frequently detected in patients with CN-AML and frequently associated with FLT3 mutation. While in patients with B-ALL the most frequently detected ones are CD33 and CD13 which are frequently associated with Philadelphia like chromosome.

Prognostic Biomarkers of Cell Proliferation in Colorectal Cancer (CRC): From Immunohistochemistry to Molecular Biology Techniques.

Colorectal cancer (CRC) is one of the most common and severe malignancies worldwide. Recent advances in diagnostic methods allow for more accurate identification and detection of several molecular biomarkers associated with this cancer. Nonetheless, non-invasive and effective prognostic and predictive testing in CRC patients remains challenging. Classical prognostic genetic markers comprise mutations in several genes (e.g., APC, KRAS/BRAF, TGF-β, and TP53). Furthermore, CIN and MSI serve as chromosomal markers, while epigenetic markers include CIMP and many other candidates such as SERP, p14, p16, LINE-1, and RASSF1A. The number of proliferation-related long non-coding RNAs (e.g., SNHG1, SNHG6, MALAT-1, CRNDE) and microRNAs (e.g., miR-20a, miR-21, miR-143, miR-145, miR-181a/b) that could serve as potential CRC markers has also steadily increased in recent years. Among the immunohistochemical (IHC) proliferative markers, the prognostic value regarding the patients' overall survival (OS) or disease-free survival (DFS) has been confirmed for thymidylate synthase (TS), cyclin B1, cyclin D1, proliferating cell nuclear antigen (PCNA), and Ki-67. In most cases, the overexpression of these markers in tissues was related to worse OS and DFS. However, slowly proliferating cells should also be considered in CRC therapy (especially radiotherapy) as they could represent a reservoir from which cells are recruited to replenish the rapidly proliferating population in response to cell-damaging factors. Considering the above, the aim of this article is to review the most common proliferative markers assessed using various methods including IHC and selected molecular biology techniques (e.g., qRT-PCR, in situ hybridization, RNA/DNA sequencing, next-generation sequencing) as prognostic and predictive markers in CRC.

Genomic profiles of IDH-mutant gliomas: MYCN-amplified IDH-mutant astrocytoma had the worst prognosis

This study aimed to find any ambiguous genetic outlier for “oligodendroglioma, IDH-mutant and 1p/19q-codeleted (O_IDH_mut)” and “astrocytoma, IDH-mutant (A_IDH_mut)” and to redefine the genetic landscape and prognostic factors of IDH-mutant gliomas. Next-generation sequencing (NGS) using a brain tumor-targeted gene panel, methylation profiles, and clinicopathological features were analyzed for O_IDH_mut (n = 74) in 70 patients and for A_IDH_mut (n = 95) in 90 patients. 97.3% of O_IDH_mut and 98.9% of A_IDH_mut displayed a classic genomic landscape. Combined CIC (75.7%) and/or FUBP1 (45.9%) mutations were detected in 93.2% and MGMTp methylation in 95.9% of O_IDH_mut patients. In A_IDH_mut, TP53 mutations were found in 86.3% and combined ATRX (82.1%) and TERTp (6.3%) mutations in 88.4%. Although there were 3 confusing cases, NOS (not otherwise specified) category, based on genetic profiles, but they were clearly classified by combining histopathology and DKFZ methylation classifier algorithms. The patients with MYCN amplification and/or CDKN2A/2B homozygous deletion in the A_IDH_mut category had a worse prognosis than those without these gene alterations and MYCN-amplified A_IDH_mut showed the worst prognosis. However, there was no prognostic genetic marker in O_IDH_mut. In histopathologically or genetically ambiguous cases, methylation profiles can be used as an objective tool to avoid a diagnosis of NOS or NEC (not elsewhere classified), as well as for tumor classification. The authors have not encountered a case of true mixed oligoastrocytoma using an integrated diagnosis of histopathological, genetic and methylation profiles. MYCN amplification, in addition to CDKN2A/2B homozygous deletion, should be included in the genetic criteria for CNS WHO grade 4 A_IDH_mut.

Inherited mutations in DNA damage gene repair (gDDR) in Italian men with metastatic prostate cancer.

223 Background: The need for genetic prognostic and predictive markers is urgent in order to identify potential target therapies or personalized therapeutic sequences for men with metastatic prostate cancer (mPC). The prevalence of pathogenic germline mutations in DNA damage repair (gDDR) such as germline mutations in BRCA2 (gBRCA) is well established: in the Anglo-American population with mPC was 5.3%, while in the Chinese population was 4.3% and in Spanish population 3.3%. This prospective multicenter cohort study evaluated the prevalence of gDDR alterations in the Italian population affected by mPC. Methods: In an observational prospective trial, 300 consecutive Italian patients affected by mPC were recruited between 2015 and 2019 and were screened for gDDR mutations in 107 genes. The primary aim was to assess the frequency of ATM/BRCA1/BRCA2/PALB2 germline mutations in the Italian population of patients with mPC. Secondary aims included the association of gDDR subgroups with metastatic onset, Gleason Score ≥8, and time to castration resistance. Results: We analyzed 300 patients and we identified 297 valuable patients. 46 patients had a pathogenic/likely pathogenic variants (15.4%): the more frequent is gBRCA2 in ten cases, gATM in five (1.7%), gMUTYH in four cases (1.3%), gCHEK2 in three cases (1%) and one case in PALB2 (0.3%). No mutations in BRCA1 were identified. We also highlighted six patients (2%) with clonal hematopoiesis of indeterminate potential (CHIP) interference in ATR (n=2), ATM (n=2), CHEK1 (n=1) and BRIP1 (n=1). Finally, we identified 117 alterations of variants of unknown significance (VUS) in 98 patients. In a univariate analysis, the median time to castration resistance in gBRCA2 patients was 11.6 months versus 22.3 months in patients with other mutation versus 23.4 months in no mutated patients. There were no associations of gDDR subgroups with metastatic onset and Gleason Score ≥8. Conclusions: The prevalence of gBRCA2 in the Italian population is 3%, which is similar to those of Spanish population, identifying interesting similarities between people of the Western Mediterranean area. The presence of gBRCA2 mutations correlates with lower time to the onset of castration resistant disease, according to a more aggressive phenotype.

Discovery of the prognostic marker in the whole blood sample of gestational trophoblastic neoplasia beyond immunohistochemical tissue markers: mdm2

Gestational trophoblastic disease (GTD) is an abnormal trophoblastic proliferation disease that may show malignant progression. Despite reports on the clinical and laboratory parameters for the projection of GTD, there is still a lack of histopathologic or genetic prognostic markers for patients with higher risks of malignant progression and high-risk gestational trophoblastic neoplasia. The primary aim of this study was to identify a marker other than tissue markers for evaluating the progression potential of GTD to gestational trophoblastic neoplasia (GTN). The secondary aim was to determine the tissue marker capacity to detect the progression to neoplasia. The study design was a case-control. The data of 81 patients diagnosed with GTD and 23 control were assessed. Their detailed obstetric and gynecological history were recorded, and their whole blood sample was obtained for genetic evaluation of the mouse double minute 2 (mdm2) gene expression. We also evaluated the curettage specimens for p53, c-erythroblastic oncogene B-2 (c-erbB-2), and ki67 protein expression. The expression of p53 expression was significantly increased in GTD patients and significantly higher in the GTN progressing group than in the spontaneous remission group. Although blood mdm2 gene was significantly different between the low and high-risk GTN subgroups, its expression was not different between the GTD or GTN groups. Additionally, a significant increase in c-erbB-2 was observed in the GTN group. Mdm2 might be a promising blood prognostic factor throughout the course of GTD. p53 and c-erbB-2 might be used as predictive indicators for the early diagnosis of GTN progression. Altogether, these markers may help identify patients with high risks of malignant progression, guide earlier aggressive treatment and increase treatment outcomes.

Gene variants in pro-coagulant and anti-coagulant genes could be prognostic genetic markers of COVID-19 susceptibility

BackgroundPresent study aimed to identify DNA polymorphisms (variants) which can modulate the risk of COVID-19 infection progression to severe condition. TaqMan based SNP genotyping assay was performed for 11 single nucleotide polymorphisms (SNPs) in pro-coagulant and anti-coagulant genes. MethodologyA total of 33 COVID-19 patients, including dead, severe and moderately infected individuals were compared to 35 healthy controls. Both alleles in the SNP were labelled with two different fluorescent dyes (FAM and VIC) during assay formulation. DNA of study subjects were mixed with SNP assay and TaqMan master mix on 96 well PCR plate according to manufacturer’s protocol and RT-PCR was performed. Allelic discrimination assay gave clear results for presence of specific allele in each sample. Three SNPs were located in the pro-coagulant genes, another three involved in blood clot dissolution while rest five were in the genes encoding natural anti-coagulants. COVID-19 infected patients were further sub-divided into three groups, deceased (n = 16), severe (n = 10) and moderately infected (n = 7). ResultsSNP genotyping showed significant differences between COVID-19 patients and controls in two SNPs, rs6133 in Selectin-P (SELP) and rs5361 in Selectin-E (SELE) gene. Also, rs2020921 and rs8176592, in clot dissolution genes, tissue Plasminogen activator (tPA) and tissue factor pathway inhibitor (TFPI) respectively showed significant genotypic and allelic difference in patients of COVID-19 compared to healthy controls. Further three SNPs rs2227589, rs757583846, and rs121918476 in natural anti-coagulant genes anti-thrombin III (ATIII), protein C (PROC), and protein S (PROS) respectively showed statistically significant difference between the study groups. ConclusionOur findings indicate that gene variants, those involved in coagulation and anti-coagulation may play a major role in determining individual susceptibility to COVID-19.

Alpha-2-Heremans-Schmid-glycoprotein (AHSG) a potential biomarker associated with prognosis of chromophobe renal cell carcinoma: The PROPOLIS study.

Background and AimsChromophobe renal cell carcinoma (chRCC) is the third common pathological subtype in renal cancers. However, the underlying mechanisms of specific genetic characteristics of chRCC are currently unclear. In this study, protein expression profiles, gene ontology (GO), and survival plots were provided by integrated bioinformatics analysis to investigate key genes associated with the mechanism of tumorigenesis and prognosis of chRCC.MethodsThe chRCC data set of gene expression profiles and clinical data were obtained from the gdc‐client (https://portal.gdc.cancer.gov) deposited on The Cancer Genome Atlas (TCGA) data portal. Differentially expressed genes (DEGs) in chRCC, compared with normal samples, were analyzed by R packages “DESeq2,” “edgeR,” and “limma.” Heat maps, volcano plots, and principal component analysis (PCA) were performed for integrated analyses. GUniGO, mutant analysis, and survival plots were performed by R packages. A protein–protein interaction (PPI) network was generated and analyzed by R packages, online String software, and Cytoscape software. Survival analysis and gene expressing comparison in tumor and normal samples were used to detect the core genes of chRCC. Furthermore, the top interacting proteins were reanalyzed.ResultsA total of 306 upregulated genes and 678 downregulated genes were identified by a Venn diagram. Ten hub genes were extracted from PPI network. Furthermore, Alpha‐2‐Heremans‐Schmid‐glycoprotein (AHSG), one of 10 hub genes, was found to be associated with chRCC, and had a big difference in expression between survival and dead events. AHSG could predict potential prognostic and may be a diagnostic biomarker in chRCC.ConclusionThis study illustrated that AHSG may be a potential therapeutic target and prognostic genetic marker for chRCC.

The Ifng antisense RNA 1 (IFNG-AS1) and growth arrest-specific transcript 5 (GAS5) are novel diagnostic and prognostic markers involved in childhood ITP.

Background/aim: IFNG-AS1 is a long noncoding RNA that works as an enhancer for the Interferon-gamma (IFN-γ) transcript. GAS5 (growth arrest-specific 5) is a lncRNA that is associated with glucocorticoid resistance. Aberrant expressions of IFNG-AS1 and GAS5 are directly linked to numerous autoimmune disorders but their levels in childhood ITP are still obscure. This study aims to elucidate expressions of target lncRNAs in childhood ITP and their association with pathophysiology and clinical features of the disease as well as their association with types and treatment responses. Method: The fold changes of target lncRNAs in blood samples from children with ITP and healthy controls were analyzed using quantitative real-time PCR (qRT-PCR). Results: There were overexpressed lncRNAs IFNG-AS1 and GAS5 in serum of childhood ITP patients [(median (IQR) = 3.08 (0.2–22.39) and 4.19 (0.9–16.91) respectively, Also, significant higher IFNG-AS1 and GAS5 (p < 0.05) were present in persistent ITP (3–12 months) [ median (IQR) = 4.58 (0.31–22.39) and 3.77 (0.87–12.36) respectively] or chronic ITP (>12 months) [ median (IQR) = 5.6 (0.25–12.59) and 5.61 (1.15–16.91) respectively] when compared to newly diagnosed <3 months patients [IFNG-AS1 median (IQR) = 1.21 (0.2–8.95), and GAS5 median (IQR) = 1.07 (0.09–3.55)]. Also, significant higher lncRNAs IFNG-AS1 and GAS5 were present in patients with partial response to treatment [IFNG-AS1 median (IQR) = 4.15 (0.94–19.25), and GAS5 (median (IQR) = 4.25 (0.81–16.91)] or non-response [IFNG-AS1 median (IQR) = 4.19 (1.25–22.39) and GAS5 median (IQR) = 5.11 (2.34–15.27)] when compared to patients who completely responded to treatment (IFNG-AS1 median (IQR) = 2.09 (0.2–14.58) and GAS5 (median (IQR) = 2.51 (0.09–10.33). In addition, following therapy, the expressions of IFNG-AS1 and GAS5 are significantly negatively correlated with platelet count. Conclusion: Findings suggest that lncRNAs IFNG-AS1 and GAS5 are novel diagnostic and prognostic genetic markers for childhood ITP that can aid in a precise prediction of the disease’s progress at the time of diagnosis and could be a useful tool for treatment planning.

Radiogenomic markers enable risk stratification and inference of mutational pathway states in head and neck cancer

PurposeHead and neck squamous cell carcinomas (HNSCCs) are a molecularly, histologically, and clinically heterogeneous set of tumors originating from the mucosal epithelium of the oral cavity, pharynx, and larynx. This heterogeneous nature of HNSCC is one of the main contributing factors to the lack of prognostic markers for personalized treatment. The aim of this study was to develop and identify multi-omics markers capable of improved risk stratification in this highly heterogeneous patient population.MethodsIn this retrospective study, we approached this issue by establishing radiogenomics markers to identify high-risk individuals in a cohort of 127 HNSCC patients. Hybrid in vivo imaging and whole-exome sequencing were employed to identify quantitative imaging markers as well as genetic markers on pathway-level prognostic in HNSCC. We investigated the deductibility of the prognostic genetic markers using anatomical and metabolic imaging using positron emission tomography combined with computed tomography. Moreover, we used statistical and machine learning modeling to investigate whether a multi-omics approach can be used to derive prognostic markers for HNSCC.ResultsRadiogenomic analysis revealed a significant influence of genetic pathway alterations on imaging markers. A highly prognostic radiogenomic marker based on cellular senescence was identified. Furthermore, the radiogenomic biomarkers designed in this study vastly outperformed the prognostic value of markers derived from genetics and imaging alone.ConclusionUsing the identified markers, a clinically meaningful stratification of patients is possible, guiding the identification of high-risk patients and potentially aiding in the development of effective targeted therapies.Graphical abstract

Association between vitamin D receptor gene polymorphisms and fibrosis susceptibility in Greek patients with HCV infection.

Hepatitis C virus (HCV) infection is a prime cause of chronic hepatitis worldwide, that often silently progresses to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Notably, the majority of individuals infected with HCV develop symptoms at late stages, often associated with liver damage that cannot revert after virus clearance. Thus, current antiviral therapy alone is rather insufficient to eliminate the global burden of HCV in the near future.During the past few years, vitamin D deficiency as well as certain single nucleotide polymorphisms in the vitamin D receptor (VDR) gene have been associated with liver fibrosis. Therefore, the aim of the present study was to investigate the possible correlation between VDR polymorphisms ApaI (rs7975232) and TaqI (rs731236) and the fibrosis stage of patients with HCV infection from Thrace, Greece. Eighty-one patients with HCV infection underwent transient elastography for the assessment of their fibrosis stage, and PCR-restriction fragment length polymorphism (RFLP) genotyping for VDR ApaI and TaqI polymorphisms. VDR genotypes were then statistically associated with the patients' fibrosis stage using ordinal regression models. Non-cirrhotic stages were positively correlated with TaqI TT genotype (p=0.003) and negatively correlated with TaqI TC genotype (p=0.007). In the presence of Hardy-Weinberg equilibrium and linkage disequilibrium between the two VDR polymorphisms, mild fibrosis stages (F0-2) were correlated with ApaI/TaqI GG/TT (p=0.002) and TG/TT (p=0.008) genotypes, while cirrhotic stage F4 was associated with ApaI/TaqI TG/TC genotype (p=0.038). TaqI TT and ApaI/TaqI GG/TT, TG/TT and TG/TC genotypes could be explored as prognostic genetic markers for fibrosis susceptibility in HCV patients.

New biomarker: the gene HLA-DRA associated with low-grade glioma prognosis

BackgroundLow-grade gliomas (LGG) are WHO grade II tumors presenting as the most common primary malignant brain tumors in adults. Currently, LGG treatment involves either or a combination of surgery, radiation therapy, and chemotherapy. Despite the knowledge of constitutive genetic risk factors contributing to gliomas, the role of single genes as diagnostic and prognostic biomarkers is limited. The aim of the current study is to discover the predictive and prognostic genetic markers for LGG.MethodsTranscriptome data and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. We first performed the tumor microenvironment (TME) survival analysis using the Kaplan-Meier method. An analysis was undertaken to screen for differentially expressed genes. The function of these genes was studied by Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Following which a protein-protein interaction network (PPI) was constructed and visualized. Univariate and multivariate COX analyses were performed to obtain the probable prognostic genes. The key genes were selected by an intersection of core and prognostic genes. A clinical correlation analysis of single-gene expression was undertaken. GSEA enrichment analysis was performed to identify the function of key genes. Finally, a single gene-related correlation analysis was performed to identify the core immune cells involved in the development of LGG.ResultsA total of 529 transcriptome data and 515 clinical samples were obtained from the TCGA. Immune cells and stromal cells were found to be significantly increased in the LGG microenvironment. The top five core genes intersected with the top 38 prognostically relevant genes and two key genes were identified. Our analysis revealed that a high expression of HLA-DRA was associated with a poor prognosis of LGG. Correlation analysis of immune cells showed that HLA-DRA expression level was related to immune infiltration, positively related to macrophage M1 phenotype, and negatively related to activation of NK cells.ConclusionsHLA-DRA may be an independent prognostic indicator and an important biomarker for diagnosing and predicting survival in LGG patients. It may also be associated with the immune infiltration phenotype in LGG.

Potential genetic biomarker of Saudi Arabian patients with colorectal cancer.

Colorectal cancer (CRC) is one of the leading causes of cancer deaths globally. We implemented a comprehensive literature review regarding CRC genetics studies to offer a perception into the genes associated with CRC recognized in Saudi patients. Definite genetic variants in ABCB1, ADIPOQ, CTNNB1, SFRP3, LRP6, CYP19A1, PARP-1, TDG genes exhibited significant protection against CRC development in Saudi population. Whereas, other gene mutations in ABCB1, ABCC1, CASR, IL-17F, NOTCH1, NOTCH4, PRNCR1, TDG, TLR2, TLR4, TLR-9, TSLP, TSLPR and TNF-α genes showed irrelevant correlation with CRC risk in Saudi Arabia. On the other hand, specific mutations in ABCC1, ADIPOQ, CYP1A1, KIR, IL-17A, MMP2, NOTCH3, PRNCR1, RETN, TDG, TLR2, BRAF, PARP-1, TLR4, TLR-9, TNF-α, TSLP and XRCC1 genes demonstrated a substantial augmented CRC risk development in Saudi patients. Furthermore, ATR, ATM, BMI1, CCAT1, Chk1, Chk2, COX-2, FoxM1, FSCN1, Ki67, MALAT1, miR-29, miR-34a, miR-92, miR-182-5, PANDAR, PIK3CA, TIGAR over-expression revealed a robust association with CRC in Saudi Arabia (KSA). Moreover, gene alterations in APC, EGFR, FBXW7, TP53, PTEN, K-ras genes were concomitant in CRC. As well as, lower expression of MLH1, MSH2, MSH6, PMS2, EPCAM and MUTYH genes were recognized in LS patients and future CRC Saudi patients. These gene mutations may be used as diagnostic and/or prognostic genetic markers in CRC Saudi patients and could offer a potential therapeutic target for CRC management.

Gene Variants in Pro-Coagulant and Anti-Coagulant Genes Could Be Prognostic Genetic Markers of COVID-19 Susceptibility

Gene Variants in Pro-Coagulant and Anti-Coagulant Genes Could Be Prognostic Genetic Markers of COVID-19 Susceptibility

Personalising cancer medicine with prognostic markers.

Personalising cancer medicine with prognostic markers.

Next-Generation RNA Sequencing in Myeloid Sarcoma Tissue Sample: Benefit on Risk Stratification of Myeloid Sarcoma

Introduction: Myeloid sarcoma (MS) is a rare hematological neoplasm whose knowledge is largely based on case reports. Whether MS can be divided into different risk group as acute myeloid leukemia (AML) is an issue of concern. Molecular testing with high sensitivity may be of great help in diagnosis and outcome prediction. This study analyzed the clinical features, outcome, cytogenetical and molecular characteristics of MS patients in West China hospital of Sichuan University, China between 2006 and 2016.Method and result: Thirty-one cases of MS with clinical data available were analyzed in this study. Among them, 8 tumor samples (5 formalin-fix paraffin-embedded tissue and 3 bone marrow tissue) were appropriate for RNA-seq (NGS). The average age at diagnosis MS was 35.2±13.2 years (range 8-61). The mean follow-up period was 32 months (range 1-58). The most common molecular abnormality was FLT3-ITD (29, 4/14) and AML1-ETO fusion (21%). Eighteen patients (58%) presented as de novo MS, 9 patients had simultaneous AML, 3 patients had other hematological neoplasms. Within 18 de novo MS patients, 7 had progressed to AML in 2 to 42 months, the mean progression time was 18.7±17.7 months. The overall survival of this series was range from 2 to 58+ months, 2-year survival rates was 75.8%. Sixty-six fusion transcripts were identified by RNA-seq, including one recurrent transcript: CBFβ/MYH11. Involved genes included a number of hematologic or solid tumor associated genes. Functional annotation of fusion transcripts revealed these fusion genes might involve hematopoiesis, apoptosis, telomere stability, core binding factor, ubiquitination, transmethylation, etc.Conclusion and discussion: The prognosis of MS patients was heterogeneous and the prognostic genetic markers were similar to AML. Clinical application of NGS-based RNQ-seq profiling in tumor sample is reliable and feasible. FLT3-ITD and AML1-ETO were the most common molecular abnormalities in MS. RNA-seq could identify fusion genes and prognosis associated gene mutation in MS, thus could help to diagnose, predict prognosis and guide therapy, especially in isolated MS, or MS with trace bone marrow involvement. RNA-seq based molecular profiling of MS needs to be further elucidated in the pathogenesis of MS and in the risk stratification of MS patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Immune checkpoint inhibitors in Wilms' tumor and Neuroblastoma: What now?

BackgroundTherapeutic activation of tumor‐infiltrating lymphocytes using monoclonal antibodies targeting PD1 or PD‐L1 (immune checkpoint inhibitors—ICIs) has revolutionized treatment of specific solid tumors in adult cancer patients, and much hope has been placed on a similar effect in relapsed or refractory solid pediatric tumors. Recent clinical trials have disappointingly shown an almost nonexistent response rate, while case reports have demonstrated that some pediatric patients do achieve durable responses when treated with this type of drug.AimTo elucidate this paradox, we mapped the landscape of expressed neoantigens as well as the levels of immune cell infiltration in the two most common extracranial solid pediatric tumors: Wilms tumor and neuroblastoma using state‐of‐the‐art in silico analysis of a large cohort of patients with these tumors.MethodsBy integration of whole exome sequencing and RNA‐sequencing, we mapped the landscape of neoantigens in the TARGET cohorts for these diagnoses and correlated these findings with known genetic prognostic markers.ResultsOur analysis shows that these tumors typically have much lower levels of expressed neoantigens than commonly seen in adult cancers, but we also identify subgroups with significantly higher levels of neoantigens. For neuroblastomas, the cases with higher levels of neoantigens were confined to the group without MYCN‐amplification and for Wilms tumor restricted to the TP53‐mutated cases. Furthermore, we demonstrate that neuroblastomas have an unexpectedly high level of CD8+ tumor‐infiltrating lymphocytes, even when compared to adult tumor types where ICI is an approved treatment.ConclusionThese results could be important to consider when designing future clinical trials of ICI treatment in pediatric patients with relapsed or refractory solid tumors.

The New Therapeutic Strategies in Pediatric T-Cell Acute Lymphoblastic Leukemia.

Childhood acute lymphoblastic leukemia is a genetically heterogeneous cancer that accounts for 10–15% of T-cell acute lymphoblastic leukemia (T-ALL) cases. The T-ALL event-free survival rate (EFS) is 85%. The evaluation of structural and numerical chromosomal changes is important for a comprehensive biological characterization of T-ALL, but there are currently no genetic prognostic markers. Despite chemotherapy regimens, steroids, and allogeneic transplantation, relapse is the main problem in children with T-ALL. Due to the development of high-throughput molecular methods, the ability to define subgroups of T-ALL has significantly improved in the last few years. The profiling of the gene expression of T-ALL has led to the identification of T-ALL subgroups, and it is important in determining prognostic factors and choosing an appropriate treatment. Novel therapies targeting molecular aberrations offer promise in achieving better first remission with the hope of preventing relapse. The employment of precisely targeted therapeutic approaches is expected to improve the cure of the disease and quality of life of patients. These include therapies that inhibit Notch1 activation (bortezomib), JAK inhibitors in ETP-ALL (ruxolitinib), BCL inhibitors (venetoclax), and anti-CD38 therapy (daratumumab). Chimeric antigen receptor T-cell therapy (CAR-T) is under investigation, but it requires further development and trials. Nelarabine-based regimens remain the standard for treating the relapse of T-ALL.

Prognostic Genetic Markers for Thrombosis in COVID-19 Patients: A Focused Analysis on D-Dimer, Homocysteine and Thromboembolism.

COVID-19 is caused by Severe Acute Respiratory Syndrome Coronavirus-2, which has infected over thirty eight million individuals worldwide. Emerging evidence indicates that COVID-19 patients are at a high risk of developing coagulopathy and thrombosis, conditions that elevate levels of D-dimer. It is believed that homocysteine, an amino acid that plays a crucial role in coagulation, may also contribute to these conditions. At present, multiple genes are implicated in the development of these disorders. For example, single-nucleotide polymorphisms (SNPs) in FGG, FGA, and F5 mediate increases in D-dimer and SNPs in ABO, CBS, CPS1 and MTHFR mediate differences in homocysteine levels, and SNPs in TDAG8 associate with Heparin-induced Thrombocytopenia. In this study, we aimed to uncover the genetic basis of the above conditions by examining genome-wide associations and tissue-specific gene expression to build a molecular network. Based on gene ontology, we annotated various SNPs with five ancestral terms: pulmonary embolism, venous thromboembolism, vascular diseases, cerebrovascular disorders, and stroke. The gene-gene interaction network revealed three clusters that each contained hallmark genes for D-dimer/fibrinogen levels, homocysteine levels, and arterial/venous thromboembolism with F2 and F5 acting as connecting nodes. We propose that genotyping COVID-19 patients for SNPs examined in this study will help identify those at greatest risk of complications linked to thrombosis.