Comprehensive genomic analysis of early and late-onset hepatocellular carcinoma
Ontology highlight
ABSTRACT:
SUBMITTER: Yang J
PROVIDER: S-EPMC10950800 | biostudies-literature | 2023 Jul
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundThe incidence of colorectal cancer (CRC) in young adults has increased worldwide. Our study aimed to evaluate genomic alterations in early-onset (aged 15-39 years) sporadic CRC.MethodsFormalin-fixed, paraffin-embedded tissue samples from 90 patients with histologically confirmed colorectal adenocarcinoma with proficient mismatch repair status from Siriraj Hospital (Bangkok, Thailand) were extracted. Patients with clinically suspected familial adenomatous polyposis were excluded. A 517-gene mutational analysis was performed by next-generation sequencing using the Oncomine Comprehensive Assay Plus kit. The previously reported molecular data in adult-onset CRC from our group were used as a comparator group.ResultsThe five most frequently mutated genes were APC (66%), TP53 (51%), KRAS (47%), ARID1A (31%), and KMT2B (31%). When compare with adult-onset, NOTCH1 (11.1% vs. 1.9%), FBXW7 (23.3% vs. 14.8%), PIK3CA (20% vs. 12.1%), and FGFR3 (8.9% vs. 3.7%) mutations were more prevalent in early-onset. No differences were observed in other common mutations, such as TP53, EGFR, KRAS, NRAS and BRAF mutations. An increased prevalence in KRAS codon 12 mutations was also observed in early-onset patients compared to the adult-onset group (38.9% vs. 29.6%).ConclusionsOverall, the genomic landscape between early- and adult-onset CRC appears similar. However, our study revealed the enrichment of NOTCH1, FBXW7, PIK3CA, and FGFR3 along with KRAS G12 mutations, were more frequent in early-onset compared to adult-onset cases. Further studies with a larger cohort of patients on the comprehensive analysis of genetic/epigenetic signatures are required.
| S-EPMC11863557 | biostudies-literature
Project description:PurposeThere are few studies on early-onset and late-onset nasopharyngeal cancer (EONPC and LONPC, defined as cancers in those aged < 50 and ≥ 50 years, respectively). This study aimed to determine the clinical and survival characteristics of patients with NPC in these two age groups.MethodsThis study involved patients diagnosed with NPC between 2000 and 2018, as per the Surveillance, Epidemiology, and End Results (SEER) database, and in our institution from 2014 to 2017. The clinicopathological characteristics, treatment modalities, and survival outcomes of patients with EONPC and LONPC were analyzed and compared.ResultsA total of 2943 patients from the SEER database and 833 domestic patients from our center were enrolled in the study. The EONPC group showed a better prognosis than LONPC (p < 0.001), despite a worse staging of regional lymph node metastasis (p < 0.001). Similar results were validated at our center; further, patients with EONPC presented more EBV-DNA positive rates (58% vs. 36.8%, p < 0.001) than those with LONPC. Further, the EONPC group had a superior overall survival (OS) (p = 0.017) and cancer-specific survival (CSS) (p = 0.004) compared to that of the LONPC patients. Univariate and multivariate Cox regression analyses revealed EONPC to be independently associated with a higher five-year OS.ConclusionsThough the EONPC group presented with more advanced clinical stages and lymph node metastasis, they showed better survival than the LONPC group. Age ≤ 50 years was an independent prognostic factor for survival outcomes in patients with NPC. Further studies on EONPC are warranted to achieve a better individualized therapeutic regimen.
| S-EPMC11579260 | biostudies-literature
Project description:Age-related degenerative and malignant diseases represent major challenges for health care systems. Elucidation of the molecular mechanisms underlying carcinogenesis and age-associated pathologies is thus of growing biomedical relevance. We identified biallelic germline mutations in SPRTN (also called C1orf124 or DVC1) in three patients from two unrelated families. All three patients are affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. SPRTN was recently proposed to have a function in translesional DNA synthesis and the prevention of mutagenesis. Our in vivo and in vitro characterization of identified mutations has uncovered an essential role for SPRTN in the prevention of DNA replication stress during general DNA replication and in replication-related G2/M-checkpoint regulation. In addition to demonstrating the pathogenicity of identified SPRTN mutations, our findings provide a molecular explanation of how SPRTN dysfunction causes accelerated aging and susceptibility toward carcinoma.
| S-EPMC4343211 | biostudies-literature
Project description:Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole-exome sequencing and DNA copy number analyses, and we analyzed 196 HCC cases by DNA methylation, RNA, miRNA, and proteomic expression also. DNA sequencing and mutation analysis identified significantly mutated genes, including LZTR1, EEF1A1, SF3B1, and SMARCA4. Significant alterations by mutation or downregulation by hypermethylation in genes likely to result in HCC metabolic reprogramming (ALB, APOB, and CPS1) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1.
| S-EPMC5680778 | biostudies-literature
Project description:We evaluated a family with a 16-month-old boy with cirrhosis and hepatocellular carcinoma and his 30-month-old brother with cirrhosis. After failing to identify a diagnosis after routine metabolic evaluation, we utilized a combination of RNA-Seq and whole exome sequencing to identify a novel homozygous p.Ser171Phe Transaldolase (TALDO1) variant in the proband, his brother with cirrhosis, as well as a clinically asymptomatic older 8-year-old brother. Metabolite analysis and enzymatic testing of TALDO1 demonstrated elevated ribitol, sedoheptitol, and sedoheptulose-7P, and lack of activity of TALDO1 in the three children homozygous for the p.Ser171Phe mutation. Our findings expand the phenotype of transaldolase deficiency to include early onset hepatocellular carcinoma in humans and demonstrate that, even within the same family, individuals with the same homozygous mutation demonstrate a wide range of phenotypes.
| S-EPMC3897795 | biostudies-other
Project description:PURPOSE:The incidence rates of colorectal cancers are increasing in young adults. The objective of this study was to investigate genomic differences between tumor samples collected from younger and older patients with colorectal cancer. EXPERIMENTAL DESIGN:DNA was extracted from 18,218 clinical specimens, followed by hybridization capture of 3,769 exons from 403 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer. Genomic alterations (GA) were determined, and association with patient age and microsatellite stable/microsatellite instability high (MSS/MSI-H) status established. RESULTS:Overall genomic alteration rates in the younger (<40) and older (≥50) cohorts were similar in the majority of the genes analyzed. Gene alteration rates in the microsatellite stable (MSS) younger and older cohorts were largely similar, with several notable differences. In particular, TP53 (FDR < 0.01) and CTNNB1 (FDR = 0.01) alterations were more common in younger patients with colorectal cancer, and APC (FDR < 0.01), KRAS (FDR < 0.01), BRAF (FDR < 0.01), and FAM123B (FDR < 0.01) were more commonly altered in older patients with colorectal cancer. In the MSI-H cohort, the majority of genes showed similar rate of alterations in all age groups, but with significant differences seen in APC (FDR < 0.01), BRAF (FDR < 0.01), and KRAS (FDR < 0.01). CONCLUSIONS:Tumors from younger and older patients with colorectal cancer demonstrated similar overall rates of genomic alteration. However, differences were noted in several genes relevant to biology and response to therapy. Further study will need to be conducted to determine whether the differences in gene alteration rates can be leveraged to provide personalized therapies for young patients with early-onset sporadic colorectal cancer.
| S-EPMC6774873 | biostudies-literature
Project description:In this study, we explored the genomic and immune cell infiltration profiles among four distinct Hepatocellular carcinoma (HCC) types. This study included 100 patients (all tumors and adjacent liver tissues received WES sequencing) with HCC from the West China Hospital (WCH) and patients were divided into WCH-HBV-HCC group and WCH-NonHBV-HCC group. Additionally, this study included 106 HBV-related HCC (TCGA-HBV-HCC) and 69 alcoholic HCC (TCGA-Alcol-HCC) patients from the TCGA. We analyzed the high-frequency gene mutation, copy number variation (CNV), mutation spectrum, signatures and immune cell infiltration of these four groups. This study showed significant differences in gene mutation and CNV level among four HCC groups. Compared to genomic level, there is no significant difference between TCGA-HBV-HCC and TCGA-Alcol-HCC groups in fractions of tumor-infiltrating immune cells. According to the status of immune cell infiltration, patients were classified into immune-HIGH, immune-MIX and immune-LOW group, respectively. In the WCH-HBV-HCC and TCGA-HBV-HCC groups, more patients in the Immune-LOW group had TP53 mutation. Except for TP53, neither the other gene mutation nor tumor mutation burden was found to be associated with immune cell infiltration in the WCH-HBV-HCC, TCGA-HBV-HCC and TCGA-Alcol-HCC groups. In the CNV level, we found that samples with low immune infiltrate had higher number of deleted or amplified genes in the TCGA-HBV-HCC and TCGA-Alcol-HCC groups. We found comprehensive genomic heterogeneity among four HCC groups. The total gene CNV level, not the mutational burden of HCC, is associated with immune cell infiltration in HCC. TP53 mutation may injury the immune response of the HBV-related HCC.
| S-EPMC8109067 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is an aggressive malignancy with its global incidence and mortality rate continuing to rise, although early detection and surveillance are suboptimal. We performed serological profiling of the viral infection history in 899 individuals from an NCI-UMD case-control study using a synthetic human virome, VirScan. We developed a viral exposure signature and validated the results in a longitudinal cohort with 173 at-risk patients who had long-term follow-up for HCC development. Our viral exposure signature significantly associated with HCC status among at-risk individuals in the validation cohort (area under the curve: 0.91 [95% CI 0.87-0.96] at baseline and 0.98 [95% CI 0.97-1] at diagnosis). The signature identified cancer patients prior to a clinical diagnosis and was superior to alpha-fetoprotein. In summary, we established a viral exposure signature that can predict HCC among at-risk patients prior to a clinical diagnosis, which may be useful in HCC surveillance.
| S-EPMC8315306 | biostudies-literature
Project description:Pediatric tumors are relatively infrequent, but are often associated with significant lethality and lifelong morbidity. A major goal of pediatric cancer research has been to identify key drivers of tumorigenesis to eventually develop targeted therapies to enhance cure rate and minimize acute and long-term toxic effects. Here, we used genomic approaches to identify biomarkers and candidate drivers for fibrolamellar hepatocellular carcinoma (FL-HCC), a very rare subtype of pediatric liver cancer for which limited therapeutic options exist. In-depth genomic analyses of one tumor followed by immunohistochemistry validation on seven other tumors showed expression of neuroendocrine markers in FL-HCC. DNA and RNA sequencing data further showed that common cancer pathways are not visibly altered in FL-HCC but identified two novel structural variants, both resulting in fusion transcripts. The first, a 400 kb deletion, results in a DNAJB1-PRKCA fusion transcript, which leads to increased cAMP-dependent protein kinase (PKA) activity in the index tumor case and other FL-HCC cases compared with normal liver. This PKA fusion protein is oncogenic in HCC cells. The second gene fusion event, a translocation between the CLPTM1L and GLIS3 genes, generates a transcript whose product also promotes cancer phenotypes in HCC cell lines. These experiments further highlight the tumorigenic role of gene fusions in the etiology of pediatric solid tumors and identify both candidate biomarkers and possible therapeutic targets for this lethal pediatric disease.
| S-EPMC4262492 | biostudies-literature
Project description:BackgroundSurvival after liver resection of hepatocellular carcinoma (HCC) remains poor because of a high incidence of recurrence. We sought to investigate risk factors, patterns, and long-term prognosis among patients with early and late recurrence after liver resection for hepatitis B virus (HBV)-associated HCC.MethodsData of consecutive patients undergoing curative resection for HBV-associated HCC were analyzed. According to the time to recurrence after surgery, recurrence was divided into early (≤2 years) and late recurrence (>2 years). Characteristics, patterns of initial recurrence, and postrecurrence survival (PRS) were compared between patients with early and late recurrence. Risk factors of early and late recurrence and predictors of PRS were identified by univariable and multivariable Cox regression analyses.ResultsAmong 894 patients, 322 (36.0%) and 282 (31.5%) developed early and late recurrence, respectively. On multivariable analyses, preoperative HBV-DNA >104 copies/mL was associated with both early and late recurrence, whereas postoperative no/irregular antiviral therapy was associated with late recurrence. Compared with patients with late recurrence, patients with early recurrence had a lower proportion of intrahepatic-only recurrence (72.0% vs. 91.1%, p < .001), as well as a lower chance of receiving potentially curative treatments for recurrence (33.9% vs. 50.7%, p < .001) and a worse median PRS (19.1 vs. 37.5 months, p < .001). Multivariable analysis demonstrated that early recurrence was independently associated with worse PRS (hazard ratio, 1.361; 95% confidence interval, 1.094-1.692; p = .006).ConclusionAlthough risk factors associated with early recurrence and late recurrence were different, a high preoperative HBV-DNA load was an independent hepatitis-related risk for both early and late recurrence. Early recurrence was associated with worse postrecurrence survival among patients with recurrence.Implications for practiceLiver resection is the main curative treatment for hepatocellular carcinoma (HCC), but postoperative survival remains poor because of high recurrence rates. This study investigated the risk factors and patterns of early and late recurrence and found that a high preoperative hepatitis B virus (HBV) DNA load was an independent hepatitis-related risk factor for both. Early recurrence was also independently associated with worse postrecurrence survival. These data may provide insights into different biological origin and behavior of early versus late recurrence after resection for HBV-associated HCC, which could be helpful to make individualized treatment decision for recurrent HCC, as well as strategies for surveillance recurrence after resection.
| S-EPMC7543359 | biostudies-literature