Sporadic childhood hepatoblastomas show activation of β-catenin, mismatch repair defects and p53 mutations

Curia, Maria Cristina; Zuckermann, Michele; Lellis, Laura De; Catalano, Teresa; Lattanzio, Rossano; Aceto, Gitana María; Veschi, Serena; Cama, Alessandro; Otte, Jean Bernard; Piantelli, Mauro; Mariani-Costantini, Renato; Cetta, Francesco; Battista, Pasquale

doi:10.1038/modpathol.3800977

Cited by 50 publications

(33 citation statements)

References 28 publications

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“…However, large tumors, multifocal tumors, and metastatic spread are associated with poor prognosis [2]. Nonrandom chromosomal imbalances involving 1q, 2q, 8q, 4q, and 20q [3,4] and alterations in the wnt signaling pathway [5,6] or the insulin-like growth factor (IGF) axis are considered to contribute to the development of HBL [7,8], but the molecular mechanisms responsible for the pathogenesis and progression of HBL are largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Gene expression profiling of human hepatoblastoma using archived formalin-fixed and paraffin-embedded tissues

et al. 2011

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We elucidated the genetic profile of hepatoblastomas (HBLs) to identify diagnostic and prognostic markers. RNA was extracted from 32 formalin-fixed, paraffin-embedded HBLs and corresponding nonneoplastic liver (NNL) tissues, and cDNA-mediated annealing, selection, extension, and ligation (DASL) chip assays were performed. Immunohistochemistry was performed to confirm the expression of Yin Yang 1 (YY1) protein in HBL. Twenty-four genes that were associated with signal transduction, cell-cell adhesion, cell cycle regulation, and apoptosis were differentially expressed in HBL and NNL tissues. Two apoptosis-associated genes, MYCN and BIRC5, were highly upregulated in HBL. Eight genes, including YY1 and IGF1, were upregulated in HBL cases that had a poor prognosis. Thirty-eight genes, including YY1, were differentially expressed according to histologic differentiation of HBL, and the immunohistochemical expression of YY1 was correlated with poor HBL differentiation. Thus, using DASL chip assays, we report the gene expression profiles of HBL, which suggest new candidate prognostic and diagnostic genetic markers and putative therapeutic targets for HBL.

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Section: Introductionmentioning

confidence: 99%

Gene expression profiling of human hepatoblastoma using archived formalin-fixed and paraffin-embedded tissues

et al. 2011

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“…1 and 3) suggests that Wnt pathway activation can lead to the development of ovarian steroid cell tumors. The identification of activating b-catenin mutations in a significant percentage of sporadic tumors that are part of the FAP neoplastic spectrum (Abraham et al, 2001;Garcia-Rostan et al, 2001;Curia et al, 2008;Lazar et al, 2008;Bonnet et al, 2011;Ellison et al, 2011) suggests that Wnt pathway activation may also contribute to tumorigenesis in at least a subset of sporadic ovarian steroid cell tumors. …”

Section: Discussionmentioning

confidence: 96%

Ovarian steroid cell tumor with biallelic adenomatous polyposis coli inactivation in a patient with familial adenomatous polyposis

Hu¹,

Knoepp²,

Wu³

et al. 2011

Genes Chromosomes & Cancer

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Familial adenomatous polyposis (FAP) is an autosomal dominant cancer predisposition syndrome that accounts for approximately 0.5-1% of all colorectal cancer cases. It is caused by germline mutations in the gene encoding the adenomatous polyposis coli (APC) tumor suppressor. Somatic APC inactivation due to mutation or loss of heterozygosity (LOH) promotes the development of adenomatous polyps by stabilizing the transcriptional coactivator β-catenin. Although colorectal cancer is by far the most common malignancy seen in FAP patients, the widespread use of prophylactic colectomy in these patients has increased the clinical importance of extracolonic tumors that are part of the neoplastic spectrum in FAP. Many of these tumors exhibit LOH or somatic APC mutation, strongly supporting a causative role of APC inactivation in their pathogenesis. Here we describe a 47-year-old female FAP patient with clinical manifestations of virilization who was found to have an ovarian steroid cell tumor, a rare neoplasm not known to be associated with FAP. Immunohistochemical analysis of the ovarian tumor demonstrated strong nuclear β-catenin staining consistent with somatic APC inactivation, and molecular analysis confirmed biallelic APC inactivation in the tumor. Our findings provide the first evidence that ovarian steroid cell tumors may be an extracolonic manifestation of FAP and implicate β-catenin activation as an oncogenic mechanism in ovarian steroid cell tumorigenesis.

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“…These mutations also implicate the dis-regulation of their associated molecular pathways in HepG2. For CTNNB1, dis-regulation and mutations have been extensively documented for hepatoblastoma in general (Bläker et al 1999;Taniguchi et al 2002;Curia et al 2008;López-Terrada et al 2009b;Jia et al 2014;Crippa et al 2017).…”

Section: Discussionmentioning

confidence: 99%

Haplotype-resolved and integrated genome analysis of the cancer cell line HepG2

Zhou

Greer

Spies

et al. 2018

Preprint

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HepG2 is one of the most widely used human cell lines in biomedical research and one of the main cell lines of ENCODE. Although the functional genomic and epigenomic characteristics of HepG2 are extensively studied, its genome sequence has never been comprehensively analyzed and higher-order structural features of its genome beyond its karyotype were only cursorily known. The high degree of aneuploidy in HepG2 renders traditional genome variant analysis methods challenging and partially ineffective. Correct and complete interpretation of the extensive functional genomics data fromHepG2 requires an understanding of the cell line's genome sequence and genome structure. We performed deep whole-genome sequencing, mate-pair sequencing and linked-read sequencing to identify a wide spectrum of genome characteristics in HepG2: copy numbers of chromosomal segments, SNVs and Indels (both corrected for copynumber), phased haplotype blocks, structural variants (SVs) including complex genomic rearrangements, and novel mobile element insertions. A large number of SVs were phased, sequence assembled and experimentally validated. Several chromosomes show striking loss of heterozygosity. We re-analyzed HepG2 RNA-Seq and wholegenome bisulfite sequencing data for allele-specific expression and phased DNA methylation. We show examples where deeper insights into genomic regulatory complexity could be gained by taking knowledge of genomic structural contexts into account. Furthermore, we used the haplotype information to produce an allele-specific CRISPR targeting map. This comprehensive whole-genome analysis serves as a resource for future studies that utilize HepG2.

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Sporadic childhood hepatoblastomas show activation of β-catenin, mismatch repair defects and p53 mutations

Cited by 50 publications

References 28 publications

Gene expression profiling of human hepatoblastoma using archived formalin-fixed and paraffin-embedded tissues

Gene expression profiling of human hepatoblastoma using archived formalin-fixed and paraffin-embedded tissues

Ovarian steroid cell tumor with biallelic adenomatous polyposis coli inactivation in a patient with familial adenomatous polyposis

Haplotype-resolved and integrated genome analysis of the cancer cell line HepG2

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