martes, 26 de febrero de 2019

Childhood Cancer Genomics (PDQ®) 5/8 —Health Professional Version - National Cancer Institute

Childhood Cancer Genomics (PDQ®)—Health Professional Version - National Cancer Institute



National Cancer Institute



Medulloepithelioma
Medulloepithelioma is identified as a histologically discrete tumor within the WHO classification system.[110,111] Medulloepithelioma tumors are rare and tend to arise most commonly in infants and young children. Medulloepitheliomas, which histologically recapitulate the embryonal neural tube, tend to arise supratentorially, primarily intraventricularly, but may arise infratentorially, in the cauda, and even extraneurally, along nerve roots.[110,111] Medulloepithelioma with the classic molecular change is considered an ETMR.
Pineoblastoma
Pineoblastoma, which was previously conventionally grouped with embryonal tumors, is now categorized by the WHO as a pineal parenchymal tumor. Given that therapies for pineoblastoma are quite similar to those utilized for embryonal tumors, the previous convention of including pineoblastoma with the CNS embryonal tumors is followed here. Pineoblastoma is associated with germline mutations in both the retinoblastoma (RB1) gene and in DICER1, as described below:
  • Pineoblastoma is associated with germline mutations in RB1, with the term trilateral retinoblastoma used to refer to ocular retinoblastoma in combination with a histologically similar brain tumor generally arising in the pineal gland or other midline structures. Historically, intracranial tumors have been reported in 5% to 15% of children with heritable retinoblastoma.[112] Rates of pineoblastoma among children with heritable retinoblastoma who undergo current treatment programs may be lower than these historical estimates.[113-115]
  • Germline DICER1 mutations have also been reported in patients with pineoblastoma.[116] Among 18 patients with pineoblastoma, three patients with DICER1 germline mutations were identified, and an additional three patients known to be carriers of germline DICER1 mutations developed pineoblastoma.[116] The DICER1 mutations in patients with pineoblastoma are loss-of-function mutations that appear to be distinct from the mutations observed in DICER1 syndrome–related tumors such as pleuropulmonary blastoma.[116]
(Refer to the PDQ summary on Childhood Central Nervous System Embryonal Tumors Treatment for information about the treatment of childhood PNETs.)

Ependymomas

Molecular characterization studies have identified several biological subtypes of ependymoma based on their distinctive DNA methylation and gene expression profiles and on their distinctive spectrum of genomic alterations (refer to Figure 6).[117-119]
  • Infratentorial tumors.
    • Posterior fossa A, CpG island methylator phenotype (CIMP)-positive ependymoma, termed EPN-PFA.
    • Posterior fossa B, CIMP-negative ependymoma, termed EPN-PFB.
  • Supratentorial tumors.
    • C11orf95-RELA–positive ependymoma.
    • C11orf95-RELA–negative and YAP1 fusion–positive ependymoma.
  • Spinal tumors.
ENLARGEGraph showing key molecular and clinical characteristics of ependymal tumor subgroups.
Figure 6. Graphical summary of key molecular and clinical characteristics of ependymal tumor subgroups. Schematic representation of key genetic and epigenetic findings in the nine molecular subgroups of ependymal tumors as identified by methylation profiling. CIN, Chromosomal instability. Reprinted from Cancer Cell, Volume 27, Kristian W. Pajtler, Hendrik Witt, Martin Sill, David T.W. Jones, Volker Hovestadt, Fabian Kratochwil, Khalida Wani, Ruth Tatevossian, Chandanamali Punchihewa, Pascal Johann, Juri Reimand, Hans-Jorg Warnatz, Marina Ryzhova, Steve Mack, Vijay Ramaswamy, David Capper, Leonille Schweizer, Laura Sieber, Andrea Wittmann, Zhiqin Huang, Peter van Sluis, Richard Volckmann, Jan Koster, Rogier Versteeg, Daniel Fults, Helen Toledano, Smadar Avigad, Lindsey M. Hoffman, Andrew M. Donson, Nicholas Foreman, Ekkehard Hewer, Karel Zitterbart, Mark Gilbert, Terri S. Armstrong, Nalin Gupta, Jeffrey C. Allen, Matthias A. Karajannis, David Zagzag, Martin Hasselblatt, Andreas E. Kulozik, Olaf Witt, V. Peter Collins, Katja von Hoff, Stefan Rutkowski, Torsten Pietsch, Gary Bader, Marie-Laure Yaspo, Andreas von Deimling, Peter Lichter, Michael D. Taylor, Richard Gilbertson, David W. Ellison, Kenneth Aldape, Andrey Korshunov, Marcel Kool, and Stefan M. Pfister, Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups, Pages 728–743, Copyright (2015), with permission from Elsevier.
Approximately two-thirds of childhood ependymomas arise in the posterior fossa, and two major genomically defined subtypes of posterior fossa tumors are recognized. Similarly, most pediatric supratentorial tumors can be categorized into one of two genomic subtypes. These subtypes and their associated clinical characteristics are described below.[117] Among these subtypes, the 2016 World Health Organization (WHO) classification has accepted ependymoma, RELA fusion–positive, as a distinct diagnostic entity.[1]
The most common posterior fossa ependymoma subtype is EPN-PFA and is characterized by the following:
  • Presentation in young children (median age, 3 years).[117]
  • Low rates of mutations that affect protein structure (approximately five per genome), with no recurring mutations.[118]
  • A balanced chromosomal profile (refer to Figure 7) with few chromosomal gains or losses.[117,118]
    ENLARGEChart showing the identification of subgroup-specific copy number alterations in the posterior fossa ependymoma genome.
    Figure 7. Identification of Subgroup-Specific Copy Number Alterations in the Posterior Fossa Ependymoma Genome. (A) Copy number profiling of 75 PF ependymomas using 10K array-CGH identifies disparate genetic landscapes between Group A and Group B tumors. Toronto and Heidelberg copy number datasets have been combined and summarized in a heatmap. The heatmap also displays the association of tumors to cytogenetic risk groups 1, 2, and 3 (Korshunov et al., 2010). Statistically significant chromosomal aberrations (black boxes) are also displayed between both subgroups, calculated by Fisher's exact test. Witt H, Mack SC, Ryzhova M, et al.: Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell 20 (2): 143-57, 2011, doi:10.1016/j.ccr.2011.07.007. Copyright © 2011 Elsevier Inc. All rights reserved.
  • Gain of chromosome 1q, a known poor prognostic factor for ependymomas,[120] in approximately 25% of cases.[117,119]
  • Presence of the CIMP (i.e., CIMP positive).[119]
  • High rates of disease recurrence (33% progression-free survival [PFS] at 5 years) and low survival rates compared with other subtypes (68% at 5 years).[117]
The EPN-PFB subtype is less common than the EPN-PFA subtype in children and is characterized by the following:
  • Presentation primarily in adolescents and young adults (median age, 30 years).[117]
  • Low rates of mutations that affect protein structure (approximately five per genome), with no recurring mutations.[119]
  • Numerous cytogenetic abnormalities (refer to Figure 7), primarily involving the gain/loss of whole chromosomes.[117,119]
  • Absence of the CIMP (i.e., CIMP negative).[119]
  • Favorable outcome in comparison to EPN-PFA, with 5-year PFS of 73% and overall survival (OS) of 100%.[117]
The largest subset of pediatric supratentorial (ST) ependymomas are characterized by gene fusions involving RELA,[121,122] a transcriptional factor important in NF-κB pathway activity. This subtype is termed ST-EPN-RELA and is characterized by the following:
  • Represents approximately 70% of supratentorial ependymomas in children,[121,122] and presents at a median age of 8 years.[117]
  • Presence of C11orf95-RELA fusions resulting from chromothripsis involving chromosome 11q13.1.[121]
  • Evidence of NF-κB pathway activation at the protein and RNA level.[121]
  • Low rates of mutations that affect protein structure and absence of recurring mutations outside of C11orf95-RELA fusions.[121]
  • Presence of homozygous deletions of CDKN2A, a known poor prognostic factor for ependymomas,[120] in approximately 15% of cases.[117]
  • Gain of chromosome 1q, a known poor prognostic factor for ependymomas, in approximately one-quarter of cases.[117]
  • Unfavorable outcome in comparison to other ependymoma subtypes, with 5-year PFS of 29% and OS of 75%.[117]
  • Supratentorial clear cell ependymomas with branching capillaries commonly show the C11orf95-RELA fusion,[123] and one series of 20 patients with a median age of 10.4 years showed a relatively favorable prognosis (5-year PFS of 68% and OS of 72%).[123]
A second, less common subset of supratentorial ependymomas, termed ST-EPN-YAP1, has fusions involving YAP1 and are characterized by the following:
  • Median age at diagnosis of 1.4 years.[117]
  • Presence of a gene fusion involving YAP1, with MAMLD1 being the most common fusion partner.[117,121]
  • A relatively stable genome with few chromosomal changes other than the YAP1 fusion.[117]
  • Relatively favorable prognosis (although based on small numbers), with a 5-year PFS of 66% and OS of 100%.[117]
Clinical implications of genomic alterations
The absence of recurring mutations in the EPN-PFA and EPN-PFB subtypes at diagnosis precludes using their genomic profiles to guide therapy. The RELA and YAP1 fusion genes present in supratentorial ependymomas are not directly targetable with agents in the clinic, but can provide leads for future research.
(Refer to the PDQ summary on Childhood Ependymoma Treatment for information about the treatment of childhood ependymoma.)

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Hepatoblastoma and Hepatocellular Carcinoma


Genomic abnormalities related to hepatoblastoma include the following:
  • Hepatoblastoma mutation frequency, as determined by three groups using whole-exome sequencing, was very low (approximately three variants per tumor) in children younger than 5 years.[1-3]
  • Hepatoblastoma is primarily a disease of WNT pathway activation. The primary mechanism for WNT pathway activation is CTNNB1 activating mutations/deletions involving exon 3. CTNNB1 mutations have been reported in 70% of cases.[1] Rare causes of WNT pathway activation include mutations in AXIN1, AXIN2, and APC (APCseen only in cases associated with familial adenomatosis polyposis coli).[4]
  • The frequency of NFE2L2 mutations in hepatoblastoma specimens was reported to be 4 of 62 tumors (7%) in one study [2] and 5 of 51 specimens (10%) in another study.[1]
    Similar mutations have been found in many types of cancer, including hepatocellular carcinoma. These mutations render NFE2L2 insensitive to KEAP1-mediated degradation, leading to activation of the NFE2L2-KEAP1 pathway, which activates resistance to oxidative stress and is believed to confer resistance to chemotherapy.
  • Somatic mutations were identified in other genes related to regulation of oxidative stress, including inactivating mutations in the thioredoxin-domain containing genes, TXNDC15 and TXNDC16.[2]
  • Figure 8 shows the distribution of CTNNB1, NFE2L2, and TERT mutations in hepatoblastoma.[1]
    ENLARGEChart showing the distribution of CTNNB1, APC, NFE2L2, and TERT mutations for hepatoblastoma.
    Figure 8. Mutational status and functional relevance of NFE2L2 in hepatoblastoma. Clinicopathological characteristics and the mutational status of the CTNNB1, APC, and NFE2L2 genes, as well as the TERT promoter region are color-coded and depicted in rows for each tumor of our cohort of 43 hepatoblastoma (HB) patients and four transitional liver cell tumour (TLCT) patients and 4 HB cell lines. Reprinted from Journal of Hepatology, Volume 61 (Issue 6), Melanie Eichenmüller, Franziska Trippel, Michaela Kreuder, Alexander Beck, Thomas Schwarzmayr, Beate Häberle, Stefano Cairo, Ivo Leuschner, Dietrich von Schweinitz, Tim M. Strom, Roland Kappler, The genomic landscape of hepatoblastoma and their progenies with HCC-like features, Pages 1312–1320, Copyright 2014, with permission from Elsevier.
To date, these genetic mutations have not been used to select therapeutic agents for investigation in clinical trials.
Genomic abnormalities related to hepatocellular carcinoma include the following:
  • A first case of pediatric hepatocellular carcinoma was analyzed by whole-exome sequencing, which showed a higher mutation rate (53 variants) and the coexistence of CTNNB1 and NFE2L2 mutations.[5]
  • Fibrolamellar hepatocellular carcinoma is a rare subtype of hepatocellular carcinoma observed in older children. It is characterized by an approximately 400 kB deletion on chromosome 19 that results in production of a chimeric RNA coding for a protein containing the amino-terminal domain of DNAJB1, a homolog of the molecular chaperone DNAJ, fused in frame with PRKACA, the catalytic domain of protein kinase A.[6]
  • A rare, more aggressive subtype of childhood liver cancer (hepatocellular neoplasm, not otherwise specified, also termed transitional liver cell tumor) occurs in older children, and it has clinical and histopathological findings of both hepatoblastoma and hepatocellular carcinoma.
    TERT mutations were observed in two of four cases tested.[1] TERT mutations are also commonly observed in adults with hepatocellular carcinoma.[7]
To date, these genetic mutations have not been used to select therapeutic agents for investigation in clinical trials.

(Refer to the PDQ summary on Childhood Liver Cancer Treatment for information about the treatment of liver cancer.)
References
  1. Eichenmüller M, Trippel F, Kreuder M, et al.: The genomic landscape of hepatoblastoma and their progenies with HCC-like features. J Hepatol 61 (6): 1312-20, 2014. [PUBMED Abstract]
  2. Trevino LR, Wheeler DA, Finegold MJ, et al.: Exome sequencing of hepatoblastoma reveals recurrent mutations in NFE2L2. [Abstract] Cancer Res 73 (8 Suppl): A-4592, 2013. Also available online. Last accessed November 09, 2018.
  3. Jia D, Dong R, Jing Y, et al.: Exome sequencing of hepatoblastoma reveals novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex. Hepatology 60 (5): 1686-96, 2014. [PUBMED Abstract]
  4. Hiyama E, Kurihara S, Onitake Y: Integrated exome analysis in childhood hepatoblastoma: Biological approach for next clinical trial designs. [Abstract] Cancer Res 74 (19 Suppl): A-5188, 2014.
  5. Vilarinho S, Erson-Omay EZ, Harmanci AS, et al.: Paediatric hepatocellular carcinoma due to somatic CTNNB1 and NFE2L2 mutations in the setting of inherited bi-allelic ABCB11 mutations. J Hepatol 61 (5): 1178-83, 2014. [PUBMED Abstract]
  6. Honeyman JN, Simon EP, Robine N, et al.: Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science 343 (6174): 1010-4, 2014. [PUBMED Abstract]
  7. Nault JC, Mallet M, Pilati C, et al.: High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat Commun 4: 2218, 2013. [PUBMED Abstract]
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