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The impact of molecular analysis on the survival of children with embryonal tumors.

ABSTRACT: Embryonal tumors represent a heterogeneous group of malignancies characterized by poorly differentiated cells and generally aggressive behavior. Although advances in survival rates have been made in several of these tumor types, including Wilms' tumor, retinoblastoma, and medulloblastoma, survival of patients with central nervous system (CNS) embryonal tumors, including primitive neuro-ectodermal tumors (PNETs) and atypical teratoid rhabdoid tumors (AT/RT), are particularly poor. Advancing molecular analysis techniques and the development of gene expression profiles has led to the formulation of different subdivisions within many of the umbrella CNS tumor groups with clinical and prognostic implications. Some subgroups have been identified as having improved survivorships, likely not captured by large scale population data given their small numbers and relatively recent characterization. Importantly, identification of differing molecular pathways has begun to result in targeted therapies which may pave the way for even more surviving patients in the coming years.

SUBMITTER: Drezner NL

PROVIDER: S-EPMC4729043 | biostudies-other | 2016 Jan

REPOSITORIES: biostudies-other

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The impact of molecular analysis on the survival of children with embryonal tumors.

Drezner Nicole L NL Packer Roger J RJ

Translational pediatrics 20160101 1

Embryonal tumors represent a heterogeneous group of malignancies characterized by poorly differentiated cells and generally aggressive behavior. Although advances in survival rates have been made in several of these tumor types, including Wilms' tumor, retinoblastoma, and medulloblastoma, survival of patients with central nervous system (CNS) embryonal tumors, including primitive neuro-ectodermal tumors (PNETs) and atypical teratoid rhabdoid tumors (AT/RT), are particularly poor. Advancing molec ...[more]

PMID: 26835399

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Project description:Tremendous progress has recently been made in both molecular subgrouping, and the establishment of prognostic biomarkers for embryonal brain tumors, particularly medulloblastoma. Several prognostic biomarkers that were initially identified in retrospective cohorts of medulloblastoma, including MYC and MYCN amplification, nuclear ?-catenin accumulation, and chromosome 17 aberrations have now been validated in clinical trials. Moreover, molecular subgroups based on distinct transcriptome profiles have been consistently reported from various groups on different platforms demonstrating that the concept of distinct medulloblastoma subgroups is very robust. Well-described subgroups of medulloblastomas include tumors showing wingless signaling pathway (Wnt) activation, and another characterized by sonic hedgehog pathway activity. Two or more additional subgroups were consistently reported to contain the vast majority of high-risk tumors, including most tumors with metastatic disease at diagnosis and/or large cell/anaplastic histology. Several years ago, atypical teratoid rhabdoid tumor (AT/RT) was recognized as a separate entity based on its distinct biology and particularly aggressive clinical behavior. These tumors may occur supra or infratentorially and are usually found to have genetic alterations of SMARCB1 (INI1/hSNF5), a tumor suppressor gene located on chromosome 22q. Subsequent loss of SMARCB1 protein expression comprises a relatively specific and sensitive diagnostic marker for AT/RT. For CNS primitive neuroectodermal tumors (CNS PNETs), a consistent finding has been that they are molecularly distinct from medulloblastoma. Furthermore, a distinct fraction of CNS PNETs with particularly poor prognosis only occurring in young children was delineated, which was previously labeled ependymoblastoma or embryonal tumor with abundant neuropil and true rosettes (ETANTR) and which is morphologically characterized by the presence of multilayered "ependymoblastic" rosettes. This group of tumors shows a unique cytogenetic abnormality not seen in other brain tumors: focal amplification of a micro-RNA cluster at chromosome 19q13.42, which has never been found to be amplified in other CNS PNETs, medulloblastoma or AT/RT. In summary, these consistent findings have significantly contributed to our ability to sub-classify embryonal brain tumors into clinically and biologically meaningful strata and, for some of the subgroups, have led to the identification of specific targets for future development of molecularly targeted therapies.

Project description:Pediatric very rare tumors (VRTs) represent a heterogeneous subset of childhood cancers, with reliable survival estimates depending dramatically on each (un)registered case. The current study aimed to evaluate the number of VRTs among Lithuanian children, to assess the impact of the registration status on survival rates and to track changes in treatment outcomes over the 16-year study period. We performed a population-based retrospective study across children below 18 years old diagnosed with VRTs in Lithuania between the years 2000 and 2015. The identified cases were cross-checked with the Lithuanian Cancer Registry-a population-based epidemiology cancer registry-for the fact of registration and survival status. The overall survival was calculated in relation to the registration status and treatment period. Thirty-seven children with VRTs were identified within the defined time frame. Six of them (16.2%) were not reported to the Lithuanian Cancer Registry at diagnosis. The probability of overall survival at 5 years (OS5y) differed significantly between the registered (n = 31) and unregistered (n = 6) cohorts: 51.6% versus 100%, respectively (p = 0.049). A 5-year survival estimate for children diagnosed with a VRT at the age of 0-14 years differed by 10 percentage points according to the registration completeness: 52.1% calculated for the entire cohort versus 42.1% for registered patients only. The OS5y has not improved over the analyzed period: 61.1% in 2000-2007 versus 57.9% in 2008-2015 (p = 0.805). The survival continued to decline beyond 5 years post-diagnosis due to late cancer-related adverse events: 59.5% of patients were alive at 5 years as compared to 44.3% at 10 years. The OS5y of children affected by VRT was lower than in more common childhood cancers. The survival rate of the unregistered patients may lead to misinterpretation of treatment outcomes. Meticulous registration of VRTs is crucial for correct evaluation of treatment outcomes, especially across small countries with few cases.

Dataset Information

The impact of molecular analysis on the survival of children with embryonal tumors.

Publications

The impact of molecular analysis on the survival of children with embryonal tumors.

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