Poster Presentation Advances in Neuroblastoma Research Congress 2016

High-MKI neuroblastomas - MYC-family-driven tumors with augmented expression of MYCN/MYC protein behaves more aggressively than Non-MYC-family-driven tumors: a report from the Children’s Oncology Group (#277)

Larry L Wang 1 , Risa Teshiba 2 , Ryosuke Matsuno 2 , Naohiko Ikegaki 3 , Collin V Ryn 4 , Arlene Naranjo 4 , Wendy B London 5 , Michael D Hogarty 6 , JUlie M Gastier-Foster 7 , A Thomas Look 8 , Julie R Park 9 , John M Maris 6 , Susan L Cohn 10 , Robert C Seeger 11 , Shahab Asgharzadeh 11 , Hiroyuki Shimada 1
  1. Children Hospital Los Angeles/University of Southern California, Los Angeles, CALIFORNIA, United States
  2. Children Hospital Los Angeles, Los Angeles , California , USA
  3. Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
  4. Department of Biostatistics, Children’s Oncology Group Statistics and Data Center, University of Florida, , Gainesville, Florida , USA
  5. Division of Hematology/Oncology, Boston Children’s Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston,, MA, USA
  6. Division of Oncology and Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
  7. Department of Pathology and Laboratory Medicinel , Nationwide Children’s Hospital, Ohio State University College of Medicine, Columbus, OH, USA
  8. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
  9. Department of Pediatrics, Seattle Children’s Hospital, University of Washington School of Medicine and Fred Hutchinson Cancer Research Centere, Seattle, WA, USA
  10. Department of Pediatrics, Division of Hematology/Oncology,, University of Chicago, Chicago, IL, USA
  11. Division of Hematology/Oncology, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, California , USA

Background: In neuroblastomas (NBs), high mitotic-karyorrhectic index (High-MKI) defined by the International Neuroblastoma Pathology Classification is often associated with MYCN genomic amplification. However, little is known about MYCN and/or MYC protein expression by High-MKI NBs especially when MYCN oncogene is not amplified. 

 

Materials and Methods: A total of 241 High-MKI NBs [120 MYCN amplified (28 undifferentiated, 92 poorly differentiated subtype) and 121 MYCN non-amplified (4 undifferentiated, 117 poorly differentiated subtype)] available at the Children’s Oncology Groups Neuroblastoma Pathology Reference Laboratory were studied immunohistochemically for expression of MYCN and MYC protein. Prognostic effects by these protein expressions [(+): high, (+/-): low, (-): none] were analyzed with conventional prognostic factors and prominent nucleolar (PN) formation. 

 

Results: MYCN amplified High-MKI NBs were predominantly composed of tumors overexpressing MYCN protein: they were 101(84.2%) MYCN protein (+), one (0.8%) MYC protein (+), 2(1.7%) both proteins (+), and 16(13.3%) both proteins (-)/(+/-). In contrast, MYCN non-amplified High-MKI NBs were heterogeneous and included tumors of 7(5.8%) MYCN protein (+), 36(29.8%) MYC protein (+), 3(2.5%) both proteins (+), and 75(62.0%) both proteins (-)/(+/-). MYC-family-driven NBs defined by augmented expression of MYCN/MYC protein were more likely to show PN formation (putative site of RNA synthesis and accumulation). High-MKI NBs linked to a poor prognosis (4-year EFS 56.2+/-5.5%, 4-year OS 64.5+/-5.4%) irrespective of MYCN genomic status (amplified or non-amplified). However, patients with MYC-family-driven High-MKI NBs had significantly lower survivals (4-year EFS 50.2+/-6.2%, 4-year OS 56.1+/-6.1%) than those with Non-MYC-family-driven High MKI NBs (4-year EFS 66.3+/-11.1%, 4-year OS 80.1+/-9.5%) (p=0.0131 and p=0.0064, respectively).  MYCN protein (+) and PN (+), in addition to clinical stage, were independently predictive of poor survivals in this cohort of patients.

 

Conclusions: Among High-MKI NBs, MYC-family-driven tumors with augmented MYCN/MYC protein expression were associated with PN formation and behaved significantly more aggressively than Non-MYC-family-driven tumors.