Abstract A37: Immunohistochemical detection of MYCN protein and MYC protein identifies highly aggressive neuroblastomas
Authors: Wang Larry L. , Teshiba Risa , Ikegaki Naohiko , Tang Xao X. , Naranjo Arlene , London Wendy B. , Hogarty Michael D. , Gastier-Foster Julie M. , Look A. Thomas , Park Julie R. , Maris John M. , Cohn Susan L. , Seeger Robert C. , Asgharzadeh Shahab , Shimada Hiroyuki 
Published: October 2015

Abstract
Background:MYCN amplification with subsequent MYCN protein (MYCN-P) over-expression is a powerful indicator of a poor prognosis of neuroblastoma patients. Little is known regarding the prognostic significance of the homologous MYC protein (MYC-P) expression in this disease.
Methods: Immunohistochemical study for MYCN-P and MYC-P expression was conducted using a total of 357 cases of neuroblastoma, undifferentiated (20) or poorly differentiated (337) subtype with available unstained slides. The cases were collected and reviewed during one-year period of 2009 at the COG (Children's Oncology Group) Neuroblastoma Pathology Reference Laboratory. Relationship between these protein expressions and other prognostic markers [Clinical stage (stage 4, N=161 vs. non-stage 4, N=196); Age at diagnosis (&lt;18months, N=210 vs. ≥18months, N=147);MYCN status (amplified, N=82 vs. non-amplified, N=272); International Neuroblastoma Pathology Classification (FH-favorable histology, N=176 vs. UH-unfavorable histology, N=181); MKI (mitosis-karyorrhexis index, Low, N=159; Intermediate, N=103 vs. High, N=81); and prominent nucleolar (PN) formation (+, N=110 vs. -, N=247)] were analyzed.
Findings: Of 357 cases, there were 67 (19%) MYCN-P (+) tumors, 37 (10%) MYC-P (+) tumors, and only one (0.3%) tumor expressing both proteins. Both MYCN-P (+) and MYC-P (+) tumors were more likely diagnosed in older children with stage 4 disease. MYCN-P (+) tumors were associated with amplified MYCN and UH, and often had High MKI. MYC-P (+) tumors were also frequently UH but not associated with MYCN amplification, and more likely to have Low or Intermediate MKI. PN formation was significantly associated with either MYCN-P or MYC-P expression. FH patients without MYC-P/MYCN-P expressions exhibited the best survival (N=167, 89.7+/-5.5% 3-year EFS, 97.0+/-3.2% 3-year OS), followed by UH patients without MYC-P/MYCN-P expressions (N=84, 63.1+/-13.6% 3-year EFS, 83.5+/-9.4% 3-year OS). While MYCN-P (+) patients and MYC-P (+) patients had similar and significantly low (p&lt;0•0001) survival rates (46.2+/-12.0% 3-year EFS, 63.2+/-12.1% 3-year OS and 43.4+/-23.1% 3-year EFS, 63.5+/-19.2% 3-year OS, respectively). Notably, prognostic impact by MYC-P expression was independent from other factors.
Interpretation: In summary, about 30% of neuroblastoma cases in the undifferentiated and poorly differentiated subtypes expressed either MYCN protein (2/3 of the tumors) or MYC protein (1/3 of the tumors) in this series of cases. Those tumors were highly aggressive clinically: patients with MYC-protein expressing tumor had similarly low 3-year EFS and 3-year OS rate to those with MYCN-protein expressing tumor. MYCN-P expression was associated with MYCN amplification. In contrast, MYC-P expression was not associated with MYCN amplification, and its prognostic impact was independent from other standard prognostic factors in this disease. With the results of this report, we should move on to a prospective study of MYC-P expression as a new biomarker for high-risk neuroblastomas.
Citation Format: Larry L. Wang, Risa Teshiba, Naohiko Ikegaki, Xao X. Tang, Arlene Naranjo, Wendy B. London, Michael D. Hogarty, Julie M. Gastier-Foster, A. Thomas Look, Julie R. Park, John M. Maris, Susan L. Cohn, Robert C. Seeger, Shahab Asgharzadeh, Hiroyuki Shimada. Immunohistochemical detection of MYCN protein and MYC protein identifies highly aggressive neuroblastomas. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A37.