MYCN protein expression as a predictor of neuroblastoma prognosis

• Published in: Clinical cancer research Vol. 3; no. 10; pp. 1699 - 1706
• Main Authors: CHAN, H. S. L, GALLIE, B. L, DEBOER, G, HADDAD, G, IKEGAKI, N, DIMITROULAKOS, J, YEGER, H, LING, V
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-10-1997
• Subjects: Adolescent; Biological and medical sciences; Biomarkers, Tumor - biosynthesis; Biomarkers, Tumor - genetics; Child; Child, Preschool; Cohort Studies; Combined Modality Therapy; Disease Progression; Disease-Free Survival; Gene Amplification; Gene Expression Regulation, Neoplastic; Genes, myc; Host-tumor relations. Immunology. Biological markers; Humans; Infant; Life Tables; Medical sciences; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Neoplasm Staging; Neuroblastoma - genetics; Neuroblastoma - mortality; Neuroblastoma - pathology; Neuroblastoma - therapy; Neurology; Ontario - epidemiology; Proto-Oncogene Proteins c-myc - biosynthesis; Retrospective Studies; Risk Factors; Survival Analysis; Treatment Outcome; Tumors; Tumors of the nervous system. Phacomatoses; Ontario; Human; Immunohistochemistry; Nervous system diseases; Relapse; Prognosis; Nucleoprotein; Early stage; Tumoral marker; Malignant tumor; Neuroblastoma; Gene expression; In vitro; Gene amplification; Tumor progression; Advanced stage; Autonomic neuropathy; Onc gene
• ISSN: 1078-0432; 1557-3265

About half of nonlocalized neuroblastomas have MYCN gene amplification and usually progress rapidly, but the half without
such amplification also do poorly, albeit progressing more slowly. We hypothesize that overexpression of MYCN protein can
occur without gene amplification and that this expression reliably predicts the prognosis of neuroblastoma. To determine whether
MYCN expression correlated with outcome, we assayed MYCN protein immunohistochemically in 180 archival pretreatment and posttreatment
samples and stratified the 57 conventionally treated stage IVS, III, and IV patients by these conventional prognostic factors:
stage, age, serum ferritin, Shimada histology, urinary catecholamine ratio, and MYCN gene status. At a median follow-up of
>/=6.8 years, we found in patients with known MYCN gene status that the 23 of 37 without gene amplification fared no better
than the 14 of 37 with gene amplification (P = 0.35 and 0.21, comparing relapse-free and survival rates). Conversely, in patients
without MYCN gene amplification, 9 of 23 were found to overexpress MYCN protein pretreatment, and they did worse than the
14 of 23 without detectable MYCN protein (P = 0.0016 and 0.022, comparing relapse-free and survival rates). Furthermore, MYCN
protein expression was prognostic without (P = 0.00001) and with (P = 0.0007) stratifying all 57 patients by MYCN gene status,
each conventional prognostic factor (P ranging from 0.00001-0.013), or simultaneously by the two most important factors, stage
and age (P = 0.00076). We conclude that overexpression of MYCN protein without gene amplification correlated significantly
with the clinical behavior of neuroblastoma and predicted outcome independently of other prognostic factors. This strongly
supports the hypothesis that expression of the MYCN oncogene is critical for progression of neuroblastoma.