Differences in Genomic Profiles and Outcomes Between Thoracic and Adrenal Neuroblastoma

Abstract

Background Neuroblastoma is a biologically and clinically heterogeneous disease. Based on recent studies demonstrating an association between the primary tumor site, prognosis, and commonly measured tumor biological features, we hypothesized that neuroblastomas arising in different sites would show distinct genomic features reflective of the developmental biology of the sympathicoadrenal nervous system. Methods We first compared genomic and epigenomic data of primary diagnostic neuroblastomas originating in the adrenal gland (n = 646) compared to thoracic sympathetic ganglia (n = 118). We also evaluated association of common germline variation with these primary sites in 1027 European-American neuroblastoma patients. Results We observed higher rates of MYCN amplification, chromosome 1q gain, and chromosome 11q deletion among adrenal tumors, which were highly predictive of functional RNA signatures. Surprisingly, thoracic neuroblastomas were more likely to harbor ALK driver mutations than adrenal cases among all cases (odds ratio = 1.89, 95% confidence interval = 1.04 to 3.43), and among cases without MYCN amplification (odds ratio = 2.86, 95% confidence interval = 1.48 to 5.49). Common germline single nucleotide polymorphisms (SNPs) in BARD1 (previously associated with high-risk neuroblastoma) were found to be strongly associated with predisposition for origin at adrenal, rather than thoracic, sites. Conclusions Neuroblastomas arising in the adrenal gland are more likely to harbor structural DNA aberrations including MYCN amplification, whereas thoracic tumors show defects in mitotic checkpoints resulting in hyperdiploidy. Despite the general association of ALK mutations with high-risk disease, thoracic tumors are more likely to harbor gain-of-function ALK aberrations. Site of origin is likely reflective of stage of sympathetic nervous system development when malignant transformation occurs and is a surrogate for underlying tumor biology.

Genomic coamplification of CDK4/MDM2/FRS2 is associated with very poor prognosis and atypical clinical features in neuroblastoma patients

“…The high coamplification ratios of CDK4 / MDM2 / FRS2 genes may be the contributing factors to atypical features in NB patients. Recently, it has been described that NB arising in different sites show peculiar genomic features reflective of the developmental biology of the sympathetic nervous system . Atypical metastases were seen in our patients carrying 12q coamplifications, who had a low degree of bone marrow involvement promoting other rare metastatic sites such as lung.…”

“…Recently, it has been described that NB arising in different sites show peculiar genomic features reflective of the developmental biology of the sympathetic nervous system. 38 Atypical metastases were seen in our patients carrying 12q coamplifications, who had a low degree of bone marrow involvement promoting other rare metastatic sites such as lung. Interestingly, one patient had a less common location, that is, pelvis.…”

Implementation of the plasma MYCN/NAGK ratio to detect MYCN amplification in patients with neuroblastoma

“…Although substantial progresses have been made in therapy of NB, including chemotherapy, radiotherapy, surgery, hematopoietic stem cell transfusion, and immunotherapy, the 5-year survival rate of patients with high-risk NB remains still less than 50% [4][5][6][7][8][9]. Besides age of onset, primary location, and metastasis, MYCN amplification is widely considered to correlate with risk stratification, relapse, progressive disease, and unfavorable survival rate in NB patients [5,[10][11][12][13][14][15][16][17].…”

Impact of MYCN status on response of high-risk neuroblastoma to neoadjuvant chemotherapy

“…Thoracic primary tumor location was negatively associated with percent reduction in tumor volume after neoadjuvant chemotherapy, although this effect became insignificant after adjusting for MYCN and initial tumor volume. In a larger study, it would not be surprising to find that thoracic tumors have significantly different responses to chemotherapy as they have been shown to have superior event free survival and overall survival as well as distinct genomic profiles compared to adrenal primary tumors [26].…”