Childhood Cancer Genomics (PDQ®) 7/8 —Health Professional Version - National Cancer Institute

Childhood Cancer Genomics (PDQ®)—Health Professional Version - National Cancer Institute

Childhood Cancer Genomics (PDQ®)–Health Professional Version

Neuroblastoma

Children with neuroblastoma can be subdivided into subsets with different predicted risks of relapse on the basis of clinical factors and biological markers at the time of diagnosis.

• Low-risk or intermediate-risk neuroblastoma patients. Patients classified as low-risk or intermediate-risk have a favorable prognosis, with survival rates exceeding 95%. Low-risk and intermediate-risk neuroblastoma usually occur in children younger than 18 months. These tumors commonly have gains of whole chromosomes and are hyperdiploid when examined by flow cytometry.[1,2]
• High-risk neuroblastoma patients. The prognosis is more guarded for patients with high-risk neuroblastoma, with less than a 50% long-term survival rate. High-risk neuroblastoma generally occurs in children older than 18 months, is often metastatic to bone, and segmental chromosome abnormalities (gains or losses) and/or MYCNgene amplification are usually detected in these tumors. They are near diploid or near tetraploid by flow cytometric measurement.[1-7] High-risk tumors may rarely harbor exonic mutations (refer to the Exonic mutations in neuroblastoma section of this summary for more information), but most high-risk tumors lack such gene mutations. Compared with adult cancers, neuroblastoma tumors show a low number of mutations per genome that affect protein sequence (10–20 per genome).[8]

Key genomic characteristics of high-risk neuroblastoma that are discussed below include the following:

• Segmental chromosomal aberrations.
• MYCN gene amplifications.
• Low rates of exonic mutations, with activating mutations in ALK being the most common recurring alteration.
• Genomic alterations that promote telomere lengthening.

Segmental chromosomal aberrations

Segmental chromosomal aberrations, found most frequently in 1p, 1q, 3p, 11q, 14q, and 17p, are best detected by comparative genomic hybridization and are seen in most high-risk and/or stage 4 neuroblastoma tumors.[3-7] Among all patients with neuroblastoma, a higher number of chromosome breakpoints (i.e., a higher number of segmental chromosome aberrations) correlated with the following:[3-7][Level of evidence: 3iiD]

• Advanced age at diagnosis.
• Advanced stage of disease.
• Higher risk of relapse.
• Poorer outcome.

An international collaboration studied 556 patients with high-risk neuroblastoma and identified two types of segmental copy number aberrations that are associated with extremely poor outcome. Distal 6q losses were found in 6% of patients and were associated with a 10-year survival rate of only 3.4%; amplifications of regions not encompassing the MYCN locus, in addition to MYCN amplification, were detected in 18% of the patients and were associated with a 10-year survival rate of 5.8%.[9]

In a study of children older than 12 months who had unresectable primary neuroblastomas without metastases, segmental chromosomal aberrations were found in most, and older children were more likely to have them and to have more of them per tumor cell. In children aged 12 to 18 months, the presence of segmental chromosomal aberrations had a significant effect on event-free survival (EFS) but not on overall survival (OS). However, in children older than 18 months, there was a significant difference in OS between children with segmental chromosomal aberrations (67%) and children without segmental chromosomal aberrations (100%), regardless of tumor histology.[7]

Segmental chromosomal aberrations are also predictive of recurrence in infants with localized unresectable or metastatic neuroblastoma without MYCN gene amplification.[1,2]

MYCN gene amplification

MYCN amplification is detected in 16% to 25% of neuroblastoma tumors.[10] Among patients with high-risk neuroblastoma, 40% to 50% of cases show MYCN amplification.[11]

In all stages of disease, amplification of the MYCN gene strongly predicts a poorer prognosis, in both time to tumor progression and OS, in almost all multivariate regression analyses of prognostic factors.[1,2] Within the localized-tumor MYCN-amplified cohort, patients with hyperdiploid tumors have better outcomes than do patients with diploid tumors.[12] However, patients with hyperdiploid tumors with MYCN amplification or any segmental chromosomal aberrations do relatively poorly compared with patients with hyperdiploid tumors without MYCN amplification.[3]

In a Children’s Oncology Group study of MYCN copy number in 4,672 patients with neuroblastoma, the following results were reported:[13]

• 79% of patients had MYCN–wild-type tumors, 3% had tumors with MYCN gain (defined as a twofold to fourfold increase in signal by fluorescence in situ hybridization), and 18% had MYCN-amplified tumors.
• When individual clinical/biological features were examined, the percentage of patients with unfavorable features was lowest in the MYCN–wild-type category, intermediate in the MYCN-gain category, and highest in the MYCN-amplified category (P < .0001), except for the tumors with 11q aberration, for which the highest rates were in the MYCN-gain category.
• Patients with non–stage 4 disease and patients with non–high-risk disease and MYCNgain had a significantly increased risk of death than did patients with MYCN–wild-type tumors.

Most unfavorable clinical and pathobiological features are associated, to some degree, with MYCN amplification; in a multivariable logistic regression analysis of 7,102 International Neuroblastoma Risk Group patients, pooled segmental chromosomal aberrations and gains of 17q were poor prognostic features even when not associated with MYCN amplification. However, another poor prognostic feature, segmental chromosomal aberrations at 11q, are almost entirely mutually exclusive of diffuse MYCN amplification.[14,15]

Exonic mutations in neuroblastoma

Multiple reports have documented that a minority of high-risk neuroblastomas have a low incidence of recurrently mutated genes. The most commonly mutated gene is ALK, which is mutated in approximately 10% of patients (see below). Other genes with even lower frequencies of mutations include ATRX, PTPN11, ARID1A, and ARID1B.[16-22] As shown in Figure 10, most neuroblastoma cases lack mutations in genes that are altered in a recurrent manner.

ENLARGE

Figure 10. Data tracks (rows) facilitate the comparison of clinical and genomic data across cases with neuroblastoma (columns). The data sources and sequencing technology used were whole-exome sequencing (WES) from whole-genome amplification (WGA) (light purple), WES from native DNA (dark purple), Illumina WGS (green), and Complete Genomics WGS (yellow). Striped blocks indicate cases analyzed using two approaches. The clinical variables included were sex (male, blue; female, pink) and age (brown spectrum). Copy number alterations indicates ploidy measured by flow cytometry (with hyperdiploid meaning DNA index >1) and clinically relevant copy number alterations derived from sequence data. Significantly mutated genes are those with statistically significant mutation counts given the background mutation rate, gene size, and expression in neuroblastoma. Germline indicates genes with significant numbers of germline ClinVar variants or loss-of-function cancer gene variants in our cohort. DNA repair indicates genes that may be associated with an increased mutation frequency in two apparently hypermutated tumors. Predicted effects of somatic mutations are color coded according to the legend. Reprinted by permission from Macmillan Publishers Ltd: Nature GeneticsExit Disclaimer (Pugh TJ, Morozova O, Attiyeh EF, et al.: The genetic landscape of high-risk neuroblastoma. Nat Genet 45 (3): 279-84, 2013), copyright (2013).

ALK, the exonic mutation found most commonly in neuroblastoma, is a cell surface receptor tyrosine kinase, expressed at significant levels only in developing embryonic and neonatal brains. Germline mutations in ALK have been identified as the major cause of hereditary neuroblastoma. Somatically acquired ALK-activating exonic mutations are also found as oncogenic drivers in neuroblastoma.[21]

The presence of an ALK mutation correlates with significantly poorer survival in high-risk and intermediate-risk neuroblastoma patients. ALK mutations were examined in 1,596 diagnostic neuroblastoma samples and the following results were observed:[21]

• ALK tyrosine kinase domain mutations occurred in 8% of samples—at three hot spots and 13 minor sites—and correlated significantly with poorer survival in patients with high-risk and intermediate-risk neuroblastoma.
• ALK mutations were found in 10.9% of MYCN-amplified tumors versus 7.2% of those without MYCN amplification.
• ALK mutations occurred at the highest frequency (11%) in patients older than 10 years.
• The frequency of ALK aberrations was 14% in the high-risk neuroblastoma group, 6% in the intermediate-risk neuroblastoma group, and 8% in the low-risk neuroblastoma group.
• The high-risk group included tumors with ALK aberrations, consisting of ALK co-amplification with MYCN amplification, which may also result in ALK activation.

Small-molecule ALK kinase inhibitors such as crizotinib (added to conventional therapy) are being tested in patients with newly diagnosed high-risk neuroblastoma and activated ALK(COG ANBL1531).[21] (Refer to the Treatment Options Under Clinical Evaluation for Recurrent or Refractory Neuroblastoma section in the PDQ summary on Neuroblastoma Treatment for more information about crizotinib clinical trials.)

Genomic evolution of exonic mutations

There are limited data regarding the genomic evolution of exonic mutations from diagnosis to relapse for neuroblastoma. Whole-genome sequencing was applied to 23 paired diagnostic and relapsed neuroblastoma tumor samples to define somatic genetic alterations associated with relapse,[23] while a second study evaluated 16 paired diagnostic and relapsed specimens.[24] Both studies identified an increased number of mutations in the relapsed samples compared with the samples at diagnosis; this has been confirmed in a study of neuroblastoma tumor samples sent for next-generation sequencing.[25]

• In the first study, an increased incidence of mutations in genes associated with RAS-MAPK signaling were found in tumors at relapse compared with tumors from the same patient at diagnosis; 15 of 23 relapse samples contained somatic mutations in genes involved in this pathway and each mutation was consistent with pathway activation.[23]
  In addition, three relapse samples showed structural alterations involving MAPK pathway genes consistent with pathway activation, so aberrations in this pathway were detected in 18 of 23 relapse samples (78%). Aberrations were found in ALK (n = 10), NF1(n = 2), and one each in NRAS, KRAS, HRAS, BRAF, PTPN11, and FGFR1. Even with deep sequencing, 7 of the 18 alterations were not detectable in the primary tumor, highlighting the evolution of mutations presumably leading to relapse and the importance of genomic evaluations of tissues obtained at relapse.
• In the second study, ALK mutations were not observed in either diagnostic or relapse specimens, but relapse-specific recurrent single-nucleotide variants were observed in 11 genes, including the putative CHD5 neuroblastoma tumor suppressor gene located at chromosome 1p36.[24]

In a deep-sequencing study, 276 neuroblastoma samples (comprised of all stages and from patients of all ages at diagnosis) underwent very deep (33,000X) sequencing of just two amplified ALK mutational hot spots, which revealed 4.8% clonal mutations and an additional 5% subclonal mutations, suggesting that subclonal ALK gene mutations are common.[26] Thus, deep sequencing can reveal the presence of mutations in tiny subsets of neuroblastoma tumor cells that may be able to survive during treatment and grow to constitute a relapse.

Genomic alterations promoting telomere lengthening

Lengthening of telomeres, the tips of chromosomes, promotes cell survival. Telomeres otherwise shorten with each cell replication, resulting eventually in the lack of a cell’s ability to replicate. Low-risk neuroblastoma tumors have little telomere lengthening activity. Aberrant genetic mechanisms for telomere lengthening have been identified in high-risk neuroblastoma tumors.[16,17,27] Thus far, the following three mechanisms, which appear to be mutually exclusive, have been described:

• Chromosomal rearrangements involving a chromosomal region at 5p15.33 proximal to the TERT gene, which encodes the catalytic unit of telomerase, occur in approximately 25% of high-risk neuroblastoma cases and are mutually exclusive with MYCNamplifications and ATRX mutations.[16,17] The rearrangements induce transcriptional upregulation of TERT by juxtaposing the TERT coding sequence with strong enhancer elements.
• Another mechanism promoting TERT overexpression is MYCN amplification,[28] which is associated with approximately 40% to 50% of high-risk neuroblastoma cases.
• The ATRX mutation or deletion is found in 10% to 20% of high-risk neuroblastoma tumors, almost exclusively in older children,[18] and is associated with telomere lengthening by a different mechanism, termed alternative lengthening of telomeres.[18,27]

Additional biological factors associated with prognosis

MYC and MYCN expression

Immunostaining for MYC and MYCN proteins on a restricted subset of 357 undifferentiated/poorly differentiated neuroblastoma tumors demonstrated that elevated MYC/MYCN protein expression is prognostically significant.[29] Sixty-eight tumors (19%) highly expressed the MYCN protein, and 81 were MYCN amplified. Thirty-nine tumors (10.9%) expressed MYC highly and were mutually exclusive of high MYCN expression; in the MYC-expressing tumors, MYC or MYCN gene amplification was not seen. Segmental chromosomal aberrations were not examined in this study.[29]

• Patients with favorable-histology tumors without high MYC/MYCN expression had favorable survival (3-year EFS, 89.7% ± 5.5%; 3-year OS, 97% ± 3.2%).
• Patients with undifferentiated or poorly differentiated histology tumors without MYC/MYCN expression had a 3-year EFS rate of 63.1% (± 13.6%) and a 3-year OS rate of 83.5% (± 9.4%).
• Three-year EFS rates in patients with MYCN amplification, high MYCN expression, and high MYC expression were 48.1% (± 11.5%), 46.2% (± 12%), and 43.4% (± 23.1%), respectively, and OS rates were 65.8% (± 11.1%), 63.2% (± 12.1%), and 63.5% (± 19.2%), respectively.
• Additionally, when high expression of MYC and MYCN proteins underwent multivariate analysis with other prognostic factors, including MYC/MYCN gene amplification, high MYC and MYCN protein expression was independent of other prognostic markers.

Neurotrophin receptor kinases

Expression of neurotrophin receptor kinases and their ligands vary between high-risk and low-risk tumors. TrkA is found on low-risk tumors, and absence of its ligand NGF is postulated to lead to spontaneous tumor regression. In contrast, TrkB is found in high-risk tumors that also express its ligand, BDNF, which promotes neuroblastoma cell growth and survival.[30]

Immune system inhibition

Anti-GD2 antibodies, along with modulation of the immune system to enhance the antibody's antineuroblastoma activity, are often used to help treat neuroblastoma. The clinical effectiveness of one such antibody led to U.S. Food and Drug Administration approval of dinutuximab. The patient response to immunotherapy may, in part, be caused by variation in immune function among patients. One anti-GD2 antibody, termed 3F8, used for treating neuroblastoma exclusively at one institution, utilizes natural killer cells to kill the neuroblastoma cells. However, the natural killer cells can be inhibited by the interaction of HLA antigens and killer immunoglobulin receptor (KIR) subtypes.[31,32] This finding was confirmed and expanded by an analysis of outcomes for patients treated on the national randomized COG-ANBL0032 (NCT00026312) study with the anti-GD2 antibody dinutuximab combined with granulocyte-macrophage colony-stimulating factor and interleukin-2. The study found that certain KIR/KIR-ligand genotypes were associated with better outcomes for patients who were treated with immunotherapy.[33][Level of evidence: 1A] The presence of inhibitory KIR/KIR ligands was associated with a decreased effect of immunotherapy. Thus, the patient's immune system genes help determine response to immunotherapy for neuroblastoma. Additional studies are needed to determine whether this immune system genotyping can guide patient selection for certain immunotherapies.

(Refer to the PDQ summary on Neuroblastoma Treatment for information about the treatment of neuroblastoma.)

References

1. Cohn SL, Pearson AD, London WB, et al.: The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol 27 (2): 289-97, 2009. [PUBMED Abstract]
2. Schleiermacher G, Mosseri V, London WB, et al.: Segmental chromosomal alterations have prognostic impact in neuroblastoma: a report from the INRG project. Br J Cancer 107 (8): 1418-22, 2012. [PUBMED Abstract]
3. Janoueix-Lerosey I, Schleiermacher G, Michels E, et al.: Overall genomic pattern is a predictor of outcome in neuroblastoma. J Clin Oncol 27 (7): 1026-33, 2009. [PUBMED Abstract]
4. Schleiermacher G, Michon J, Ribeiro A, et al.: Segmental chromosomal alterations lead to a higher risk of relapse in infants with MYCN-non-amplified localised unresectable/disseminated neuroblastoma (a SIOPEN collaborative study). Br J Cancer 105 (12): 1940-8, 2011. [PUBMED Abstract]
5. Carén H, Kryh H, Nethander M, et al.: High-risk neuroblastoma tumors with 11q-deletion display a poor prognostic, chromosome instability phenotype with later onset. Proc Natl Acad Sci U S A 107 (9): 4323-8, 2010. [PUBMED Abstract]
6. Schleiermacher G, Janoueix-Lerosey I, Ribeiro A, et al.: Accumulation of segmental alterations determines progression in neuroblastoma. J Clin Oncol 28 (19): 3122-30, 2010. [PUBMED Abstract]
7. Defferrari R, Mazzocco K, Ambros IM, et al.: Influence of segmental chromosome abnormalities on survival in children over the age of 12 months with unresectable localised peripheral neuroblastic tumours without MYCN amplification. Br J Cancer 112 (2): 290-5, 2015. [PUBMED Abstract]
8. Pugh TJ, Morozova O, Attiyeh EF, et al.: The genetic landscape of high-risk neuroblastoma. Nat Genet 45 (3): 279-84, 2013. [PUBMED Abstract]
9. Depuydt P, Boeva V, Hocking TD, et al.: Genomic Amplifications and Distal 6q Loss: Novel Markers for Poor Survival in High-risk Neuroblastoma Patients. J Natl Cancer Inst : , 2018. [PUBMED Abstract]
10. Ambros PF, Ambros IM, Brodeur GM, et al.: International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee. Br J Cancer 100 (9): 1471-82, 2009. [PUBMED Abstract]
11. Kreissman SG, Seeger RC, Matthay KK, et al.: Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial. Lancet Oncol 14 (10): 999-1008, 2013. [PUBMED Abstract]
12. Bagatell R, Beck-Popovic M, London WB, et al.: Significance of MYCN amplification in international neuroblastoma staging system stage 1 and 2 neuroblastoma: a report from the International Neuroblastoma Risk Group database. J Clin Oncol 27 (3): 365-70, 2009. [PUBMED Abstract]
13. Campbell K, Gastier-Foster JM, Mann M, et al.: Association of MYCN copy number with clinical features, tumor biology, and outcomes in neuroblastoma: A report from the Children's Oncology Group. Cancer 123 (21): 4224-4235, 2017. [PUBMED Abstract]
14. Plantaz D, Vandesompele J, Van Roy N, et al.: Comparative genomic hybridization (CGH) analysis of stage 4 neuroblastoma reveals high frequency of 11q deletion in tumors lacking MYCN amplification. Int J Cancer 91 (5): 680-6, 2001. [PUBMED Abstract]
15. Maris JM, Hogarty MD, Bagatell R, et al.: Neuroblastoma. Lancet 369 (9579): 2106-20, 2007. [PUBMED Abstract]
16. Peifer M, Hertwig F, Roels F, et al.: Telomerase activation by genomic rearrangements in high-risk neuroblastoma. Nature 526 (7575): 700-4, 2015. [PUBMED Abstract]
17. Valentijn LJ, Koster J, Zwijnenburg DA, et al.: TERT rearrangements are frequent in neuroblastoma and identify aggressive tumors. Nat Genet 47 (12): 1411-4, 2015. [PUBMED Abstract]
18. Cheung NK, Zhang J, Lu C, et al.: Association of age at diagnosis and genetic mutations in patients with neuroblastoma. JAMA 307 (10): 1062-71, 2012. [PUBMED Abstract]
19. Molenaar JJ, Koster J, Zwijnenburg DA, et al.: Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature 483 (7391): 589-93, 2012. [PUBMED Abstract]
20. Sausen M, Leary RJ, Jones S, et al.: Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma. Nat Genet 45 (1): 12-7, 2013. [PUBMED Abstract]
21. Bresler SC, Weiser DA, Huwe PJ, et al.: ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. Cancer Cell 26 (5): 682-94, 2014. [PUBMED Abstract]
22. Janoueix-Lerosey I, Lequin D, Brugières L, et al.: Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature 455 (7215): 967-70, 2008. [PUBMED Abstract]
23. Eleveld TF, Oldridge DA, Bernard V, et al.: Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. Nat Genet 47 (8): 864-71, 2015. [PUBMED Abstract]
24. Schramm A, Köster J, Assenov Y, et al.: Mutational dynamics between primary and relapse neuroblastomas. Nat Genet 47 (8): 872-7, 2015. [PUBMED Abstract]
25. Padovan-Merhar OM, Raman P, Ostrovnaya I, et al.: Enrichment of Targetable Mutations in the Relapsed Neuroblastoma Genome. PLoS Genet 12 (12): e1006501, 2016. [PUBMED Abstract]
26. Bellini A, Bernard V, Leroy Q, et al.: Deep Sequencing Reveals Occurrence of Subclonal ALK Mutations in Neuroblastoma at Diagnosis. Clin Cancer Res 21 (21): 4913-21, 2015. [PUBMED Abstract]
27. Kurihara S, Hiyama E, Onitake Y, et al.: Clinical features of ATRX or DAXX mutated neuroblastoma. J Pediatr Surg 49 (12): 1835-8, 2014. [PUBMED Abstract]
28. Mac SM, D'Cunha CA, Farnham PJ: Direct recruitment of N-myc to target gene promoters. Mol Carcinog 29 (2): 76-86, 2000. [PUBMED Abstract]
29. Wang LL, Teshiba R, Ikegaki N, et al.: Augmented expression of MYC and/or MYCN protein defines highly aggressive MYC-driven neuroblastoma: a Children's Oncology Group study. Br J Cancer 113 (1): 57-63, 2015. [PUBMED Abstract]
30. Maris JM, Matthay KK: Molecular biology of neuroblastoma. J Clin Oncol 17 (7): 2264-79, 1999. [PUBMED Abstract]
31. Forlenza CJ, Boudreau JE, Zheng J, et al.: KIR3DL1 Allelic Polymorphism and HLA-B Epitopes Modulate Response to Anti-GD2 Monoclonal Antibody in Patients With Neuroblastoma. J Clin Oncol 34 (21): 2443-51, 2016. [PUBMED Abstract]
32. Venstrom JM, Zheng J, Noor N, et al.: KIR and HLA genotypes are associated with disease progression and survival following autologous hematopoietic stem cell transplantation for high-risk neuroblastoma. Clin Cancer Res 15 (23): 7330-4, 2009. [PUBMED Abstract]
33. Erbe AK, Wang W, Carmichael L, et al.: Neuroblastoma Patients' KIR and KIR-Ligand Genotypes Influence Clinical Outcome for Dinutuximab-based Immunotherapy: A Report from the Children's Oncology Group. Clin Cancer Res 24 (1): 189-196, 2018. [PUBMED Abstract]

Retinoblastoma

Retinoblastoma is a tumor that occurs in heritable (25%–30%) and nonheritable (70%–75%) forms. Heritable disease is defined by the presence of a germline mutation of the RB1gene. This germline mutation may have been inherited from an affected progenitor (25% of cases) or may have occurred in a germ cell before conception or in utero during early embryogenesis in patients with sporadic disease (75% of cases). The presence of positive family history or bilateral or multifocal disease is suggestive of heritable disease.

Heritable retinoblastoma may manifest as unilateral or bilateral disease. The penetrance of the RB1 mutation (laterality, age at diagnosis, and number of tumors) is probably dependent on concurrent genetic modifiers such as MDM2 and MDM4 polymorphisms.[1,2] All children with bilateral disease and approximately 15% of patients with unilateral disease are presumed to have the heritable form, even though only 25% have an affected parent.

In heritable retinoblastoma, tumors tend to be diagnosed at a younger age than in the nonheritable form of the disease. Unilateral retinoblastoma in children younger than 1 year raises concern for heritable disease, whereas older children with a unilateral tumor are more likely to have the nonheritable form of the disease.[3]

The genomic landscape of retinoblastoma is driven by alterations in RB1 that lead to biallelic inactivation.[4,5] A rare cause of RB1 inactivation is chromothripsis, which may be difficult to detect by conventional methods.[6] Other recurring genomic changes that occur in a small minority of tumors include BCOR mutation/deletion, MYCN amplification, and OTX2 amplification.[4-6] A study of 1,068 unilateral nonfamilial retinoblastoma tumors reported that a small percentage of cases (approximately 3%) lacked evidence of RB1 loss. Approximately one-half of these cases with no evidence of RB1 loss (representing approximately 1.5% of all unilateral nonfamilial retinoblastoma) showed MYCNamplification.[5] The functional status of the retinoblastoma protein (pRb) is inferred to be inactive in retinoblastoma with MYCN amplification. This suggests that inactivation of RB1by mutation or inactive pRb is a requirement for the development of retinoblastoma, independent of MYCN amplification.[7]

(Refer to the PDQ summary on Retinoblastoma Treatment for information about the treatment of retinoblastoma.)

References

1. Castéra L, Sabbagh A, Dehainault C, et al.: MDM2 as a modifier gene in retinoblastoma. J Natl Cancer Inst 102 (23): 1805-8, 2010. [PUBMED Abstract]
2. de Oliveira Reis AH, de Carvalho IN, de Sousa Damasceno PB, et al.: Influence of MDM2 and MDM4 on development and survival in hereditary retinoblastoma. Pediatr Blood Cancer 59 (1): 39-43, 2012. [PUBMED Abstract]
3. Zajaczek S, Jakubowska A, Kurzawski G, et al.: Age at diagnosis to discriminate those patients for whom constitutional DNA sequencing is appropriate in sporadic unilateral retinoblastoma. Eur J Cancer 34 (12): 1919-21, 1998. [PUBMED Abstract]
4. Zhang J, Benavente CA, McEvoy J, et al.: A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature 481 (7381): 329-34, 2012. [PUBMED Abstract]
5. Rushlow DE, Mol BM, Kennett JY, et al.: Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies. Lancet Oncol 14 (4): 327-34, 2013. [PUBMED Abstract]
6. McEvoy J, Nagahawatte P, Finkelstein D, et al.: RB1 gene inactivation by chromothripsis in human retinoblastoma. Oncotarget 5 (2): 438-50, 2014. [PUBMED Abstract]
7. Ewens KG, Bhatti TR, Moran KA, et al.: Phosphorylation of pRb: mechanism for RB pathway inactivation in MYCN-amplified retinoblastoma. Cancer Med 6 (3): 619-630, 2017. [PUBMED Abstract]