Tuesday, February 26, 2019

Childhood Cancer Genomics (PDQ®) 3/8 —Health Professional Version - National Cancer Institute

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

National Cancer Institute







Juvenile Myelomonocytic Leukemia (JMML)

The genomic landscape of JMML is characterized by mutations in one of five genes of the Ras pathway: NF1, NRAS, KRAS, PTPN11, and CBL.[333,334] In a series of 118 consecutively diagnosed JMML cases with Ras pathway–activating mutations, PTPN11 was the most commonly mutated gene, accounting for 51% of cases (19% germline and 32% somatic) (refer to Figure 5).[333] Patients with mutated NRAS accounted for 19% of cases, and patients with mutated KRAS accounted for 15% of cases. NF1 mutations accounted for 8% of cases and CBL mutations accounted for 11% of cases. Although mutations among these five genes are generally mutually exclusive, 10% to 17% of cases have mutations in two of these Ras pathway genes,[333,334] a finding that is associated with poorer prognosis.[333]
The mutation rate in JMML leukemia cells is very low, but additional mutations beyond those of the five Ras pathway genes described above are observed.[333,334] Secondary genomic alterations are observed for genes of the transcriptional repressor complex PRC2 (e.g., ASXL1 was mutated in 7%–8% of cases). Some genes associated with myeloproliferative neoplasms in adults are also mutated at low rates in JMML (e.g., SETBP1was mutated in 7%–9% of cases).[333-335] JAK3 mutations are also observed in a small percentage (4%–12%) of JMML cases.[333-335] Cases with germline PTPN11 and germline CBL mutations showed low rates of additional mutations (refer to Figure 5).[333]
ENLARGEChart showing alteration profiles in individual JMML cases.
Figure 5. Alteration profiles in individual JMML cases. Germline and somatically acquired alterations with recurring hits in the RAS pathway and PRC2 network are shown for 118 patients with JMML who underwent detailed genetic analysis. Blast excess was defined as a blast count ≥10% but <20% of nucleated cells in the bone marrow at diagnosis. Blast crisis was defined as a blast count ≥20% of nucleated cells in the bone marrow. NS, Noonan syndrome. Reprinted by permission from Macmillan Publishers Ltd: Nature Genetics (Caye A, Strullu M, Guidez F, et al.: Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network. Nat Genet 47 [11]: 1334-40, 2015), copyright (2015).
General characteristics of leukemia cells provide both prognostic information and guidance regarding therapeutic opportunities for JMML:
  • Number of non-RAS pathway mutations. A strong predictor of prognosis for children with JMML is the number of mutations beyond the disease-defining RAS-pathway mutations.[333,334] Of 64 patients (65.3%) at diagnosis, zero or one somatic alteration (pathogenic mutation or monosomy 7) was identified, whereas two or more alterations were identified in 34 (34.7%) patients.[334] In multivariate analysis, mutation number (two or more vs. zero or one) maintained significance as a predictor of inferior event-free survival and overall survival. A higher proportion of patients diagnosed with two or more alterations were older and male, and these patients also demonstrated a higher rate of monosomy 7 or somatic NF1 mutation.[334] Similar findings and observations reported that patients with RAS-pathway double mutations (15 of 96 patients) were at the highest risk of treatment failure.[333]
  • RAS-MAPK pathway inhibitors. Because JMML is a disease defined by mutations in the RAS-MAPK pathway, one might speculate that inhibitors of this pathway (e.g., MEK inhibitors) may have clinical utility in the treatment of JMML. However, preclinical data to support this hypothesis are inconsistent,[336,337] and there are no clinical data available.

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  337. Chang T, Krisman K, Theobald EH, et al.: Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice. J Clin Invest 123 (1): 335-9, 2013. [PUBMED Abstract]

Non-Hodgkin Lymphoma


Mature B-cell Lymphoma

The mature B-cell lymphomas include Burkitt and Burkitt-like lymphoma, diffuse large B-cell lymphoma, and primary mediastinal B-cell lymphoma.

Burkitt and Burkitt-like lymphoma

The malignant cells show a mature B-cell phenotype and are negative for the enzyme terminal deoxynucleotidyl transferase. These malignant cells usually express surface immunoglobulin, most bearing a clonal surface immunoglobulin M with either kappa or lambda light chains. A variety of additional B-cell markers (e.g., CD19, CD20, CD22) are usually present, and most childhood Burkitt and Burkitt-like lymphomas/leukemias express CALLA (CD10).[1]
Burkitt lymphoma/leukemia expresses a characteristic chromosomal translocation, usually t(8;14) and more rarely t(8;22) or t(2;8). Each of these translocations juxtaposes the MYConcogene and immunoglobulin locus regulatory elements, resulting in the inappropriate expression of MYC, a gene involved in cellular proliferation.[2-4] The presence of one of the variant translocations t(2;8) or t(8;22) does not appear to affect response or outcome.[5]
While MYC translocations are present in all Burkitt lymphoma, cooperating genomic alterations appear to be required for lymphoma development. Recurring mutations that have been identified in Burkitt lymphoma in pediatric and adult cases are listed below. The clinical significance of these mutations for pediatric Burkitt lymphoma remains to be elucidated.
  • Activating mutations in the transcription factor TCF3 and inactivating mutations in its negative regulator ID3 are observed in approximately 70% of Burkitt lymphoma cases.[6-9]
  • Mutations in TP53 are observed in one-third to one-half of cases.[6,8]
  • Mutations in cyclin D3 (CCND3) are commonly observed in sporadic Burkitt lymphoma (approximately 40% of cases) but are rare in endemic Burkitt lymphoma.[6,8]
  • Mutations in MYC itself are observed in approximately one-half of Burkitt lymphoma cases and appear to increase MYC stability.[6,10]
The distinction between Burkitt and Burkitt-like lymphoma/leukemia is controversial. Burkitt lymphoma/leukemia consists of uniform, small, noncleaved cells, whereas the diagnosis of Burkitt-like lymphoma/leukemia is highly disputed among pathologists because of features that are consistent with diffuse large B-cell lymphoma.[11]
Cytogenetic evidence of MYC rearrangement is the gold standard for diagnosis of Burkitt lymphoma/leukemia. For cases in which cytogenetic analysis is not available, the World Health Organization (WHO) has recommended that the Burkitt-like diagnosis be reserved for lymphoma resembling Burkitt lymphoma/leukemia or with more pleomorphism, large cells, and a proliferation fraction (i.e., MIB-1 or Ki-67 immunostaining) of 99% or greater.[1] BCL2 staining by immunohistochemistry is variable. The absence of a translocation involving the BCL2 gene does not preclude the diagnosis of Burkitt lymphoma/leukemia and has no clinical implications.[12]
Studies have demonstrated that the vast majority of Burkitt-like or atypical Burkittlymphoma/leukemia has a gene expression signature similar to Burkitt lymphoma/leukemia.[13,14] Additionally, as many as 30% of pediatric diffuse large B-cell lymphoma cases will have a gene signature similar to Burkitt lymphoma/leukemia.[13,15]
(Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for information about the treatment of childhood non-Hodgkin lymphoma.)

Diffuse large B-cell lymphoma

The World Health Organization (WHO) classification system does not recommend subclassification of diffuse large B-cell lymphoma on the basis of morphologic variants (e.g., immunoblastic, centroblastic).[16]
Diffuse large B-cell lymphoma in children and adolescents differs biologically from diffuse large B-cell lymphoma in adults in the following ways:
  • The vast majority of pediatric diffuse large B-cell lymphoma cases have a germinal center B-cell phenotype, as assessed by immunohistochemical analysis of selected proteins found in normal germinal center B cells, such as the BCL6 gene product and CD10.[5,17,18] The age at which the favorable germinal center subtype changes to the less favorable nongerminal center subtype was shown to be a continuous variable.[19]
  • Pediatric diffuse large B-cell lymphoma rarely demonstrates the t(14;18) translocation involving the immunoglobulin heavy-chain gene and the BCL2 gene that is seen in adults.[17]
  • As many as 30% of patients younger than 14 years with diffuse large B-cell lymphoma will have a gene signature similar to Burkitt lymphoma/leukemia.[13,15]
  • In contrast to adult diffuse large B-cell lymphoma, pediatric cases show a high frequency of abnormalities at the MYC locus (chromosome 8q24), with approximately one-third of pediatric cases showing MYC rearrangement and with approximately one-half of the nonrearranged cases showing MYC gain or amplification.[15,20]
  • A subset of pediatric diffuse large B-cell lymphoma cases was found to have a translocation that juxtaposes the IRF4 oncogene next to one of the immunoglobulin loci. Diffuse large B-cell lymphoma cases with an IRF4 translocation were significantly more frequent in children than in adults (15% vs. 2%), were germinal center–derived B-cell lymphomas, and were associated with favorable prognosis compared with diffuse large B-cell lymphoma cases lacking this abnormality.[21] Large B-cell lymphoma with IRF4 rearrangement was added as a distinct entity in the 2016 revision of the WHO classification of lymphoid neoplasms.[22]
(Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for information about the treatment of childhood non-Hodgkin lymphoma.)

Primary mediastinal B-cell lymphoma

Primary mediastinal B-cell lymphoma was previously considered a subtype of diffuse large B-cell lymphoma, but is now a separate entity in the most recent World Health Organization (WHO) classification.[23] These tumors arise in the mediastinum from thymic B-cells and show a diffuse large cell proliferation with sclerosis that compartmentalizes neoplastic cells.
Primary mediastinal B-cell lymphoma can be very difficult to distinguish morphologically from the following types of lymphoma:
  • Diffuse large B-cell lymphoma: Cell surface markers are similar to the ones seen in diffuse large B-cell lymphoma, such as CD19, CD20, CD22, CD79a, and PAX-5. Primary mediastinal B-cell lymphoma often lacks cell surface immunoglobulin expression but may display cytoplasmic immunoglobulins. CD30 expression is commonly present.[23]
  • Hodgkin lymphoma: Primary mediastinal B-cell lymphoma may be difficult to clinically and morphologically distinguish from Hodgkin lymphoma, especially with small mediastinal biopsies because of extensive sclerosis and necrosis.
Primary mediastinal B-cell lymphoma has a distinctive gene expression profile compared with diffuse large B-cell lymphoma; however, its gene expression profile has features similar to those seen in Hodgkin lymphoma.[24,25] Primary mediastinal B-cell lymphoma is also associated with a distinctive constellation of chromosomal aberrations compared with other NHL subtypes. Because primary mediastinal B-cell lymphoma is primarily a cancer of adolescents and young adults, the genomic findings are presented without regard to age.
  • Structural rearrangements and copy number gains at chromosome 9p24 are common in primary mediastinal B-cell lymphoma. This region encodes the immune checkpoint genes PD-L1 (PDL1) and PD-L2 (PDCD1LG2), and the genomic alterations lead to increased expression of these checkpoint proteins.[26-28]
  • Genomic alterations in CIITA, which is the master transcriptional regulator of MHC class II expression, are common in primary mediastinal B-cell lymphoma and lead to loss of MHC class II expression. Loss of MHC class II expression provides another mechanism of immune escape for primary mediastinal B-cell lymphoma.[29]
  • Genomic alterations involving JAK-STAT pathway genes are observed in most cases of primary mediastinal B-cell lymphoma.[30]
    • The chromosome 9p region that shows gains and amplification in primary mediastinal B-cell lymphoma encodes Janus kinase 2 (JAK2), which activates the signal transducer and activator of transcription (STAT) pathway.[31,32]
    • SOCS1, a negative regulator of JAK-STAT signaling, is inactivated in approximately 50% of primary mediastinal B-cell lymphoma by either mutation or gene deletion.[33,34]
    • The interleukin-4 receptor gene (IL4R) shows activating mutations in approximately 20% of primary mediastinal B-cell lymphoma cases, and IL4R activation leads to increased JAK-STAT pathway activity.[30]
  • Copy number gains and amplifications at 2p16.1, a region that encodes BCL11A and REL, also occur in primary mediastinal B-cell lymphoma.[31,32]
(Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for information about the treatment of childhood non-Hodgkin lymphoma.)

Lymphoblastic Lymphoma

Lymphoblastic lymphomas are usually positive for terminal deoxynucleotidyl transferase, with more than 75% having a T-cell immunophenotype and the remainder having a precursor B-cell phenotype.[2,35]
As opposed to pediatric acute lymphoblastic leukemia, chromosomal abnormalities and the molecular biology of pediatric lymphoblastic lymphoma are not well characterized. The Berlin-Frankfurt-Münster group reported that loss of heterozygosity at chromosome 6q was observed in 12% of patients and NOTCH1 mutations were seen in 60% of patients, but NOTCH1 mutations are rarely seen in patients with loss of heterozygosity in 6q16.[36,37]
(Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for information about the treatment of childhood non-Hodgkin lymphoma.)

Anaplastic Large Cell Lymphoma

While the predominant immunophenotype of anaplastic large cell lymphoma is mature T-cell, null-cell disease (i.e., no T-cell, B-cell, or natural killer-cell surface antigen expression) does occur. The World Health Organization (WHO) classifies anaplastic large cell lymphoma as a subtype of peripheral T-cell lymphoma.[22]
All anaplastic large cell lymphoma cases are CD30-positive. More than 90% of pediatric anaplastic large cell lymphoma cases have a chromosomal rearrangement involving the ALK gene. About 85% of these chromosomal rearrangements will be t(2;5)(p23;q35), leading to the expression of the fusion protein NPM-ALK; the other 15% of cases are composed of variant ALK translocations.[38] Anti-ALK immunohistochemical staining pattern is quite specific for the type of ALK translocation. Cytoplasm and nuclear ALK staining is associated with NPM-ALK fusion protein, whereas cytoplasmic staining only of ALK is associated with the variant ALK translocations, as shown in Table 2.[39]

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