PMC:5003446 / 4569-13790 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/5003446","sourcedb":"PMC","sourceid":"5003446","source_url":"https://www.ncbi.nlm.nih.gov/pmc/5003446","text":"2. Acute Lymphoblastic Leukemia/Lymphoma\nAcute lymphoblastic leukemia/lymphoma is the most frequent pediatric malignancy, affecting 20–40 patients per million children in developed countries [14], and accounts for 20% of all acute leukemias in adults. B-lymphoblastic leukemia/lymphoma (B-ALL) is the most common type of acute lymphoblastic leukemia, and comprises genetically distinct subtypes including B-ALL with Philadelphia chromosome t(9;22)(q34;q11.2) (BCR-ABL1), t(v;11q23) (MLL rearranged), t(12;21)(p13;q22) (TEL-AML1), t(5;14)(q31;q32) (IL3-IGH), t(1;19)(q23;p13.3) (E2A-PBX1), hyperdiploidy, hypodiploidy, and about 25% cases without defined cytogenetic abnormalities [15]. Pediatric B-ALL has a favorable prognosis with approximately 80% rate of cure, while adult B-ALL has an inferior prognosis with about 40% rate of cure [16,17,18,19,20,21,22,23,24]. B-ALL with t(9;22)(q34;q11.2) (BCR-ABL1) is associated with the worst prognosis in both children and adults. Studies have shown that the currently identified chromosomal translocations are early initiating genetic events but are not sufficient to induce ALL [25].\nTo identify additional genetic lesions important for leukaemogenesis, a SNP array is well-suited for global genomic mapping of B-ALL. Irving et al. [26] first applied The Affymetrix 10K SNP array with resolution of 100 to 200 kb was used in 10 cases of pediatric B-ALL and demonstrated the usefulness of this technique in studying B-ALL. Of the 10 cases, LOH was detected in eight cases with the most frequent abnormality (50%) in chromosome 9p harboring the CDKN2A/B (INK4) gene locus. The loss of INK4 gene locus was only observed at relapse in three of the four cases, suggesting its association with treatment failure. Subsequently, Mullighan et al. [27] performed the first large-scale study of 242 cases of paediatric ALL, including 192 B-ALL and 50 T-ALL, by using Affymetrix SNP arrays that examine over 350,000 loci with an average resolution of less than 5 kb. Matched remission samples allowed the identification of somatic CNAs and LOH in leukemic blasts. The SNP arrays showed a low number of somatic copy number alterations (mean of 6.46) per case in ALL, with deletions outnumbering amplifications almost 2:1. The frequency of CNAs varied significantly between different cytogenetically defined ALL subtypes, with deletions more frequent than gains of DNA. Chromosomal deletions occurred more frequently in B-ALL with ETV6–RUNX1 and hypodiploidy with average of six deletions per case, up to 21 deletions, and only one deletion in MLL rearranged B-ALL. Gains of DNA occurred most frequently in hyperdiploid B-ALL (average of 10 gains), and uncommon in other types of ALL. The study identified 54 recurring regions of deletion that were mostly focal with the minimal deletion less than 1 Mb, and 24 deletions harboring only one single gene. The most important finding was that genes regulating normal B-cell development were deleted or mutated in approximately 40% cases of B-ALL. Copy number changes of PAX5, which is essential for B-cell differentiation, occurred in about 30% cases of B-ALL, making PAX5 the most frequently altered gene in B-ALL. These changes resulted in either reduced level or hypomorphic alleles of PAX5. Sequencing studies also identified a variety of somatic mutations in PAX5 resulting in either lost or altered DNA-binding or transcriptional functions. Other important genes deleted in ALL included EBF1, TCF3, LEF1, IKZF1 (IKAROS), and IKZF3 (AIOLOS). These findings suggest that ALL is not a neoplasm characterized by chromosomal instability, and genetic alterations in genes controlling B-cell development (PAX5, EBF1 and IKZF1) are common and play important roles in B-ALL leukaemogenesis. In a separate study, Kawamata et al. [28] studied 399 pediatric ALL samples with matched remission marrow using Affymetrix 50K SNP arrays, and identified three most common genetic alterations: deletion of ETV6, deletion of CDKN2A/p16INK4A, and hyperdiploidy. This study also confirmed the deletions of PAX5 (9p13), EBF (5q33), IKAROS (7p12.2), AIOLOS (17q12), LEF1 (4q25), RAG1 (11p12), and RAG2 (11p12) in pediatric ALL, albeit with a lower frequency except PAX5. Uniparental disomy (UPD) was frequently identified, especially in chromosome 9. In addition, hyperdiploid ALL without gains of chromosomes 17 and 18 was found to have poor prognosis. The common deletions of CDKN2A at 9p21 (29%) and ETV6 (TEL) at 12p13 (3/24, 12%) were also confirmed by Bungaro et al. [29] in a separate study.\nT-ALL comprises about 25% cases of adult ALL and approximately 15% cases of childhood ALL and is most commonly present in adolescents as mediastinal lymphoma. The most frequent recurrent cytogenetic abnormalities involve translocation of T-cell receptor gene locus (14q11.2, 7q35, and 7p14-15) with a variety of partner genes such as HOX11, MYC, TAL1, RBTN1/2, and LYL1 [30,31] and, thus, T-ALL is genetically more heterogeneous. In their SNP array analysis of 50 cases of T-ALL, Mullighan et al. [32] identified multiple new genomic changes in T-ALL, including deletions of TAL1, RB1, and PTEN, and duplications of protooncogene MYB. Most recently, Karrman et al. [33] investigated 47 cases of T-ALL with an Illumina HumanOmni1-Quad BeadChip containing \u003e1 million markers and a median marker interval of 1.5 kb. Copy number changes and UPD were identified in the majority of cases (92%), with a median of three changes/per case. This study identified recurring region of deletion harboring genes CDKN2A, CDKN2B, LEF1, PTEN, RBI, and STIL. In terms of uniparental disomy (UPD), the T-ALL lacked whole chromosome UPD, but showed segmental UPDs (sUPDs) in 42% of cases, with a high proportion of sUPD 9p (30% of the cases) associated with homozygous CDKN2A deletion. Therefore, disruption of the p53 and RB1 pathways through deletion of INK4/ARF on CDKN2A gene locus appears to be important in the pathogenesis of T-ALL.\nThe genomic changes that may explain the difference in survival between pediatric and adult ALL were addressed by Okamoto et al. [34] with Affymetrix 50K or 250K SNP arrays. The authors studied 75 cases of adult ALL and 399 cases of pediatric ALL. This study showed 572 genomic alterations with a mean of 7.6 genomic changes per case in adult ALL. The genomic changes in adult ALL were comparable to those identified in pediatric ALL, including deletions of 3p14.2 (FHIT), 5q33.3 (EBF), 6q, 9p21.3 (CDKN2A/B), 9p13.2 (PAX5), 13q14.2 (RB1), and 17q11.2 (NF1). The recurrent genomic alterations had similar rate of occurrence in pediatric and adult ALL. As the adult ALL cases were all non-hyperdiploid, the pediatric ALL cases were divided into hyperdiploid (HD) and non-hyperdiploid groups. There was no significant difference between adult and non-HD pediatric ALL in terms of deletions of 3p14.2 (FHIT), 9p21.3 (CDKN2A/B), 9p13.2 (PAX5), 13q14.2 (RB1), and 17q11.2 (NF1), and adult ALL showed more frequent deletion of 17p (TP53) and duplication of 17q than non-HD pediatric ALL (11% vs. 2%, and 9% vs. 1%, respectively). Overall, there were no unequivocal CNAs identified by SNP array that can account for the differences of prognosis between adult and pediatric ALL. The characteristic deletions of CDKN2A, PAX5, IKZF1, ETV6, RB1, and EBF1 genes were also identified by Safavi et al. [35] in adult ALL using SNP array covering 5 million markers and a resolution of 10 kb. A number of novel recurrent cryptic genetic changes involving BCAT1, SERP2, RAB30, SRPR, ST3GAL4, ASS1, RASSF3, FUBP3, BCL11A, GAB1, LINGO2, TOX, and CXCR4 genes, and partial and whole-chromosome UPDs were also discovered in adult ALL. Their significance in pediatric and adult ALL remains to be determined.\nSNP arrays were designed for genome-wide association (GWA) study, and it was naturally applied in ALL for germline SNPs that may have an association with ALL. Trevino et al. [36] studied 317 cases of pediatric ALL along with 17,958 control cases with an Affymetrix 500K Mapping array, and found two SNPs at chromosome 10q21 (rs10821936 and rs10994982) located in intron 3 of the ARID5B gene to be associated pediatric ALL. In addition, both SNPs discriminated hyperdiploid B-ALL from other major ALL subtypes. A genome-wide association study by Papaemmanuil et al. [37] on two case-control series with 907 ALL cases and 2398 controls also identified an association between a SNP at 10q21.2 in the ARID5B gene (rs7089424) and pediatric ALL. The 10q21.2 (ARID5B) risk association was selective for hyperdiploid B-ALL. In addition, they also found two additional risk loci for ALL at 7p12.2 (IKZF1, rs4132601), and 14q11.2 (CEBPE, rs2239633). The association between genetic variations at 7p12.2 (IKZF1), 10q21.2 (ARIDB5), and 14q11.2 (CEBPE) with pediatric ALL was replicated by Prasad et al. [38] in genotyping 1384 cases of pediatric B-ALL and 1877 controls. These findings indicate that common germline variants contribute to the risk of development of pediatric ALL. As both ARID5B and IKZF1 play important roles in B-lymphocyte growth and differentiation, the possibility of SNPs in these genes predispose the patients to the development of B-ALL is high.","divisions":[{"label":"Title","span":{"begin":0,"end":40}}],"tracks":[{"project":"2_test","denotations":[{"id":"27600067-9039726-69477813","span":{"begin":192,"end":194},"obj":"9039726"},{"id":"27600067-10828010-69477814","span":{"begin":838,"end":840},"obj":"10828010"},{"id":"27600067-11187913-69477815","span":{"begin":841,"end":843},"obj":"11187913"},{"id":"27600067-11187914-69477816","span":{"begin":844,"end":846},"obj":"11187914"},{"id":"27600067-11222362-69477817","span":{"begin":847,"end":849},"obj":"11222362"},{"id":"27600067-11187918-69477818","span":{"begin":850,"end":852},"obj":"11187918"},{"id":"27600067-14559953-69477819","span":{"begin":853,"end":855},"obj":"14559953"},{"id":"27600067-12196212-69477820","span":{"begin":856,"end":858},"obj":"12196212"},{"id":"27600067-10653870-69477821","span":{"begin":859,"end":861},"obj":"10653870"},{"id":"27600067-12011123-69477822","span":{"begin":862,"end":864},"obj":"12011123"},{"id":"27600067-12951583-69477823","span":{"begin":1126,"end":1128},"obj":"12951583"},{"id":"27600067-15833833-69477824","span":{"begin":1280,"end":1282},"obj":"15833833"},{"id":"27600067-17344859-69477825","span":{"begin":1786,"end":1788},"obj":"17344859"},{"id":"27600067-17890455-69477826","span":{"begin":3805,"end":3807},"obj":"17890455"},{"id":"27600067-18803328-69477827","span":{"begin":4535,"end":4537},"obj":"18803328"},{"id":"27600067-12196211-69477828","span":{"begin":4931,"end":4933},"obj":"12196211"},{"id":"27600067-16826225-69477829","span":{"begin":4934,"end":4936},"obj":"16826225"},{"id":"27600067-18519632-69477830","span":{"begin":5058,"end":5060},"obj":"18519632"},{"id":"27600067-25903014-69477831","span":{"begin":5226,"end":5228},"obj":"25903014"},{"id":"27600067-20435627-69477832","span":{"begin":6109,"end":6111},"obj":"20435627"},{"id":"27600067-25261097-69477833","span":{"begin":7368,"end":7370},"obj":"25261097"},{"id":"27600067-19684603-69477834","span":{"begin":7938,"end":7940},"obj":"19684603"},{"id":"27600067-19684604-69477835","span":{"begin":8329,"end":8331},"obj":"19684604"},{"id":"27600067-20042726-69477836","span":{"begin":8855,"end":8857},"obj":"20042726"}],"attributes":[{"subj":"27600067-9039726-69477813","pred":"source","obj":"2_test"},{"subj":"27600067-10828010-69477814","pred":"source","obj":"2_test"},{"subj":"27600067-11187913-69477815","pred":"source","obj":"2_test"},{"subj":"27600067-11187914-69477816","pred":"source","obj":"2_test"},{"subj":"27600067-11222362-69477817","pred":"source","obj":"2_test"},{"subj":"27600067-11187918-69477818","pred":"source","obj":"2_test"},{"subj":"27600067-14559953-69477819","pred":"source","obj":"2_test"},{"subj":"27600067-12196212-69477820","pred":"source","obj":"2_test"},{"subj":"27600067-10653870-69477821","pred":"source","obj":"2_test"},{"subj":"27600067-12011123-69477822","pred":"source","obj":"2_test"},{"subj":"27600067-12951583-69477823","pred":"source","obj":"2_test"},{"subj":"27600067-15833833-69477824","pred":"source","obj":"2_test"},{"subj":"27600067-17344859-69477825","pred":"source","obj":"2_test"},{"subj":"27600067-17890455-69477826","pred":"source","obj":"2_test"},{"subj":"27600067-18803328-69477827","pred":"source","obj":"2_test"},{"subj":"27600067-12196211-69477828","pred":"source","obj":"2_test"},{"subj":"27600067-16826225-69477829","pred":"source","obj":"2_test"},{"subj":"27600067-18519632-69477830","pred":"source","obj":"2_test"},{"subj":"27600067-25903014-69477831","pred":"source","obj":"2_test"},{"subj":"27600067-20435627-69477832","pred":"source","obj":"2_test"},{"subj":"27600067-25261097-69477833","pred":"source","obj":"2_test"},{"subj":"27600067-19684603-69477834","pred":"source","obj":"2_test"},{"subj":"27600067-19684604-69477835","pred":"source","obj":"2_test"},{"subj":"27600067-20042726-69477836","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#c493ec","default":true}]}]}}