HAEM5:B-lymphoblastic leukaemia/lymphoma with hypodiploidy: Difference between revisions
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==Individual Region Genomic Gain/Loss/LOH== | ==Individual Region Genomic Gain/Loss/LOH== | ||
Please refer to section "Characteristic Chromosomal or Other Global Mutational Patterns" below. | Hypodiploid B-ALL is characterized by widespread genomic losses consistent with the hypodiploid karyotype<ref name=":13" />. Please refer to section "Characteristic Chromosomal or Other Global Mutational Patterns" below. | ||
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==Characteristic Chromosomal or Other Global Mutational Patterns== | ==Characteristic Chromosomal or Other Global Mutational Patterns== | ||
This entity is defined by the presence of neoplastic lymphoblasts containing less than 46 chromosomes | This entity is defined by the presence of neoplastic lymphoblasts containing less than 46 chromosomes, and can be subdivided into near-haploid B-ALL/LBL with hypodiploidy (24–31 chromosomes); low-hypodiploid B-ALL/LBL with hypodiploidy (32–39 chromosomes); and high-hypodiploid B-ALL/LBL with hypodiploidy (40–43 chromosomes)<ref name=":13" /><ref name=":18">{{Cite journal|last=Harrison|first=Christine J.|last2=Moorman|first2=Anthony V.|last3=Broadfield|first3=Zoë J.|last4=Cheung|first4=Kan L.|last5=Harris|first5=Rachel L.|last6=Reza Jalali|first6=G.|last7=Robinson|first7=Hazel M.|last8=Barber|first8=Kerry E.|last9=Richards|first9=Sue M.|date=2004|title=Three distinct subgroups of hypodiploidy in acute lymphoblastic leukaemia|url=https://www.ncbi.nlm.nih.gov/pubmed/15147369|journal=British Journal of Haematology|volume=125|issue=5|pages=552–559|doi=10.1111/j.1365-2141.2004.04948.x|issn=0007-1048|pmid=15147369}}</ref>. Of note, near-diploid cases (44–45 chromosomes) are not included in the hypodiploid category in clinical therapy–directed classification schemes because they do not share the poor prognosis observed<ref name=":14" />. In a study, for patients with 44 chromosomes, monosomy 7, the presence of a dicentric chromosome, or both predicted a worse event-free survival (EFS) but similar overall survival (OS)<ref name=":3">{{Cite journal|last=Nachman|first=James B.|last2=Heerema|first2=Nyla A.|last3=Sather|first3=Harland|last4=Camitta|first4=Bruce|last5=Forestier|first5=Erik|last6=Harrison|first6=Christine J.|last7=Dastugue|first7=Nicole|last8=Schrappe|first8=Martin|last9=Pui|first9=Ching-Hon|date=2007|title=Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/17473063|journal=Blood|volume=110|issue=4|pages=1112–1115|doi=10.1182/blood-2006-07-038299|issn=0006-4971|pmc=1939895|pmid=17473063}}</ref>. | ||
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|No (NCCN) | |No (NCCN) | ||
|Chromosome abnormalities include whole chromosome loss, specifically one sex chromosome and often chromosomes 7, 9, and/or 13. Also detected are structural anomalies especially dicentric chromosomes involving chromosomes 7, 9 or 12. | |Chromosome abnormalities include whole chromosome loss, specifically one sex chromosome and often chromosomes 7, 9, and/or 13. Also detected are structural anomalies especially dicentric chromosomes involving chromosomes 7, 9 or 12. | ||
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==Gene Mutations (SNV/INDEL)== | ==Gene Mutations (SNV/INDEL)== | ||
Holmfeldt et al sequenced 124 cases of low-hypodiploid B-ALL and showed that more than two-thirds (70.6%) of near-haploid ALL cases harbored genetic alterations known or predicted to result in activation of RTK or Ras signaling, including deletion, amplification and/or sequence mutation of ''NF1'', ''NRAS'', ''KRAS'', ''MAPK1'', ''FLT3'' or ''PTPN11<ref name=":2" />''. | |||
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|''NF1'' | |''NF1'' | ||
|Mutations and focal deletions. In 68% of the cases, the ''NF1'' deletions were intragenic involving exons 15 through 35<ref name=":2" /> | |Mutations and focal deletions. In 68% of the cases, the ''NF1'' deletions were intragenic involving exons 15 through 35. Because of aneuploidy, the ''NF1'' alterations were biallelic in 76.7% of near-haploid cases.<ref name=":2" /> | ||
|Tumor supressor gene | |Tumor supressor gene | ||
|Mutations: Recurrent | |Mutations: Recurrent | ||
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|''FLT3'' | |''FLT3'' | ||
| | |Mutation<ref name=":2" /> | ||
|Oncogene | |Oncogene | ||
|Recurrent | |Recurrent | ||
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|''NRAS'' | |''NRAS'' | ||
| | |Mutation<ref name=":2" /> | ||
|Oncogene | |Oncogene | ||
|Recurrent | |Recurrent | ||
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|''IKZF2'' | |''IKZF2'' | ||
|Focal deletion<ref name=": | |Focal deletion. Alterations of ''IKZF2'' and ''IKZF3'' were biallelic as a result of aneuploidy<ref name=":2" />. | ||
|Tumor supressor | |Tumor supressor | ||
|Common | |Common | ||
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|''IKZF3'' | |''IKZF3'' | ||
<br /> | <br /> | ||
|Focal deletion<ref name=": | |Focal deletion and one frameshift mutation<ref name=":2" /> | ||
|Tumor supressor | |Tumor supressor | ||
|Recurrent | |Recurrent | ||
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|''PAG1'' | |''PAG1'' | ||
|Focal deletion<ref name=":2" /> | |Focal deletion<ref name=":2" />. Most ''PAG1'' deletions were homozygous and involved the upstream region and first exon, leading to a complete loss of ''PAG1'' expression. | ||
|Tumor supressor | |Tumor supressor | ||
|Recurrent | |Recurrent | ||
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==Epigenomic Alterations== | ==Epigenomic Alterations== | ||
In near haploid 19% of the cases had focal deletions of histone gene cluster at 6p22, however, non-hypodiploid ALL had 8%, lower frequency of these deletions<ref name=":2" />. | In near haploid 19% of the cases had focal deletions of histone gene cluster at 6p22, however, non-hypodiploid ALL had 8%, lower frequency of these deletions<ref name=":2" />. Of the 25 next generation sequenced haploid cases 16 (64%) cases had twenty six histone modifier gene mutations and of the 15 low hypodiploid ALL cases 9 (60%) cases had 9 mutations; the most common mutation (32%) of the near haploid cases was transcriptional co-activator and histone acetyltransferase ''CREBBP''<ref name=":2" />. | ||
Of the 25 next generation sequenced haploid cases 16 (64%) cases had twenty six histone modifier gene mutations and of the 15 low hypodiploid ALL cases 9 (60%) cases had 9 mutations; the most common mutation (32%) of the near haploid cases was transcriptional co-activator and histone acetyltransferase ''CREBBP''<ref name=":2" />. | |||
==Genes and Main Pathways Involved== | ==Genes and Main Pathways Involved== | ||
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|Constitutive activation of mitogenic and anti-apoptotic pathways, driving uncontrolled cell proliferation, survival, and malignant transformation. | |Constitutive activation of mitogenic and anti-apoptotic pathways, driving uncontrolled cell proliferation, survival, and malignant transformation. | ||
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|''CDKN2A/B, TP53, RB1''; Loss of function mutations | |''CDKN2A/B, TP53, RB1''; Loss of function mutations<ref name=":2" /> | ||
|Cell cycle and apoptosis | |Cell cycle and apoptosis | ||
|Propagation of genetically altered cells. | |Propagation of genetically altered cells. | ||
|- | |- | ||
|''IKZF1, IKZF2, IKZF3, PAX5, EBF1, VPREB1'' | |''IKZF1, IKZF2, IKZF3, PAX5, EBF1, VPREB1''<ref name=":16" /> | ||
|B-cell development | |B-cell development | ||
| | |Altered lymphoid development and differentiation. | ||
|- | |||
|''PAG1<ref name=":16" />'' | |||
|BCR signaling | |||
|Altered regulatory function in proximal B cell–receptor signaling. | |||
|- | |- | ||
|''ETV6'' | |''ETV6<ref name=":16" />'' | ||
|Hematopoiesis | |Hematopoiesis | ||
| | |Not fully elucidated in this entity | ||
|- | |- | ||
|''ARPP21'' | |''ARPP21<ref name=":16" />'' | ||
|Calmodulin signaling | |Calmodulin signaling | ||
| | |Not fully elucidated in this entity | ||
|- | |- | ||
|''SLX4IP'' | |''SLX4IP<ref name=":16" />'' | ||
|Telomere length maintenance | |Telomere length maintenance | ||
| | |Not fully elucidated in this entity | ||
|- | |- | ||
|''CUL5'' | |''CUL5<ref name=":16" />'' | ||
|Ubiquitin pathway | |Ubiquitin pathway | ||
| | |Not fully elucidated in this entity | ||
|- | |- | ||
|''FAM53B'' | |''FAM53B<ref name=":16" />'' | ||
|Wnt signaling | |Wnt signaling | ||
| | |Not fully elucidated in this entity | ||
|- | |- | ||
|''PDS5B'' | |''PDS5B<ref name=":16" />'' | ||
|Cohesis complex | |Cohesis complex | ||
| | |Not fully elucidated in this entity | ||
|- | |- | ||
|''ANKRD11, DMD'' | |''ANKRD11, DMD<ref name=":16" />'' | ||
|Cell adhesion | |Cell adhesion | ||
| | |Not fully elucidated in this entity | ||
|} | |} | ||