HAEM5:B-lymphoblastic leukaemia/lymphoma with hypodiploidy: Difference between revisions

!Clinical Relevance Details/Other Notes

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|Near haploidy may be the primary event with loss of chromosomes, followed by a secondary event of doubling of chromosomes indicating uniparental isodisomy (UPID), microdeletions if any may occur after the secondary event<ref name=":5">{{Cite journal|last=Safavi|first=S.|last2=Forestier|first2=E.|last3=Golovleva|first3=I.|last4=Barbany|first4=G.|last5=Nord|first5=K. H.|last6=Moorman|first6=A. V.|last7=Harrison|first7=C. J.|last8=Johansson|first8=B.|last9=Paulsson|first9=K.|date=2013|title=Loss of chromosomes is the primary event in near-haploid and low-hypodiploid acute lymphoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/22889820|journal=Leukemia|volume=27|issue=1|pages=248–250|doi=10.1038/leu.2012.227|issn=1476-5551|pmid=22889820}}</ref>. The chromosomal loss alone may be enough for leukemogenesis and the unconserved random chromosomes may contain specific genes that increase the oncogenic potential of leukemic cells<ref name=":15">{{Cite journal|last=Harrison|first=Christine J.|last2=Moorman|first2=Anthony V.|last3=Barber|first3=Kerry E.|last4=Broadfield|first4=Zoë J.|last5=Cheung|first5=Kan L.|last6=Harris|first6=Rachel L.|last7=Jalali|first7=G. Reza|last8=Robinson|first8=Hazel M.|last9=Strefford|first9=Jonathan C.|date=2005-05|title=Interphase molecular cytogenetic screening for chromosomal abnormalities of prognostic significance in childhood acute lymphoblastic leukaemia: a UK Cancer Cytogenetics Group Study|url=https://pubmed.ncbi.nlm.nih.gov/15877734|journal=British Journal of Haematology|volume=129|issue=4|pages=520–530|doi=10.1111/j.1365-2141.2005.05497.x|issn=0007-1048|pmid=15877734}}</ref><ref>{{Cite journal|last=Raimondi|first=Susana C.|last2=Zhou|first2=Yinmei|last3=Mathew|first3=Susan|last4=Shurtleff|first4=Sheila A.|last5=Sandlund|first5=John T.|last6=Rivera|first6=Gaston K.|last7=Behm|first7=Frederick G.|last8=Pui|first8=Ching-Hon|date=2003-12-15|title=Reassessment of the prognostic significance of hypodiploidy in pediatric patients with acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/14669294|journal=Cancer|volume=98|issue=12|pages=2715–2722|doi=10.1002/cncr.11841|issn=0008-543X|pmid=14669294}}</ref>.

|Rare (0.5%)<ref name=":8" />

Near-haploid and low-hypodiploid B-ALL/LBL may undergo doubling, resulting in a pseudohyperdiploid or near-triploid clone containing up to 78 chromosomes, and can present as a diagnostic challenge. If the original hypodiploid clone is not present, the hypodiploidy is regarded as masked, and the case may be mistaken for high-hyperdiploid B-ALL/LBL, resulting in an inappropriate prognostication<ref name=":1" /><ref>{{Cite journal|last=Carroll|first=Andrew J.|last2=Shago|first2=Mary|last3=Mikhail|first3=Fady M.|last4=Raimondi|first4=Susana C.|last5=Hirsch|first5=Betsy A.|last6=Loh|first6=Mignon L.|last7=Raetz|first7=Elizabeth A.|last8=Borowitz|first8=Michael J.|last9=Wood|first9=Brent L.|date=2019-10|title=Masked hypodiploidy: Hypodiploid acute lymphoblastic leukemia (ALL) mimicking hyperdiploid ALL in children: A report from the Children's Oncology Group|url=https://pubmed.ncbi.nlm.nih.gov/31425927|journal=Cancer Genetics|volume=238|pages=62–68|doi=10.1016/j.cancergen.2019.07.009|issn=2210-7762|pmc=6768693|pmid=31425927}}</ref><ref>{{Cite journal|last=Creasey|first=Thomas|last2=Enshaei|first2=Amir|last3=Nebral|first3=Karin|last4=Schwab|first4=Claire|last5=Watts|first5=Kathryn|last6=Cuthbert|first6=Gavin|last7=Vora|first7=Ajay|last8=Moppett|first8=John|last9=Harrison|first9=Christine J.|date=2021-09|title=Single nucleotide polymorphism array-based signature of low hypodiploidy in acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/33938069|journal=Genes, Chromosomes & Cancer|volume=60|issue=9|pages=604–615|doi=10.1002/gcc.22956|issn=1098-2264|pmc=8600946|pmid=33938069}}</ref>. The two subtypes may be differentiated by SNP array analysis, demonstrating copy-neutral loss of heterozygosity for doubled monosomic chromosomes. The DNA index assessed by flow cytometry may also be helpful if distinct peaks representing the hypodiploid and doubled clones are both detectable<ref>{{Cite journal|last=Yu|first=Chih-Hsiang|last2=Lin|first2=Tze-Kang|last3=Jou|first3=Shiann-Tarng|last4=Lin|first4=Chien-Yu|last5=Lin|first5=Kai-Hsin|last6=Lu|first6=Meng-Yao|last7=Chen|first7=Shu-Huey|last8=Cheng|first8=Chao-Neng|last9=Wu|first9=Kang-Hsi|date=2020-07-13|title=MLPA and DNA index improve the molecular diagnosis of childhood B-cell acute lymphoblastic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/32661308|journal=Scientific Reports|volume=10|issue=1|pages=11501|doi=10.1038/s41598-020-68311-9|issn=2045-2322|pmc=7359332|pmid=32661308}}</ref>.

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|More than 90% of low-hypodiploid patients have been identified with ''TP53'' mutations, which occur in virtually all low-hypodiploid B-ALL cases due to the very recurrent loss of chromosome 17<ref name=":6" /><ref name=":9">{{Cite journal|last=Safavi|first=Setareh|last2=Olsson|first2=Linda|last3=Biloglav|first3=Andrea|last4=Veerla|first4=Srinivas|last5=Blendberg|first5=Molly|last6=Tayebwa|first6=Johnbosco|last7=Behrendtz|first7=Mikael|last8=Castor|first8=Anders|last9=Hansson|first9=Markus|date=2015|title=Genetic and epigenetic characterization of hypodiploid acute lymphoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/26544893|journal=Oncotarget|volume=6|issue=40|pages=42793–42802|doi=10.18632/oncotarget.6000|issn=1949-2553|pmc=4767471|pmid=26544893}}</ref><ref name=":10">{{Cite journal|last=Stengel|first=Anna|last2=Schnittger|first2=Susanne|last3=Weissmann|first3=Sandra|last4=Kuznia|first4=Sabrina|last5=Kern|first5=Wolfgang|last6=Kohlmann|first6=Alexander|last7=Haferlach|first7=Torsten|last8=Haferlach|first8=Claudia|date=2014-07-10|title=TP53 mutations occur in 15.7% of ALL and are associated with MYC-rearrangement, low hypodiploidy, and a poor prognosis|url=https://pubmed.ncbi.nlm.nih.gov/24829203|journal=Blood|volume=124|issue=2|pages=251–258|doi=10.1182/blood-2014-02-558833|issn=1528-0020|pmid=24829203}}</ref>. p53 is one of the most prominent tumor suppressors. Its activation as a transcription factor stimulates downstream pathways leading to protective cellular processes, including cell-cycle arrest, apoptosis, and senescence, to prevent the propagation of genetically altered cells<ref>{{Cite journal|last=Vogelstein|first=B.|last2=Lane|first2=D.|last3=Levine|first3=A. J.|date=2000-11-16|title=Surfing the p53 network|url=https://pubmed.ncbi.nlm.nih.gov/11099028|journal=Nature|volume=408|issue=6810|pages=307–310|doi=10.1038/35042675|issn=0028-0836|pmid=11099028}}</ref>.

|Rare in children, recurrent in adolescents, young adults, and adults

The most common targets of aneuploidy are chromosomes 2–4, 7, 9, 12–13, 15–17 and 20<ref name=":7" />.

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|Genetic alterations involve ''CDKN2A'' and ''TP53''<ref name=":9" />.

|Rare, occurring in approximately 4% of diagnosed cases of hypodiploidy in both children and adults, but with a predominance of the younger group<ref name=":11" /><ref name=":12">{{Cite journal|last=Moorman|first=Anthony V.|date=2016|title=New and emerging prognostic and predictive genetic biomarkers in B-cell precursor acute lymphoblastic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/27033238|journal=Haematologica|volume=101|issue=4|pages=407–416|doi=10.3324/haematol.2015.141101|issn=1592-8721|pmc=5004393|pmid=27033238}}</ref>.

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|''TP53''<br />

|Tumor supressor gene

|Common  (>90%)

|No (NCCN)

|These alterations correlate with low-hypodiploid ALL (32–39 chromosomes) and poorer clinical outcomes<ref name=":2" />. Approximately 50% of children with low-hypodiploid B-ALL/LBL carry germline ''TP53'' variants associated with Li–Fraumeni syndrome. Accordingly, genetic counseling is recommended for children with low-hypodiploid B-ALL carrying ''TP53'' mutations, and their relatives<ref name=":17" />. In contrast to childhood cases, ''TP53'' mutations in low-hypodiploid adult B-ALL are somatic, are not found in healthy hematopoietic cells, and not detectable in remission samples<ref name=":2" /><ref name=":6" />.