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Molecular profiling of gene copy number abnormalities in key regulatory genes in high-risk B-lineage acute lymphoblastic leukemia: frequency and their association with clinicopathological findings in Indian patients.

Abstract Genes related to key cellular pathways are frequently altered in B cell ALL and are associated with poor survival especially in high-risk (HR) subgroups. We examined gene copy number abnormalities (CNA) in 101 Indian HR B cell ALL patients and their correlation with clinicopathological features by multiplex ligation-dependent probe amplification. Overall, CNA were detected in 59 (59%) cases, with 26, 10 and 23% of cases harboring 1, 2 or +3 CNA. CNA were more prevalent in BCR-ABL1 (60%), pediatric (64%) and high WCC (WBC count) (63%) patients. Frequent genes deletions included CDNK2A/B (26%), IKZF1 (25%), PAX5 (14%), JAK2 (7%), BTG1 (6%), RB1 (5%), EBF1 (4%), ETV6 (4%), while PAR1 region genes were predominantly duplicated (20%). EBF1 deletions selectively associated with adults, IKZF1 deletions occurred frequently in high WCC and BCR-ABL1 cases, while PAR1 region gains significantly associated with MLL-AF4 cases. IKZF1 haploinsufficiency group was predominant, especially in adults (65%), high WCC (60%) patients and BCR-ABL1-negative (78%) patients. Most cases harbored multiple concurrent CNA, with IKZF1 concomitantly occurring with CDNK2A/B, PAX5 and BTG1, while JAK2 occurred with CDNK2A/B and PAX5. Mutually exclusive CNA included ETV6 and IKZF1/RB1, and EBF1 and JAK2. Our results corroborate with global reports, aggregating molecular markers in Indian HR B-ALL cases. Integration of CNA data from rapid methods like MLPA, onto background of existing gold-standard methods detecting significant chromosomal abnormalities, provides a comprehensive genetic profile in B-ALL.
PMID
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Authors

Mayor MeshTerms

Gene Dosage

Keywords

Copy number abnormalities (CNA)

High-risk B-ALL

IKZF1

MLPA

Journal Title medical oncology (northwood, london, england)
Publication Year Start




PMID- 28401483
OWN - NLM
STAT- MEDLINE
DA  - 20170412
DCOM- 20170414
LR  - 20170414
IS  - 1559-131X (Electronic)
IS  - 1357-0560 (Linking)
VI  - 34
IP  - 5
DP  - 2017 May
TI  - Molecular profiling of gene copy number abnormalities in key regulatory genes in 
      high-risk B-lineage acute lymphoblastic leukemia: frequency and their association
      with clinicopathological findings in Indian patients.
PG  - 92
LID - 10.1007/s12032-017-0940-3 [doi]
AB  - Genes related to key cellular pathways are frequently altered in B cell ALL and
      are associated with poor survival especially in high-risk (HR) subgroups. We
      examined gene copy number abnormalities (CNA) in 101 Indian HR B cell ALL
      patients and their correlation with clinicopathological features by multiplex
      ligation-dependent probe amplification. Overall, CNA were detected in 59 (59%)
      cases, with 26, 10 and 23% of cases harboring 1, 2 or +3 CNA. CNA were more
      prevalent in BCR-ABL1 (60%), pediatric (64%) and high WCC (WBC count) (63%)
      patients. Frequent genes deletions included CDNK2A/B (26%), IKZF1 (25%), PAX5
      (14%), JAK2 (7%), BTG1 (6%), RB1 (5%), EBF1 (4%), ETV6 (4%), while PAR1 region
      genes were predominantly duplicated (20%). EBF1 deletions selectively associated 
      with adults, IKZF1 deletions occurred frequently in high WCC and BCR-ABL1 cases, 
      while PAR1 region gains significantly associated with MLL-AF4 cases. IKZF1
      haploinsufficiency group was predominant, especially in adults (65%), high WCC
      (60%) patients and BCR-ABL1-negative (78%) patients. Most cases harbored multiple
      concurrent CNA, with IKZF1 concomitantly occurring with CDNK2A/B, PAX5 and BTG1, 
      while JAK2 occurred with CDNK2A/B and PAX5. Mutually exclusive CNA included ETV6 
      and IKZF1/RB1, and EBF1 and JAK2. Our results corroborate with global reports,
      aggregating molecular markers in Indian HR B-ALL cases. Integration of CNA data
      from rapid methods like MLPA, onto background of existing gold-standard methods
      detecting significant chromosomal abnormalities, provides a comprehensive genetic
      profile in B-ALL.
FAU - Bhandari, Prerana
AU  - Bhandari P
AD  - Research and Development Division, Molecular Pathology, Clinical Research
      Services, SRL Limited, Plot No.1, Prime Square Building, S.V. Road, Goregaon (W),
      Mumbai, 400062, India.
FAU - Ahmad, Firoz
AU  - Ahmad F
AD  - Research and Development Division, Molecular Pathology, Clinical Research
      Services, SRL Limited, Plot No.1, Prime Square Building, S.V. Road, Goregaon (W),
      Mumbai, 400062, India.
FAU - Das, Bibhu Ranjan
AU  - Das BR
AD  - Research and Development Division, Molecular Pathology, Clinical Research
      Services, SRL Limited, Plot No.1, Prime Square Building, S.V. Road, Goregaon (W),
      Mumbai, 400062, India. [email protected]
LA  - eng
PT  - Journal Article
DEP - 20170411
PL  - United States
TA  - Med Oncol
JT  - Medical oncology (Northwood, London, England)
JID - 9435512
RN  - 0 (IKZF1 protein, human)
RN  - 148971-36-2 (Ikaros Transcription Factor)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Age Factors
MH  - Aged
MH  - Child
MH  - Child, Preschool
MH  - Female
MH  - Gene Deletion
MH  - *Gene Dosage
MH  - Gene Expression Profiling
MH  - Humans
MH  - Ikaros Transcription Factor/genetics
MH  - India
MH  - Infant
MH  - Male
MH  - Middle Aged
MH  - Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/*genetics/pathology
MH  - Young Adult
OTO - NOTNLM
OT  - Copy number abnormalities (CNA)
OT  - High-risk B-ALL
OT  - IKZF1
OT  - MLPA
EDAT- 2017/04/13 06:00
MHDA- 2017/04/15 06:00
CRDT- 2017/04/13 06:00
PHST- 2017/02/27 [received]
PHST- 2017/03/31 [accepted]
AID - 10.1007/s12032-017-0940-3 [doi]
AID - 10.1007/s12032-017-0940-3 [pii]
PST - ppublish
SO  - Med Oncol. 2017 May;34(5):92. doi: 10.1007/s12032-017-0940-3. Epub 2017 Apr 11.

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