title: Characteristics of BCR-ABL kinase domain mutations in chronic myeloid leukemia from India: not just missense mutations but insertions and deletions are also associated with TKI resistance.
abstract: We document the characteristics of BCR-ABL kinase domain mutations (KDM) in the largest study from India comprising of 385 patients and demonstrate that more than half (51.9%) of these patients have detectable abnormalities in the KD both in adult and in pediatric chronic myelogenous leukemia (CML). These comprise singly occurring missense mutations (25.5%), polyclonal/compound point mutations (4.9%), and insertions/deletions (29.6%). Missense mutations were most commonly seen in the imatinib-binding region followed by the P-loop. The commonest mutation in our dataset was T315I. Other common missense mutations were Y253H, M244V, and F317L. A high prevalence of BCR-ABL exon7 deletion (p.R362fs*) was also seen (25.5% of the entire cohort), whereas the 35bpintron-derived insertion/truncation mutation detected in 12 patients. In the pediatric age group, 58.8% of patients harbored missense mutations, polyclonal/compound mutations as well as insertions and deletions. We detected 11 novel mutations (seven missense mutations and four insertions/deletions).
authors.affiliation: a Hematopathology Laboratory , Tata Memorial Centre, Ernest Borges Marg, Parel , Mumbai , Maharashtra , India ;
authors.forename: Nikhil
authors.initials: N
authors.lastname: Patkar
authors.affiliation: a Hematopathology Laboratory , Tata Memorial Centre, Ernest Borges Marg, Parel , Mumbai , Maharashtra , India ;
authors.forename: Kiran
authors.initials: K
authors.lastname: Ghodke
authors.affiliation: a Hematopathology Laboratory , Tata Memorial Centre, Ernest Borges Marg, Parel , Mumbai , Maharashtra , India ;
authors.forename: Swapnali
authors.initials: S
authors.lastname: Joshi
authors.affiliation: a Hematopathology Laboratory , Tata Memorial Centre, Ernest Borges Marg, Parel , Mumbai , Maharashtra , India ;
authors.forename: Shruti
authors.initials: S
authors.lastname: Chaudhary
authors.affiliation: a Hematopathology Laboratory , Tata Memorial Centre, Ernest Borges Marg, Parel , Mumbai , Maharashtra , India ;
authors.forename: Russel
authors.initials: R
authors.lastname: Mascerhenas
authors.affiliation: a Hematopathology Laboratory , Tata Memorial Centre, Ernest Borges Marg, Parel , Mumbai , Maharashtra , India ;
authors.forename: Sona
authors.initials: S
authors.lastname: Dusseja
authors.affiliation: a Hematopathology Laboratory , Tata Memorial Centre, Ernest Borges Marg, Parel , Mumbai , Maharashtra , India ;
authors.forename: Shashikant
authors.initials: S
authors.lastname: Mahadik
authors.affiliation: a Hematopathology Laboratory , Tata Memorial Centre, Ernest Borges Marg, Parel , Mumbai , Maharashtra , India ;
authors.forename: Sheetal
authors.initials: S
authors.lastname: Gaware
authors.affiliation: a Hematopathology Laboratory , Tata Memorial Centre, Ernest Borges Marg, Parel , Mumbai , Maharashtra , India ;
authors.forename: Prashant
authors.initials: P
authors.lastname: Tembhare
authors.affiliation: a Hematopathology Laboratory , Tata Memorial Centre, Ernest Borges Marg, Parel , Mumbai , Maharashtra , India ;
authors.forename: Sumeet
authors.initials: S
authors.lastname: Gujral
authors.affiliation: b Department of Cancer Cytogenetics , Tata Memorial Centre, Ernest Borges Marg , Parel , Mumbai , Maharashtra , India ;
authors.forename: Sharayu
authors.initials: S
authors.lastname: Kabre
authors.affiliation: b Department of Cancer Cytogenetics , Tata Memorial Centre, Ernest Borges Marg , Parel , Mumbai , Maharashtra , India ;
authors.forename: Pratibha
authors.initials: P
authors.lastname: Kadam-Amare
authors.affiliation: c Adult Haemato-lymphoid Disease Management Group , Tata Memorial Centre, Ernest Borges Marg , Parel , Mumbai , Maharashtra , India ;
authors.forename: Hasmukh
authors.initials: H
authors.lastname: Jain
authors.affiliation: c Adult Haemato-lymphoid Disease Management Group , Tata Memorial Centre, Ernest Borges Marg , Parel , Mumbai , Maharashtra , India ;
authors.forename: Uma
authors.initials: U
authors.lastname: Dangi
authors.affiliation: c Adult Haemato-lymphoid Disease Management Group , Tata Memorial Centre, Ernest Borges Marg , Parel , Mumbai , Maharashtra , India ;
authors.forename: Bhausaheb
authors.initials: B
authors.lastname: Bagal
authors.affiliation: c Adult Haemato-lymphoid Disease Management Group , Tata Memorial Centre, Ernest Borges Marg , Parel , Mumbai , Maharashtra , India ;
authors.forename: Navin
authors.initials: N
authors.lastname: Khattry
authors.affiliation: c Adult Haemato-lymphoid Disease Management Group , Tata Memorial Centre, Ernest Borges Marg , Parel , Mumbai , Maharashtra , India ;
authors.forename: Manju
authors.initials: M
authors.lastname: Sengar
authors.affiliation: d Pediatric Haemato-lymphoid Disease Management Group , Tata Memorial Centre, Ernest Borges Marg , Parel , Mumbai , Maharashtra , India.
authors.forename: Brijesh
authors.initials: B
authors.lastname: Arora
authors.affiliation: d Pediatric Haemato-lymphoid Disease Management Group , Tata Memorial Centre, Ernest Borges Marg , Parel , Mumbai , Maharashtra , India.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Narula
authors.affiliation: d Pediatric Haemato-lymphoid Disease Management Group , Tata Memorial Centre, Ernest Borges Marg , Parel , Mumbai , Maharashtra , India.
authors.forename: Shripad
authors.initials: S
authors.lastname: Banavali
authors.affiliation: c Adult Haemato-lymphoid Disease Management Group , Tata Memorial Centre, Ernest Borges Marg , Parel , Mumbai , Maharashtra , India ;
authors.forename: Hari
authors.initials: H
authors.lastname: Menon
authors.affiliation: a Hematopathology Laboratory , Tata Memorial Centre, Ernest Borges Marg, Parel , Mumbai , Maharashtra , India ;
authors.forename: Papagudi Ganesan
authors.initials: PG
authors.lastname: Subramanian
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D002648:Child; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D054643:INDEL Mutation; D007194:India / Q000453:epidemiology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D011159:Population Surveillance; D011379:Prognosis; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl
keywords: BCR-ABL Kinase domain mutations; CML India; imatinib resistance