Novel germline TRAF3IP3 mutation in a dyad with familial acute B lymphoblastic leukemia. Cancer Rep (Hoboken) 2021 Jun;4(3):e1335
Date
01/28/2021Pubmed ID
33503336Pubmed Central ID
PMC8222551DOI
10.1002/cnr2.1335Scopus ID
2-s2.0-85099938449 (requires institutional sign-in at Scopus site) 1 CitationAbstract
BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children, representing 25% of all new cancer diagnoses. Advances in genomic sequencing have demonstrated that inherited genetic risk factors play a larger role in leukemia development than previously appreciated.
AIM: We identified a father-daughter dyad with childhood B-cell ALL and aimed to investigate whether the pair shared a gene associated with leukemia predisposition.
METHODS: We performed whole exome sequencing on their leukemia and germline samples and RNA-seq on their leukemia samples.
RESULTS: We discovered a novel germline chromosomal structural variant in chromosome 1q32.2 within the TRAF3IP3 gene. TRAF3IP3 regulates B-cell lymphopoiesis, and this mutation likely resulted in a predisposition to leukemia by causing expansion of immature B-cell precursors which are highly vulnerable to secondary somatic mutations. Based on the lack of concordance in the somatic mutational profiles between this dyad's leukemia samples, we suspect that the acquired somatic mutations rather than this germline mutation are what dictated their leukemia phenotypes, which we confirmed through RNA-seq by comparing to sporadic cases of B-cell ALL.
CONCLUSION: This research may have identified a novel gene involved in leukemogenesis which may also be involved in de novo cases of ALL. Additional studies are needed to further characterize this TRAF3IP3 structural variant, the co-occurring somatic mutations within these leukemia samples and their combined role in leukemogenesis.
Author List
Pommert L, Burns R, Furumo Q, Pulakanti K, Brandt J, Burke MJ, Rao SAuthors
Michael James Burke MD Professor in the Pediatrics department at Medical College of WisconsinSridhar Rao MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AdultChild
Child, Preschool
DNA Mutational Analysis
Female
Genetic Predisposition to Disease
Germ-Line Mutation
Humans
Male
Microtubule-Associated Proteins
Precursor Cell Lymphoblastic Leukemia-Lymphoma
