Sex Differences in Childhood Leukemia Genomics
Abstract
Receipt of this Career Development Award would greatly impact the progression of Dr. Williams’ academic career as she works to establish herself as an independent academic researcher focused on the molecular epidemiology of pediatric cancer. Pediatric cancer is a leading cause of morbidity and mortality among children and adolescents and disproportionately affects males; therefore, understanding the biologic role of sex in the most common pediatric cancer, childhood leukemia, may help to identify common germline variants that play an important role in the male excess in incidence. Further, this work may also help us identify potential sex-specific therapies that may improve outcomes for males and females with leukemias. Dr. Williams will complete two advanced computational genomics courses that will bolster her past training in epidemiology, biology, and statistical genetics and expand her knowledge of the proposed genomic analyses to identify sex differences in the germline genetics and cancer biology of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) using various genomic data types. Additionally, Dr. Williams will present these findings at national meetings where she will continue to establish her professional network and identify future collaborations. Dr. Williams will publish the findings from each aim in peer-reviewed journals to disseminate this knowledge to the scientific community. Childhood leukemias, both ALL and AML, are diagnosed in males up to 1.5-2 times as often as females, particularly during the teen years when more aggressive disease is often diagnosed. The male excess in leukemia diagnoses has long been recognized, but the reason for this sex difference is unknown and has not been thoroughly investigated to date. Dr. Williams published a paper examining whether high birth weight was the reason males were more frequently diagnosed with childhood cancer, including ALL and AML, as birth weight is an established risk factor that differs by sex. The association between male sex and most childhood cancers, including leukemia, was largely attributed to sex rather than birth weight, leading her to conclude that the observed sex differences in leukemia incidence may depend on sex differences in biology or genetics. Sex differences: the association of common germline variants have yet to be investigated in children with leukemia, particularly on the sex chromosomes, which may be important, as the X chromosome contains hundreds of immune-related genes. Therefore, genome-wide association analyses will be stratified by sex and include the sex chromosomes for both ALL and AML. Concerning sex differences in survival after a childhood leukemia diagnosis, Dr. Williams reported that males have significantly worse survival for some childhood cancers, including ALL, which displayed a 24% excess in the risk of death among males. While there was not an observed sex difference in survival among males and females with AML, both sexes fared poorly, with only 61% of children alive five years after diagnosis. Therefore, we need to identify the biologic mechanisms underlying the male excess in death among ALL cases and the poor survival by both sexes for AML. As such, using data on gene expression, methylation, somatic mutation, and copy number variation, Dr. Williams will characterize sex differences in ALL and AML biology, which may help identify sex-specific biologic mechanisms responsible for the male excess in ALL death and the poor survival for males and females in AML. Using pathway analysis and an integrative data approach considering all genomic findings together, she will identify broad genomic sex differences in childhood leukemia biology. Dr. Williams will identify existing Food and Drug Administration-approved therapies that may be of more benefit in males or females that could be tested immediately in laboratory and clinical settings. This could improve the outcomes for females and,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110397
Entities
People
- Lindsay A Williams
Organizations
- United States Army
- University of Minnesota