Kyle Walsh

Overview:

Dr. Walsh is Associate Professor of Neurosurgery and Pathology, Director of the Division of Neuro-epidemiology, and a Senior Fellow in the Duke Center for the Study of Aging and Human Development. He leads Duke’s Neuro-epidemiology Lab, which integrates bench science with statistical methods to study the neurobiology of glial senescence and gliomagenesis. This research interrogates human genomic and epigenomic profiles to identify both heritable and modifiable factors that contribute to neurologic and physical decline, applying these approaches to studying the shared neurobiology of cognition, glial senescence, and gliomagenesis. The lab has a long history studying telomere maintenance in pre-malignant cells and its role in the development of cancer, most notably glioblastoma.

Positions:

Associate Professor in Neurosurgery

Neurosurgery
School of Medicine

Associate Professor in Pathology

Pathology
School of Medicine

Associate Professor in Pediatrics

Pediatrics, Children's Health Discovery Institute
School of Medicine

Associate Professor in Population Health Sciences

Population Health Sciences
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2011

Yale University School of Medicine

Grants:

Genetic Susceptibility to Pediatric Glioma in Individuals and Diverse populations

Administered By
Neurosurgery
Awarded By
University of Southern California
Role
Principal Investigator
Start Date
End Date

The role of rare and common variants in genetic predisposition to medulloblastoma

Administered By
Neurosurgery
Awarded By
Sontag Foundation
Role
Principal Investigator
Start Date
End Date

Genetic Susceptibility to pediatric Osteosarcoma and Interaction with Measures of Childhood Growth

Administered By
Neurosurgery
Awarded By
Alex's Lemonade Stand
Role
Principal Investigator
Start Date
End Date

Immune Correlates and Mechanisms of Perinatal Cytomegalovirus Infection and Later Life ALL Development

Administered By
Pediatrics, Children's Health Discovery Institute
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Genetic Susceptibility to Pediatric Glioma in Individuals and Diverse populations

Administered By
Neurosurgery
Awarded By
University of Southern California
Role
Principal Investigator
Start Date
End Date

Publications:

Assisted reproductive technology and association with childhood cancer subtypes

<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Objectives</jats:title><jats:p>Use of assisted reproductive technology (ART) may alter the typical course of fetal development. We sought to investigate the association between ART use and childhood cancer subtype.</jats:p></jats:sec><jats:sec><jats:title>Study design</jats:title><jats:p>We surveyed 1701 parents of children with cancer about ART use, demographics, and gestational and perinatal factors. Multivariable logistic regression modeled the association between ART use and childhood cancer subtypes, birthweight and multiple gestation status.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Among childhood cancer patients, ART use was highest among children with osteosarcoma (OR=2.81; 95% CI=1.2-6.4; P=0.01). ART use was also elevated among children with hepatoblastoma, and this relationship appeared mediated by low birthweight. No specific type of ART appeared to drive these associations. Low birthweight was itself strongly associated with increased hepatoblastoma risk, even after adjustment for ART use, multiple gestation status, sex, and parental income (P&lt;0.001). Birthweight was higher in patients with germ cell tumors (P=0.02) and with neuroblastoma (P=0.06). Multiple gestation status was associated with neuroblastoma among females (OR=3.6, 95% CI=1.2-10.5, P=0.02), but not among males (OR=0.97, 95% CI=0.27-3.4, P=0.96) (P<jats:sub>interaction</jats:sub>=0.02).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Associations between ART use and hepatoblastoma risk may be mediated by birthweight, a strong hepatoblastoma risk factor that was replicated in our study. ART use may also be associated with osteosarcoma independent of birthweight, an association not previously observed in studies limited to cancers diagnosed before adolescence. Evaluating long-term health outcomes in children conceived by ART, throughout adolescence and potentially into adulthood, appears warranted.</jats:p></jats:sec>
Authors
Gulrajani, NB; Montes, S; McGough, D; Wimberly, CE; Khattab, A; Semmes, EC; Towry, L; Cohen, JL; Hurst, JH; Landi, D; Hill, SN; Walsh, KM
MLA Citation
Gulrajani, Natalie B., et al. Assisted reproductive technology and association with childhood cancer subtypes. Cold Spring Harbor Laboratory. Crossref, doi:10.1101/2021.04.26.21256117.
URI
https://scholars.duke.edu/individual/pub1481197
Source
crossref
DOI
10.1101/2021.04.26.21256117

Genetic variation associated with childhood and adult stature and risk of MYCN-amplified neuroblastoma.

BACKGROUND: Neuroblastoma is the most common pediatric solid tumor. MYCN-amplification is an important negative prognostic indicator and inherited genetic contributions to risk are incompletely understood. Genetic determinants of stature increase risk of several adult and childhood cancers, but have not been studied in neuroblastoma despite elevated neuroblastoma incidence in children with congenital overgrowth syndromes. METHODS: We investigated the association between genetic determinants of height and neuroblastoma risk in 1538 neuroblastoma cases, stratified by MYCN-amplification status, and compared to 3390 European-ancestry controls using polygenic scores for birth length (five variants), childhood height (six variants), and adult height (413 variants). We further examined the UK Biobank to evaluate the association of known neuroblastoma risk loci and stature. RESULTS: An increase in the polygenic score for childhood stature, corresponding to a ~0.5 cm increase in pre-pubertal height, was associated with greater risk of MYCN-amplified neuroblastoma (OR = 1.14, P = .047). An increase in the polygenic score for adult stature, corresponding to a ~1.7 cm increase in adult height attainment, was associated with decreased risk of MYCN-amplified neuroblastoma (OR = 0.87, P = .047). These associations persisted in case-case analyses comparing MYCN-amplified to MYCN-unamplified neuroblastoma. No polygenic height scores were associated with MYCN-unamplified neuroblastoma risk. Previously identified genome-wide association study hits for neuroblastoma (N = 10) were significantly enriched for association with both childhood (P = 4.0 × 10-3 ) and adult height (P = 8.9 × 10-3 ) in >250 000 UK Biobank study participants. CONCLUSIONS: Genetic propensity to taller childhood height and shorter adult height were associated with MYCN-amplified neuroblastoma risk, suggesting that biological pathways affecting growth trajectories and pubertal timing may contribute to MYCN-amplified neuroblastoma etiology.
Authors
Semmes, EC; Shen, E; Cohen, JL; Zhang, C; Wei, Q; Hurst, JH; Walsh, KM
MLA Citation
Semmes, Eleanor C., et al. “Genetic variation associated with childhood and adult stature and risk of MYCN-amplified neuroblastoma.Cancer Med, vol. 9, no. 21, Nov. 2020, pp. 8216–25. Pubmed, doi:10.1002/cam4.3458.
URI
https://scholars.duke.edu/individual/pub1460895
PMID
32945147
Source
pubmed
Published In
Cancer Medicine
Volume
9
Published Date
Start Page
8216
End Page
8225
DOI
10.1002/cam4.3458

Impacts of COVID-19 on caregivers of childhood cancer survivors.

PURPOSE: We sought to assess the impact of disruptions due to coronavirus disease 2019 (COVID-19) on caregivers of childhood cancer survivors. METHODS: A 13-question survey containing multiple-choice, Likert-type, and free-text questions on experiences, behaviors, and attitudes during the COVID-19 outbreak was sent to childhood cancer caregivers and completed between April 13 and May 17, 2020. Ordered logistic regression was used to investigate relationships between demographics, COVID-related experiences, and caregiver well-being. RESULTS: Caregivers from 321 unique families completed the survey, including 175 with children under active surveillance/follow-up care and 146 with children no longer receiving oncology care. Overall, caregivers expressed exceptional resiliency, highlighting commonalities between caring for a child with cancer and adopting COVID-19 prophylactic measures. However, respondents reported delayed/canceled appointments (50%) and delayed/canceled imaging (19%). Eleven percent of caregivers reported struggling to pay for basic needs, which was associated with greater disruption to daily life, greater feelings of anxiety, poorer sleep, and less access to social support (p < .05). Caregivers who were self-isolating reported greater feelings of anxiety and poorer sleep (p < .05). Respondents who expressed confidence in the government response to COVID-19 reported less disruption to their daily life, decreased feelings of depression and anxiety, better sleep, and greater hopefulness (p < .001) CONCLUSIONS: Caregivers are experiencing changes to medical care, financial disruptions, and emotional distress due to COVID-19. To better serve caregivers and medically at-risk children, clinicians must evaluate financial toxicity and feelings of isolation in families affected by childhood cancer, and work to provide reliable information on how COVID-19 may differentially impact their children.
Authors
Wimberly, CE; Towry, L; Caudill, C; Johnston, EE; Walsh, KM
MLA Citation
Wimberly, Courtney E., et al. “Impacts of COVID-19 on caregivers of childhood cancer survivors.Pediatr Blood Cancer, vol. 68, no. 4, Apr. 2021, p. e28943. Pubmed, doi:10.1002/pbc.28943.
URI
https://scholars.duke.edu/individual/pub1473732
PMID
33565259
Source
pubmed
Published In
Pediatr Blood Cancer
Volume
68
Published Date
Start Page
e28943
DOI
10.1002/pbc.28943

The genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis.

Down syndrome is associated with genome-wide perturbation of gene expression, which may be mediated by epigenetic changes. We perform an epigenome-wide association study on neonatal bloodspots comparing 196 newborns with Down syndrome and 439 newborns without Down syndrome, adjusting for cell-type heterogeneity, which identifies 652 epigenome-wide significant CpGs (P < 7.67 × 10-8) and 1,052 differentially methylated regions. Differential methylation at promoter/enhancer regions correlates with gene expression changes in Down syndrome versus non-Down syndrome fetal liver hematopoietic stem/progenitor cells (P < 0.0001). The top two differentially methylated regions overlap RUNX1 and FLI1, both important regulators of megakaryopoiesis and hematopoietic development, with significant hypermethylation at promoter regions of these two genes. Excluding Down syndrome newborns harboring preleukemic GATA1 mutations (N = 30), identified by targeted sequencing, has minimal impact on the epigenome-wide association study results. Down syndrome has profound, genome-wide effects on DNA methylation in hematopoietic cells in early life, which may contribute to the high frequency of hematological problems, including leukemia, in children with Down syndrome.
Authors
Muskens, IS; Li, S; Jackson, T; Elliot, N; Hansen, HM; Myint, SS; Pandey, P; Schraw, JM; Roy, R; Anguiano, J; Goudevenou, K; Siegmund, KD; Lupo, PJ; de Bruijn, MFTR; Walsh, KM; Vyas, P; Ma, X; Roy, A; Roberts, I; Wiemels, JL; de Smith, AJ
MLA Citation
Muskens, Ivo S., et al. “The genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis.Nat Commun, vol. 12, no. 1, Feb. 2021, p. 821. Pubmed, doi:10.1038/s41467-021-21064-z.
URI
https://scholars.duke.edu/individual/pub1473803
PMID
33547282
Source
pubmed
Published In
Nature Communications
Volume
12
Published Date
Start Page
821
DOI
10.1038/s41467-021-21064-z

Associations between genetic variants of KIF5B, FMN1, and MGAT3 in the cadherin pathway and pancreatic cancer risk.

Because the cadherin-mediated signaling pathway promotes cancer progression, we assessed associations between genetic variants in 109 cadherin-related genes and risk of pancreatic cancer (PanC) by using genotyping data from publically available genome-wide association studies (GWAS) datasets comprising 15,423 individuals of European ancestry. After initial single-locus analyses and subsequent meta-analysis with multiple testing correction for 29,963 single-nucleotide polymorphisms (SNPs), 11 SNPs remained statistically significant (p < 0.05). In the stepwise logistic regression analysis, three independent PanC risk-associated SNPs (KIF5B rs211304 C > G, FMN1 rs117648907 C > T, and MGAT3 rs34943118 T > C) remained statistically significant (p < 0.05), with odds ratios of 0.89 (95% confidence interval = 0.82-0.95 and p = 6.93 × 10-4 ), 1.33 (1.13-1.56 and 2.11 × 10-4 ), and 1.11 (1.05-1.17 and 8.10 × 10-5 ), respectively. Combined analysis of unfavorable genotypes of these three independent SNPs showed an upward trend in the genotype-risk association (ptrend  < 0.001). Expression quantitative trait loci analyses indicated that the rs211304 G and rs34943118 C alleles were associated with increased mRNA expression levels of KIF5B and MGAT3, respectively (all p < 0.05). Additional bioinformatics prediction suggested that these three SNPs may affect enhancer histone marks that likely have an epigenetic effect on the genes. Our findings provide biological clues for these PanC risk-associated SNPs in cadherin-related genes in European ancestry populations, possibly by regulating the expression of the affected genes. However, our findings need to be validated in additional population, molecular and mechanistic investigations.
Authors
Zhao, L; Liu, H; Luo, S; Moorman, PG; Walsh, KM; Li, W; Wei, Q
MLA Citation
Zhao, Lingling, et al. “Associations between genetic variants of KIF5B, FMN1, and MGAT3 in the cadherin pathway and pancreatic cancer risk.Cancer Med, vol. 9, no. 24, Dec. 2020, pp. 9620–31. Pubmed, doi:10.1002/cam4.3603.
URI
https://scholars.duke.edu/individual/pub1465304
PMID
33200553
Source
pubmed
Published In
Cancer Medicine
Volume
9
Published Date
Start Page
9620
End Page
9631
DOI
10.1002/cam4.3603