Genes May Predict Cancer Patients at Risk of Chemo Brain

In a study published in the Journal of Clinical Oncology, researchers found associations between global cognitive impairment in patients with hematologic malignancies treated with blood or marrow transplantation (BMT) and genetic mechanisms that influence DNA repair, BBB, and telomere homeostasis.¹

Additionally, significant single nucleotide polymorphisms (SNPs) were found to enhance the risk prediction model performance beyond standard demographic and clinical factors.

“A better understanding of post-BMT health care needs could result in targeted strategies that yield better quality of survival and reduced utilization of health care resources,” senior author Smita Bhatia, MD, MPH, from the University of Alabama at Birmingham’s (UAB) Institute for Cancer Outcomes and Survivorship, said in a press release.²

In a discovery cohort of 277 subjects, BMT recipients underwent a standardized battery of neuropsychological tests pre-BMT and at 6 months, 1 year, 2 years, and 3 years post-BMT. Associations between 68 candidate genes and cognitive impairment were then assessed using generalized estimating equation models.

Researchers used Elastic-Net regression to build Base (sociodemographic), Clinical, and Combined (Base plus Clinical plus genetic) risk prediction models of post-BMT impairment. Additionally, an independent nonoverlapping cohort from the BMT Survivor Study with self-reported data of learning and memory problems as identified by their health care provider was utilized for model replication. 

Of those in the discovery cohort, 46.6% were allogeneic BMT recipients. Adjusting for BMT type, age at BMT, sex, race and ethnicity, and cognitive reserve, SNPs in the blood-brain barrier, telomere homeostasis, and DNA repair genes were found to be significantly associated with cognitive impairment. Compared with the Clinical Model, the Combined Model had higher predictive power in both the discovery cohort (mean area under the receiver operating characteristic curve ([AUC], 0.89; 95% CI, 0.85-0.93 vs 0.77; 95% CI, 0.71-0.83; P = 1.24 3 1029) and the replication cohort (AUC, 0.71; 95% CI, 0.66-0.76 vs 0.63; 95% CI, 0.57-0.68; P = .004). 

“The cost of SNP testing technologies is declining steadily,” first author Noha Sharafeldin, MD, PhD, assistant professor in the UAB School of Medicine’s Division of Hematology and Oncology, said in a press release. “What we envision is a custom array with a few selected SNPs that can help us in the clinic in addition to the other information we already collect. Incorporating SNPs in a risk prediction model can enable a more informed clinical decision-making process.”

However, the researchers indicated that they used a candidate gene approach, which may have limited identifying novel associations. Because of this, SNP-set refinement may be necessary in future studies. Additionally, the difference in the measurement of cognitive impairment between the discovery and replication cohorts was another notable limitation. Nonetheless though, these findings overall would likely be of more potential clinical or public health relevance than examining single factors. 

“This study represents a first step toward identification of BMT survivors at high risk for cognitive impairment, informing personalized management of cognitive outcomes in patients undergoing BMT,” the authors wrote.

References:

1. Sharafeldin N, Richman J, Bosworth A, et al. Clinical and Genetic Risk Prediction of Cognitive Impairment After Blood or Marrow Transplantation for Hematologic Malignancy. Journal of Clinical Oncology. doi:10.1200/JCO.19.01085.

2. Genes may predict cancer patients at highest risk of chemo brain after BMT [news release]. Birmingham, Alabama. Published March 10, 2020. uab.edu/news/research/item/11167-genes-may-predict-cancer-patients-at-highest-risk-of-chemo-brain-after-bmt. Accessed March 17, 2020.