NCI Corner: Racial Differences in the Transcriptomes of Lung Tumors

Dr. Brid M. Ryan

Investigators at the National Cancer Institute (NCI) compared the transcriptional profiles of lung cancers from African American patients to those from white patients and identified molecular differences that may result in population differences in tumor biology. Researchers led by Brid M. Ryan, PhD, MPH, an investigator from the Laboratory of Human Carcinogenesis at the Center for Cancer Research, published their results in the journal of Clinical Cancer Research.1

Molecular differences between lung tumors in African American and white patients could lead to differences between these populations in risk and response to treatment. As more precision medicine oncology treatments are approved, understanding the molecular profiles of patients and tumors is becoming ever more important, but African American patients are still under-represented in clinical trials in oncology.

Dr. Ryan and her colleagues compared the expression levels of both protein coding messenger RNA (mRNA) and noncoding micro-RNA (miRNA) transcripts in tumor and lung samples from African American and white patients with NSCLC. Genes and miRNAs that were differentially expressed only in tumors from African American patients were enriched for those involved in stem cell and invasion pathways, a finding that Dr. Ryan noted is consistent with observations in other types of cancer in African American patients, including breast, colorectal, and prostate cancer.

Dr. Ryan told the IASLC Lung Cancer News, “Precision medicine is fundamentally about improving health outcomes by providing the most precise, molecular-based cancer diagnosis and matching it to the most effective, least toxic therapy.” To that end, she and her colleagues used a tool called the Connectivity Map to predict the effects that these transcriptional profiles would have on the response to various oncology drugs.2 Drug resistance was predicted in African American patients to 53 drugs that were expected to be effective in white patients, including irinotecan. The authors noted that several of these drugs, including betulinic acid, rosiglitazone, and adiphenine, target stem cell and invasion pathways.

In addition to drug responses, the authors analyzed the mRNA and miRNA profiles of the cancer samples to evaluate population differences in the immune infiltration of the tumor microenvironment. The data suggested that inflammatory marker profiles could vary between African American and white patients, but no difference was observed in the expression of the checkpoint inhibitor genes PD-L1 or PD-L2. Another checkpoint inhibitor gene, CTLA-4, was more highly expressed in tumors from African American patients, but the investigators could not determine whether expression was increased in tumor cells, infiltrating T cells, or both.

The authors are currently working on ways to test and validate potential differences in drug responses in preclinical models as a step toward exploring population differences in a clinical setting. They are also expanding their research into other aspects of tumor biology beyond mRNA and miRNA profiles. Their ultimate goal, Dr. Ryan said, “is to map [the molecular differences between tumor subtypes], understand [their effects], and then, as much as we can, leverage [that information] to improve lung cancer outcomes.” ✦

References:
1. Mitchell KA, Zingone A, Toulabi L, Boeckelman J, Ryan BM. Comparative Transcriptome Profiling Reveals Coding and Noncoding RNA Diff erences in NSCLC from African Americans and European Americans. Clin Cancer Res. 2017;23(23):7412-7425.

2. The Connectivity Map. Broad Institute website. clue.io/cmap. Accessed February 22, 2018