Limited Diversity in Genomic Datasets May Impact Cancer Outcomes

March 24, 2021 - Limited diversity in genomic datasets may affect therapy selection and cancer outcomes for black patients, a study published in npj Precision Oncology revealed.

Researchers noted that clinicians use biomarkers, or indicators of a disease or condition, to determine whether patients might benefit from immunotherapy. One of those biomarkers is tumor mutation burden, the number of mutations within a tumor compared to normal cells.

Often when clinicians calculate the tumor mutation burden, they don’t use normal cells, so providers use genomic databases of mutations or algorithms to filter results.

The research team collected data from 701 patients who were newly diagnosed with multiple myeloma, including 575 self-reported white patients and 126 self-reported black patients. The group analyzed DNA from patients’ tumor cells and healthy cells to examine the differences.

Researchers paired tumor and germline exome sequencing data to analyze differences between the two sources of DNA, and then used public datasets to filter mutation variants from the tumor sequencing data.

"Currently, the FDA has approved a threshold of more than ten mutations per megabase of DNA to select patients to receive immunotherapy," said Yan Asmann, PhD, a Mayo Clinic bioinformatician and first author of the study.

Immunotherapy with immune checkpoint inhibitors – a type of drug that blocks proteins called checkpoints – helps the body recognize and attack cancer cells. This treatment has drastically improved patient survival with many types of cancer.

However, because the autoimmune toxicities with these inhibitors can be severe, it’s critical to have an accurate tumor mutational burden as a biomarker to improve the ability to predict the optimal treatment for patients. Tumor mutational burden is determined by counting the number of changes in the DNA of a patient’s tumor.

"Determining tumor mutation burden becomes difficult when you do not have DNA from a patient's normal cells," said Aaron Mansfield, MD, a Mayo Clinic medical oncologist and corresponding author of the paper. "For this reason, reference genomes are used for comparisons to tumors to estimate the burden."

Researchers were concerned that this type of approach to determining tumor mutation burden was inaccurate, especially in patients with ancestral backgrounds that aren’t well-represented in reference genomic databases.

"At the level of an individual patient, our findings suggest that when we sequence tumors, it is also important to sequence paired normal tissues to accurately identify differences," said Mansfield. "At the level of the research community, we need to continue to improve the representation of patients with diverse ancestral backgrounds in reference genome databases."

The results showed that tumor mutation burden was significantly inflated in black patients compared to white patients. The findings demonstrate that clinicians who use public genomic databases need to be aware of the potential for inflated tumor mutation burden values. Providers should also consider how these values may impact therapy selection and outcomes, particularly in patients from underrepresented groups.

Additionally, the team noted that accurate tumor mutational burden is especially important in cancers currently treated with immune checkpoint inhibitors, including breast, colon, bladder, cervical, head and neck, liver, lung, renal cell, stomach, and rectal cancers; as well as Hodgkin lymphoma, melanoma, and any other solid tumor that is not able to repair errors during DNA replication.

"It needs to be recognized that we performed this proof-of-principle study in patients with multiple myeloma. However, the findings of racially disparate tumor mutation burden inflation might be generalizable to all cancer types," said Mansfield.

The team noted that the limited diversity of genomic research is well-known. Of more than 60,000 people genotyped and sequenced, only 8.6 percent are of African ancestry, while 54.9 percent are of non-Finnish European ancestry.

"Many investigators around the world are looking at ways to improve the ability to select patients to receive immunotherapy," said Mansfield. "We have identified a problem with one approach and have recommended a solution for it."