Field of Genes: Hispanic Children and ALL

Eight-year-old Johan Antigua is a switch-hitting, hard-throwing shortstop with a major-league smile. His love of baseball stems from an early age. The youngest of five ball-playing brothers, he took his first steps on a baseball diamond. It’s no surprise that he’s most at home at the ballpark. Since January 2018, however, he’s been a spectator, unable to join his team on the field.

In December 2017, Johan’s mother, Jessica, grew concerned when he developed fever, a dry cough and a swollen face. Johan soon recovered, but the symptoms returned a few weeks later during a January baseball practice. Jessica took him to the hospital immediately, where physicians initially diagnosed lymphoma. A few days later, further tests revealed that Johan had acute lymphoblastic leukemia (ALL), the most common childhood cancer.

“The first thing I thought was that I was going to lose him,” Jessica says. “When you hear the word cancer, you think the worst.”

Johan was referred to St. Jude Children’s Research Hospital, where his clinicians explained the course of treatment: two-and-a-half years of chemotherapy. He’s currently approaching the midway point of therapy.

Johan, who is of Puerto Rican descent, is the first member of his family to have pediatric cancer. Because of his Hispanic ethnicity, Johan may have had a higher risk of developing ALL. Researchers at St. Jude are trying to find out why.

Full count

For the past decade, St. Jude scientists have examined racial disparities in children with ALL. Jun J. Yang, PhD, of St. Jude Pharmaceutical Sciences, has looked at gene variations to explore why Hispanic children have an increased risk of leukemia. The most recent study from his lab is one of the largest efforts yet focused on Hispanic patients with ALL.

Researchers found a new gene associated with an increased risk in these children. The gene, ERG, was already known to play a role in childhood leukemia.

“We looked at the entire genome, and out of the 20,000-plus genes sequenced, ERG emerged as the one at the top in the Hispanic population,” Yang says.

High-risk variations in ERG were associated with a 1.56-fold increased risk of ALL in Hispanic children.

Although the individual risk remains low, Yang says the finding shows that abnormalities in ERG are critical for the development of this cancer.

On deck

One of the challenges researchers faced when studying why Hispanic patients are more likely to develop ALL is the diverse makeup of the population. Hispanic children come from many geographical areas, but they still have the highest incidence of this cancer in the U.S. and are less likely than other children with ALL to survive.

In the study, Hispanic ethnicity was defined as having more than 10 percent Native American genetic ancestry. Yang and his colleagues confirmed previous findings that variations in three other genes — ARID5B, GATA3 and PIP4K2A — were more common in Hispanic children and were linked with an increased chance of developing ALL.

The risk was highest for children with the highest percentage of Native American ancestry. Scientists found no significant increase in the ALL risk of African-American children with the high-risk ERG variations and a small increase in children of European ancestry.

That was surprising, because for previously discovered leukemia genes, the effects on ALL genetic risk have usually been consistent across ancestries.

“St. Jude has taken a comprehensive and genomic approach to look into the biology behind the racial disparities in this disease,” Yang says. “In terms of looking at ALL in Hispanics, I think we are at the forefront of scientific discovery.”

Extra innings

Researchers collaborated with the Children’s Oncology Group and scientists from 15 other institutions in the U.S. and Guatemala. Through the new St. Jude Global program, the institution has partnerships in Central and South America to further study Hispanic populations with ALL. Additional research is needed to determine whether environmental or other factors might trigger ERG to cause cancer more often in these children.

“We are looking into performing genomic research in those populations, not only to have a better understanding of the biology of ALL, but to identify factors that might improve treatment outcomes for Hispanic patients and children with high Native American ancestry everywhere in the world,” Yang said.

That’s good news for children like Johan, who is interested in returning to the activities and games he loves.

“His coaches and teammates have been asking about him,” Jessica says. “He’s used to being active, and he just wants to play baseball again.”