Genomic Differences by Race Emerge in Colorectal Cancer

Black, white, and Asian/Pacific Islander patients with early-onset colorectal cancer have different patterns of nonsilent mutations than their late-onset counterparts, researchers have reported. Additionally, within the early-onset population, Black patients had a significantly higher tumor mutation burden (TMB) than white patients. These findings, while preliminary, offer a glimpse of the biological basis of disparities—information that could eventually have therapeutic implications.

“Incidence rates of colorectal cancer among adults younger than age 50 years—also known as early-onset colorectal cancer—have continued to rise each year,” said Andreana Holowatyj, PhD, of the Vanderbilt-Ingram Cancer Center in Nashville, TN, who presented the findings during the first week of the virtual American Association for Cancer Research (AACR) Annual Meeting 2021, being held April 10–15. At the same time, disparities have emerged: The disease is almost twice as prevalent in people who aren't white, and Black patients fare significantly worse than their white counterparts. Thus, Holowatyj's team decided to investigate molecular differences that might underlie colorectal cancer disparities in younger adults.

The researchers analyzed genomic data from 5,475 patients with microsatellite-stable colorectal cancer in the AACR Project GENIE database, 1,592 of whom had early-onset disease. Patients were classified as non-Hispanic white, non-Hispanic Black, or Asian/Pacific Islander.

The team found that white patients with early-onset disease were more likely to have LRP1B, TP53, TCF7L2, DOCK8, SMAD2, and SMAD3 mutations than white patients with late-onset disease, and they were less likely to have KDR and FLT4 mutations. Black patients with early-onset cancer were four times more likely to have CREBBP mutations—and more likely to have TGFBR2 mutations—than those with late-onset cancer. Asian/Pacific Islander patients with early-onset disease were 48% and 66% less likely, respectively, to have APC and PIK3CA mutations, and were 4.7 times more likely to have FAT1 mutations than those with late-onset cancer.

Among all patients with early-onset disease, Black patients had a significantly higher TMB than white patients. Also, the frequency of LRP1B, TGFBR2, APC, and PIK3CA mutations varied by race/ethnicity.

“These findings suggest that there indeed are distinct genomic patterns of early-onset microsatellite-stable colorectal cancer by race,” Holowatyj said. However, validation is needed, she added—especially because the database lacks information on cancer stage, tumor grade, and survival. Additionally, future research should categorize patients based on genetic ancestry rather than self-identification of race/ethnicity.

Holowatyj and her team will begin delving into the mechanistic underpinnings of these genomic patterns, exploring how mutations affect the formation and progression of tumors.

“I think this study is really unique—it's outstanding work, and utilizes a great database,” said Christopher Lieu, MD, of the University of Colorado Cancer Center in Aurora, who was not involved in the research. The next step, he said, should be to link the genomic data with clinical outcomes such as survival.

He also noted that factors other than biology contribute to disparities, such as structural barriers to healthcare. “I see this as the launching pad for even deeper research into early-onset colorectal cancer, disparities in care, and what we can do to prevent this.”

Benjamin Weinberg, MD, of the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, found the higher TMB in Black patients with early-onset disease intriguing. “That has a lot of potential clinical relevance,” he said, noting that the PD-1 inhibitor pembrolizumab (Keytruda; Merck) is approved by the FDA for TMB-high solid tumors.

Weinberg, who was not connected to the research, would like to see studies move from genomics to multi-omics. “Are there differences in methylation patterns? The microbiome? Those are broader questions that we want to ask in similar patient populations.” –Catherine Caruso