Racial differences in genetic mutations were observed among patients with early-onset colorectal cancer, according to data presented by Andreana N. Holowatyj, PhD, MS, during the virtual American Association for Cancer Research (AACR) Annual Meeting 2021 (Abstract 101).

The incidence of early-onset colorectal cancer—defined as colorectal cancer diagnosed in adults younger than 50—has risen dramatically in recent decades, explained Dr. Holowatyj, an Assistant Professor of Medicine and Cancer Biology at the Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center.

“It’s quite striking that there has been, on average, a 1.5% increase in early-onset colorectal cancer incidence each year over the last 25 years or so,” she said. “It has burgeoned into a public health crisis and highlighted the need to understand the factors that may be contributing to the rise in cases.”

Andreana N. Holowatyj, PhD, MS

In a previous study published in the Journal of Clinical Oncology, Dr. Holowatyj and colleagues observed that Black patients—but not Hispanic patients—with early-onset colorectal cancer had a greater risk of death compared with White patients. Since Hispanic and Black populations often have similar socioeconomic situations, Dr. Holowatyj and colleagues hypothesized that underlying biologic factors, together with other complex factors, may contribute to the observed disparities in early-onset colorectal cancer.

Study Details

In the latest study, Dr. Holowatyj and colleagues utilized the AACR Project GENIE database, which is a publicly accessible international cancer registry of real-world data, to examine genetic data from the tumors of 6,120 patients with colorectal cancer, of whom 1,761 had early-onset colorectal cancer. Six hundred and forty-five tumors with microsatellite instability were excluded from the analysis, since this phenotype may be associated with inherited genetic mutations that could confound the results. The final sample included 133 non-Hispanic Black, 144 Asian or Pacific Islander, and 1,315 non-Hispanic White patients with early-onset colorectal cancer and 3,883 patients with late-onset colorectal cancer.

Differences Between Races

Although the researchers found no differences in tumor mutational burden between White and Asian/Pacific Islander patients with early-onset colorectal cancer, their analysis revealed that Black patients with early-onset colorectal cancer had significantly higher tumor mutational burden than White patients. Furthermore, distinct genetic mutations were observed among patients of different races.

Compared with the tumors of White patients with late-onset colorectal cancer, tumors from those with early-onset colorectal cancer were more likely to have nonsilent mutations (which lead to alterations in the protein product) in LRP1B, TP53, TCF7L2, DOCK8, SMAD2, and SMAD3, and less likely to have nonsilent KDR and FLT4 mutations after adjusting for sex, site and histology, sequencing assay, sample type, and tumor mutational burden. Among Black patients, early-onset colorectal cancer tumors were four times more likely to have nonsilent mutations in CREBBP and also more likely to have nonsilent mutations in TGFBR2 than tumors from Black patients with late-onset colorectal cancer. Tumors from Asian patients with early-onset colorectal cancer were 48% and 66% less likely to present with nonsilent mutations in APC and PIK3CA, respectively, and were 4.7 times more likely to have nonsilent mutations in FAT1 compared with those of Asian patients with late-onset colorectal cancer.

Moreover, different mutation frequencies in colorectal cancer among young patients across racial groups were observed for LRP1B, TGFBR2, APC, and PIK3CA.

Next Steps

Future research from Dr. Holowatyj and colleagues will explore how these differentially mutated genes may uniquely contribute to early-onset colorectal carcinogenesis. Using preclinical models, the researchers plan to study the molecular pathways that are affected by these different mutations to understand how tumor formation, progression, and treatment response may differ by race.

“This first-of-its-kind study revealed molecular differences in early-onset colorectal cancer by race,” said Dr. Holowatyj. “Although validation is needed, these findings may help us understand if molecular features of the tumor contribute to disparities in disease burden. In the long term, our findings could also help develop diagnostic and/or therapeutic biomarkers for early-onset colorectal cancer and could facilitate precision medicine for young patients.”

“The unique consortium of information found within the AACR Project GENIE database—including clinical-grade sequencing data, demographics, and other clinical data from around the world—provided us with sufficient cases to study this disease across diverse populations in a way that we would not be able to at individual institutions,” she added.

“While this study revealed potential biologic determinants of disparities in early-onset colorectal cancer, it is important to acknowledge that race is a social construct and this is just one piece of the puzzle,” Dr. Holowatyj noted. “Several complex and related factors, including genetic ancestry and systemic racism, also may contribute to such disparities.”

Limitations of the study include the lack of data on patient outcomes, genetic ancestry, and the tumors’ clinical features, such as stage and grade, as well as the small population of Hispanic individuals in the database, which precluded their inclusion in the analysis. An additional limitation was that age was defined as age at tumor sequencing in the database, rather than age at diagnosis. However, this would not be expected to alter the results of the study, according to Dr. Holowatyj. “Tumor sequencing occurs after diagnosis, so those who were under 50 years old at the time of sequencing and classified as having early-onset colorectal cancer would also have been younger than 50 years at diagnosis,” she explained.

Disclosure: This study was supported by the National Institutes of Health and the American Cancer Society. For full disclosures of the study authors, visit abstractsonline.com.