Molecular characteristics of early-onset colorectal cancer appear to vary by race
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Black patients with early-onset, microsatellite-stable colorectal cancer had substantially higher tumor mutational burden than their white counterparts, according to study results.
The findings, presented during the virtual American Association for Cancer Research Annual Meeting, also showed that early-onset colorectal cancer tumors of Black patients were more likely to have non-silent mutations in CREBBP and TGFBR2 than late-onset colorectal cancer tumors.
“The incidence of early-onset colorectal cancer among adults younger than age 50 years has been increasing during the past several decades, both in the U.S. and countries worldwide, with causes unexplained,” Andreana N. Holowatyj, MS, PhD, assistant professor of medicine and cancer biology at Vanderbilt University School of Medicine and Vanderbilt-Ingram Cancer Center, told Healio. “Disparities in early-onset colorectal cancer across diverse population subgroups have grown more pronounced. Yet, in the absence of studies that explore the biology of early-onset colorectal cancer across these groups, our understanding of the molecular mechanisms underpinning early-onset colorectal cancer disparities remains limited.”
For this reason, Holowatyj and colleagues sought to characterize unique somatic mutation patterns by race among 6,120 patients with colorectal cancer (mean age, 57.1 years; standard deviation, 13.1 years) included in AACR Project GENIE database — a publicly accessible international cancer registry of real-world data from 12 worldwide institutions.
The final cohort for the current analysis included 133 Black, 144 Asian or Pacific Islander and 1,315 white patients with early-onset colorectal cancer and 3,883 patients with late-onset colorectal cancer.
After excluding 500 patients with hypermutated colorectal cancers, researchers found that patients with early-onset colorectal cancer had 5.6 mutations/megabase [Mb] compared with 6.2 mutations/Mb among cases of late-onset disease. In addition, Black patients with early-onset disease had significantly higher tumor mutational burden than white patients (P = .02), with no differences observed between Asian/Pacific Islander patients and white patients.
After adjusting for sex, race, histology, sequencing assay, sample type and tumor mutational burden, young patients with early-onset non-hypermutated colorectal cancer had significantly higher odds of presenting with non-silent mutations in TP53 (OR = 1.26; 95% CI, 1.09-1.45) and SMAD2 (OR = 1.69; 95% CI, 1.19-2.4) and lower odds of presenting with non-silent mutations in KDR (OR = 0.6; 95% CI, 0.38-0.95) and FLT4 (OR = 0.56; 95% CI, 0.33-0.94) than those with late-onset non-hypermutated disease.
Researchers observed mutational heterogeneity in TGFBR2 (P = .003) and NOTCH1 (P = .02) between patients with early-onset and late-onset colorectal cancer.
Analysis by race revealed distinct genomic patterns of early-onset disease, including frequencies of TGFBR2 (P = .0001) and NOTCH1 (P = .02) mutations, according to researchers.
Black patients with early-onset colorectal cancer appeared four times more likely to have non-silent mutations in CREBBP and more likely to have non-silent mutations in TGFBR2 (OR = 61.37; 95%CI, 2.24-1,680.45) than Black patients who had late-onset colorectal cancer tumors.
Asian patients with early-onset disease were 48% less likely to present with non-silent mutations in APC, 66% less likely to present with non-silent mutations in PIK3CA and 4.7 times more likely to have non-silent mutations in FAT1 than Asian patients with late-onset disease. They also had six times higher odds of presenting with non-silent mutations in NOTCH1 (OR = 6.26; 95% CI, 1.32-29.68).
White patients with early-onset vs. late-onset non-hypermutated colorectal cancer had higher odds of SMAD2 (OR = 1.88; 95% CI, 1.28-2.78) and TP53 (OR = 1.25; 95% CI, 1.06-1.48) mutations but decreased odds of FLT4 mutations (OR = 0.56; 95% CI, 0.32-0.99).
“The higher tumor mutational burden among young Black patients with microsatellite-stable colorectal cancer yields potential clinical relevance upon validation,” Holowatyj said. “There is potential to target distinct molecular features via therapeutic modalities, which could facilitate precision medicine and close the gaps in health disparities among young patients diagnosed with colorectal cancer.”
Although this study identified potential biological determinants in early-onset colorectal cancer, it is important to consider that race is a social construct and that distinct early-onset colorectal cancer patterns across diverse population subgroups reflect a complex interplay of biology, genetics, behaviors and social determinants of health, Holowatyj added.
“We plan to validate our findings in cohorts with available data on genetic ancestry, investigate whether these genomic differences are associated with prognostic outcomes and leverage a multi-omics approach in characterizing the biology of early-onset colorectal cancer disparities,” Holowatyj said. “We also plan to translate this work into the laboratory setting and study the molecular pathways affected by these mutations using patient-derived models.”
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Holowatyj AN, et al. Abstract 101. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.
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