Study reveals unique features of early-onset colorectal cancer in racial and ethnic minorities

Colorectal cancer typically is diagnosed after age 50, but in recent years the disease has been increasingly found in younger people and disproportionately affecting racial and ethnic minorities.

In the current study published in Clinical Epigenetics, researchers at Baylor College of Medicine, University of California at Irvine and Ben Taub Hospital in Houston are the first to report molecular features of early onset colorectal cancer that are distinct from those in the late-onset form of the disease. The authors suggest that these unique features play a role in the disparity in cancer incidence and mortality among these patients.  

“In the clinic, we not only see more young people being diagnosed with an older person’s disease, but most are minority patients who present with an advanced condition and poor prognosis. We wondered, what is happening here?” said Dr. Karen Riggins, assistant professor of medicine – hematology and oncology at Baylor. “Literature research did not provide an explanation, so we conducted this study to try to find answers.”

“There is evidence supporting that the early and late-onset forms of colorectal cancer are different,” said co-corresponding author Dr. Lanlan Shen, professor of pediatrics – nutrition and member of the Dan L Duncan Comprehensive Cancer Center at Baylor.

The early onset form arises predominantly on the left side of the colon and is more aggressive. Approximately 80% of early onset cases are sporadic, meaning that no underlying genetic mutations have been found, and, in the United States, compared to Caucasians, the incidence of the early form has increased faster among Hispanics and African Americans with significantly lower five-year survival.

The causes of these disparities are unclear but given that most cases do not seem to have a genetic cause, the researchers proposed that environmental risk factors such as diet, stress and the gut microbiome are likely to contribute to the differences in incidence and mortality among races.

The team investigated how environmental influences could affect gene expression in ways that may lead to cancer without changing the underlying DNA sequence – epigenetic modification of genes. Epigenetic modification of genes refers to changes in molecular markings on DNA, such as addition or removal of methyl chemical groups, that tell cells in the body which genes to turn on or off. Turning off genes that protect from cancer or turning on others that promote cancer can tilt the balance in favor of the disease.

“Dysregulation of DNA methylation plays an important role in the colorectal cancer,” Shen said. “Our study is the first to conduct whole-genome DNA methylation profiling in early onset colorectal cancer samples. We analyzed cancerous and non-cancerous samples from patients with the early onset form of the disease and compared the results with those from late-onset colorectal cancer samples. We found that early onset cancer cells had acquired widespread changes in DNA methylation to activated tumor-promoting programs and repressed tumor-protective programs.”

The team identified epigenetic alterations in metabolic genes that are specific to the early onset colorectal cancers in their racial/ethnic minority cohort but not in Caucasian patients from the Cancer Genome Atlas (TCGA). Top genes differentially methylated between these cohorts included the obesity-protective MFAP2 gene as well as cancer risk susceptibility genes APOL3 11 and RNASEL.

“Although preliminary, this study is important because it generates high-quality whole genome information on racial and ethnic minority patients who are severely underrepresented in research studies. For example, more than 80% of patients included in TCGA are of European descent, whereas approximately 9% are African American,” Riggins said. “The lack of tumor biospecimens from underrepresented populations presents a major barrier to our understanding of diseases with disparities between racial and ethnic groups, such as early onset colorectal cancer.”

“Not only are we identifying clear differences between early onset and late-onset colorectal cancer, but we have also identified differences within minority populations and Caucasians,” Riggins said. “As a clinician, this study helps me make sense of what I see in the clinic. We are very excited about the findings.”

“Our exploratory findings in this cohort highlight epigenetic mechanisms underlying the emergence of early onset colorectal cancer. This is promising because it suggests that treatments directed at restoring methylation markers associated with the disease might have therapeutic value,” Shen said. “Our findings also help nominate novel biomarkers for this condition in underrepresented populations, which would tell us whether a patient is at higher risk for developing cancer or having a more aggressive form of the disease, which would inform the implementation of preventive interventions.”

The findings bring hope and direction to better understand this emerging condition and support that researchers continue these studies.

Other contributors to this work include co-first author Jason Sheng Li, Li Yang, Chaorong Chen, Patricia Castro, Wedad Alfarkh, Neda Zarrin-Khameh, Michael E. Scheurer, Chad J. Creighton, and co-corresponding authors Benjamin Musher and Wei Li. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, University of California at Irvine and Ben Taub Hospital in Houston.

The authors are grateful for a generous donation from the Walter Worth family. This work was also supported by grants from the National Institutes of Health (NIH) (R01CA233472, R01HD100914, R01CA261723, R01CA228140), the US Department of Agriculture (CRIS 444 3092-51000-060) and the National Cancer Institute of the NIH under award T32CA009054.