Research News

A Cleveland Clinic-led team has identified a spectrum of colorectal cancer features that could contribute to differences in therapeutic response and disease outcomes. Through improved understanding of the contribution of genetic ancestry to clinical features and prognosis of colorectal cancer, these Cancer Research findings advance individualized healthcare for all patients. 

The research was led by Stephanie Schmit, PhD, MPH, and a data scientist in her lab, Marco Matejcic, PhD, with colleagues at Cedars Sinai Medical Center (Jane Figueiredo, PhD) and H. Lee Moffitt Cancer Center and Research Institute (Jamie Teer, PhD). The analysis uses a unique colorectal cancer sequencing dataset assembled by the Latino Colorectal Cancer Consortium in combination with other public and institutional datasets. The consortium aims to improve colorectal cancer research through the inclusion of diverse U.S. populations that are generally underrepresented in cancer genomic studies. Because of the inclusion of Hispanic/Latino participants, Dr. Schmit and her team were able to more comprehensively study the tumor landscape and contributions of genetic ancestry than previous works. 

“Studying how genetic ancestry contributes to cancer helps everyone. The future of cancer treatment tailored to individual tumor profiles relies on how well we understand the spectrum of genomic and molecular changes involved in human cancer,” Dr. Schmit explains. “Limited data from certain populations means we may have an incomplete picture of these genomic changes.” 

How does understanding genetic ancestry improve individualized medicine? 

Personalized medicine in colorectal cancer targets defined genetic mutations that cause tumors to form. Identifying an individual's specific cancer-causing mutation(s) can be difficult. Although cancer cells have many genetic changes, not all of the mutations actually change the cells’ behavior. Sequencing efforts in recent years generated publicly available cancer-specific genome databases that help identify the genetic causes of cancer and how these genomic changes affect cancer outcomes. Gene mutations that consistently appear across many patients in the database are flagged and studied. 

Currently, the demographic makeup of these databases does not match the demographic makeup of patients in the U.S. For example, less than 3% of colorectal cancer data in The Cancer Genome Atlas (TCGA) comes from Hispanic/Latino patients, even though these individuals make up 20% of the U.S. population. The lack of data can pose significant challenges. 

“Anyone can carry any gene mutation no matter what their ancestry is,” Dr. Matejcic says. “But when a mutation is more common in a population with limited research, it may not show up in a database as often as it should. Physicians and researchers might confuse this lack of data for a lack of prevalence and dismiss the mutation as harmless.” 

To address this gap, Drs. Schmit and Matejcic, alongside a multi-institutional team of researchers and clinicians, analyzed sequencing data on tumors and paired normal samples from 718 individuals with colorectal cancer. Approximately 18% of these patients were of Hispanic/Latino ethnicity, much closer to the 20% real-world population. 

Identifying opportunities to improve gene testing for medication 

The team’s new dataset identified several ways in which genetic ancestry could contribute to colorectal cancer. 

“Given that Hispanic/Latino individuals in the US descend from multiple ancestral groups, this study helps us understand how genetic similarity to reference populations from specific geographic origins can influence the mutational landscape of colorectal cancer,” says Dr. Matejcic. 

For example, tumors from individuals with increased African genetic ancestry had increased mutation frequencies in the KNCN and TMEM184B genes. 

“Neither of these genes has ever been associated with colorectal cancer,” Dr. Matejcic says. “Further research in larger sample sizes is needed to validate these findings, but studying the biological mechanisms of these or other ancestry-associated mutations in tumors could help us identify drivers of cancer that may have been overlooked in studies conducted in primarily one population.” 

The team also found that patients with high Native American genetic ancestry had a significantly lower odds of having microsatellite instable (MSI-H) colorectal cancer tumors compared to those with low Native American genetic ancestry.   

“Differences in the frequency of MSI-H colorectal cancers across groups would have important implications for which patients are eligible for certain treatments, particularly immunotherapy,” says Dr. Schmit. “We need to continue investing in and exploring new therapies and ways to boost immune responses to tumors to better help patients from a wide variety of communities.” 

With more research, Dr. Schmit thinks these findings could eventually impact how an oncologist would prescribe a therapy. 

“This work was an interim analysis; we’re currently analyzing a larger set of sequencing data including hundreds more Hispanic/Latino participants to identify more genomic and molecular features of colorectal cancer,” she says. “We also have multiple other ongoing, connected projects that will help us understand the impact of genetic ancestry on immune and gene expression profiles.”