Genomic patterns in patients with early-onset colorectal cancer (CRC) vary by race and ethnicity, according to a presentation at the 2021 AACR Virtual Special Conference: Colorectal Cancer.1

The findings highlight the need for additional research into genetic and social factors that contribute to racial and ethnic disparities in early-onset CRC, according to Andreana N. Holowatyj, PhD, of Vanderbilt University Medical Center in Nashville, Tennessee, who presented the research at the meeting.

There is urgent interest in early-onset CRC because its incidence has risen by about 1.3% per year in the past 3 decades.2 In 2020, 12% of CRC diagnoses and 7% of deaths were expected in people who were younger than 50 years of age when they were diagnosed.

Continue Reading

Distinct Biology of Early-Onset CRC

Research has shown biological differences between early-onset and later-onset CRC. In a review of more than 36,000 CRC patients, early-onset CRCs demonstrated more aggressive clinical behavior than later-onset CRCs.3

Patients with early-onset CRC were more likely to have tumors in the distal colon or rectum, synchronous metastatic disease, microsatellite instability, and fewer BRAF V600 mutations than CRC patients who were at least 50 years old at diagnosis.

Patients who were younger than 30 years at diagnosis had additional histologic and molecular patterns, including signet ring histology, in comparison with those who were 30 years or older at diagnosis. 

In a prior study, Dr Holowatyj and colleagues showed that patients with early-onset CRC whose tumors were microsatellite stable had alterations in oxidative stress response and redox homeostasis that differed from what the researchers observed in patients diagnosed at older ages.4 Moreover, the imbalances in antioxidant defense mechanisms could be correlated with changes in inflammatory biomarkers.

Differences by Race/Ethnicity

Research has shown a disproportionate burden of early-onset CRC among non-White individuals.5 For example, the proportion of early-onset CRC cases was shown to be nearly 2-fold higher in non-White individuals.

The disproportionate burden among various racial and ethnic populations may partly reflect changing demographics across the United States, according to Dr Holowatyj. However, clinical outcomes differentiate racial and ethnic groups of patients with early-onset CRC from one another.

In SEER registry data, early-onset CRC survival was significantly shorter in non-Hispanic Black patients than in White patients, even for patients with the earliest stages of disease and when data were adjusted for age, poverty, sex, surgical procedure, and radiation therapy.6

The adjusted survival curves were similar for non-Hispanic White patients and Hispanic patients with stage II colon cancer, despite the similar socioeconomic status of Hispanic and non-Hispanic Black individuals in the United States.

At least in part, these disparities may relate to distinct genomic patterns by racial and ethnic groups.

Unique Genomic Patterns

To identify genetic differences by race/ethnicity, Dr Holowatyj’s lab performed genomic analysis on tumor specimens from 6120 CRC patients from 12 centers in the Genomics Evidence Neoplasia Information Exchange (GENIE) registry.1

Patients were between the ages of 18 and 89 years when their tumors were sequenced. More than 90% of patients (n=5475) had microsatellite-stable disease, and 28.8% (n=1761) had early-onset CRC.

In models adjusted for sex, race, histology and site, sequencing assay, sample type, and tumor mutation burden, early-onset CRC patients had a distinct genomic landscape from older-onset CRC patients. 

The early-onset patients had significantly higher odds of presenting with non-silent variations in LRP1B, DOCK8, TP53, and TCF7L2 and significantly lower odds of presenting with non-silent variations in KDR and WRN.