Traditionally, right-sided colorectal cancer (CRC) — i.e., malignancy originating in the proximal colon — features a biology characterized by DNA hypermethylation and high levels of microsatellite instability (MSI) when a DNA mismatch-repair gene is methylated.
Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services Policy
In contrast, left-sided (distal) CRC has been defined predominantly by mutations in tumor suppressor genes and proto-oncogenes, resulting in chromosomal-unstable, aneuploidy cancers.
Intriguing new research conducted by Cleveland Clinic has found that CRC in African Americans tends to be right-sided, but arises through the chromosomal instability (CIN) molecular pathway rather than through MSI and hypermethylation. This unique biology may explain why African American CRC patients are less responsive to immune therapy and have a worse prognosis than Caucasians.
“We set out to prove that the predilection for proximal tumors in African Americans was due to unusually early development of BRAF variants and DNA hypermethylation in the right colon, but this study failed to confirm our hypothesis,” says Digestive Disease & Surgery Institute colorectal surgeon James Church, MB, ChB, principal author of the research presented at the 2019 annual scientific meeting of the American Society of Colon and Rectal Surgeons. “Rather, our findings suggest that CRC in African Americans is different than that in Caucasians.”
Not all parts of the large intestine are the same
Colorectal tumor sidedness is a complex and incompletely understood phenomenon. It likely is influenced by developmental and anatomical differences between the proximal and distal colon and exposure to varying bacteriological and biochemical environments.
Dr. Church and colleagues mined Cleveland Clinic’s Tumor Bank and identified CRC tissue samples from 47 African American patients obtained between 2000 and 2008. Samples from 90 Caucasian patients of similar ages were matched to the African American cohort.
All tissue samples previously had been analyzed for MSI, CpG island methylator phenotype (CIMP) and pathogenic variants in BRAF and KRAS. KRAS mutations are frequently observed in left-sided CRC patients with the CIN phenotype; BRAF mutations tend to occur in right-sided, high-MSI tumors. CIMP arises in the right colon in association with BRAF mutations and causes loss of expression of multiple genes.
The tissue samples were separated into three patient age groups (younger than 56 years, 56 to 70, and older than 70) and divided by tumor origin into right (proximal to descending colon) and left (distal to splenic flexure). In previous studies that did not account for racial differences, right-sided CRC was more prevalent in older patients, while left-sided CRC tended to occur at earlier ages.
When the Cleveland Clinic researchers compared the genotypes within each age group by tumor location, the results were surprising.
“Most African American patients had right-sided cancers, with the proportion not changing significantly with increasing age,” says Dr. Church.
“In young Caucasians, we find CRC mostly in the left side of the colon. As Caucasian patients age, both DNA methylation and right-sided cancers are increasingly common. This is not seen in African Americans. In young Caucasians, the left side of the large bowel is the high-risk zone, while in African Americans of any age it is the right side.”
Although most CRCs in African Americans are right-sided, they are not MSI or CIMP, but generally microsatellite-stable (MSS). The analysis found that 38% of African Americans aged 56 or younger had KRAS-mutant CRCs, compared with 25% of Caucasians. Among African American patients ages 56-70, KRAS-mutant cancers increased to 50%.
“Methylated and MSI-high cancers respond well to immune therapy, sometimes in an almost miraculous way,” Dr. Church says. “Patients have come with stage 4 CRC and walked out of the hospital cancer-free. African Americans have hardly any of these types of tumors, which negates the utility of immune therapy for them,” he says.
A Baffling Issue
Dr. Church, the Emeritus Director of Cleveland Clinic’s Sanford R. Weiss, MD, Center for Hereditary Colorectal Neoplasia, has dedicated his career to minimizing the impact of CRC. He conceived the current study to better understand why African Americans tend to develop CRC at a younger age and have a worse prognosis.
It was a logical step from his previous investigation into the connection between tumor location and biology in younger patients that Consult QD reported last year.
“Only 10 percent of CRCs occur under age 50, but it’s a devastating scenario. I’ve seen several patients in their early 30s die from it,” he says. “Quite often, they present with rectal bleeding, only to be told it’s due to hemorrhoids. By the time they come to us, their cancer is advanced, and we can’t do anything for them.”
Message to Clinicians
Now that the biology of CRC in African Americans is known to be different than in Caucasians, clinicians can take two steps to save lives.
“Start screening your African American patients at age 45. Don’t wait until age 50,” says Dr. Church.
“Additionally, since two-thirds of CRCs in African Americans are right-sided, screening with flexible sigmoidoscopy is insufficient because it only visualizes the distal colon. You have to look at the entire colon with a colonoscopy.”