Biomarker Predicts Colon Cancer Risk in Ulcerative Colitis

Testing for somatic genomic copy number alterations (CNAs) in ulcerative colitis patients with low-grade dysplasia was able to predict risk of advanced neoplasia more accurately than other currently used pathological features, according to a retrospective case-control study.

Among 122 patients followed for approximately 5 years, those who progressed to advanced neoplasia had a significantly higher burden of CNAs in low-grade dysplasia samples compared with non-progressors (mean 16 vs 4, P=2×10^-6), reported Trevor Graham, PhD, of Barts Cancer Institute at Queen Mary University of London, and colleagues.

In a univariate analysis, the burden of CNAs was a “very significant” predictor of advanced neoplasia risk (HR 36.0, 95% CI 9.56-172.6), they noted in the journal Gut.

CNAs detected in low-pass whole genome sequencing data from low-grade dysplasia biopsies of patients with inflammatory bowel disease “very strongly predict future risk” of high-grade dysplasia and/or colorectal cancer, Graham and colleagues wrote, adding that “this genomic measurement adds significant prognostic value to the currently used clinicopathological variables.”

Low-pass whole genome sequencing is a cost-efficient approach that uses next-generation sequencing to reliably detect CNAs, they explained. The input can be minimal amounts of DNA (as low as 500 pg), the process is compatible with the highly-degraded DNA typically found in formalin-fixed paraffin-embedded blocks in hospital archives, and it does not require a matched patient-specific reference genome for copy number estimation.

“Further, genomic analysis by [low-pass whole genome sequencing] is the single most significant predictor of progression, exceeding the predictive value of any currently used single clinical-pathological feature. We consider this level of predictive power to be clinically useful to support risk-informed decision-making in this patient cohort,” they added.

Colitis-associated colorectal cancer is chronically underdiagnosed and overdiagnosed, Graham and colleagues noted. There is uncertainty about how to monitor and treat patients, who are often enrolled into endoscopic surveillance programs to detect early signs of cancer, namely dysplasia.

Patients with low-grade dysplasia have an approximately 30% chance of progressing to colorectal cancer at 10 years, and this level of risk is considered sufficient to offer prophylactic colon resection, the authors said. However, this surgery has risks, including the potential detrimental impact on quality of life due to an ileal-pouch anal anastomosis or a stoma.

Alternatively, patients can be offered watchful waiting, but this option comes with frequent colonoscopies and worries about cancer risk that also severely impact patients’ quality of life. Furthermore, patients and clinicians sometimes have different thresholds for tolerable cancer risk, and so the joint decision-making process about which route to follow can prove challenging, Graham and team noted.

“Ultimately, these decisions are made against the backdrop where more than two-thirds of colitis patients with resected LGD [low-grade dysplasia] are not actually at elevated risk of developing [colorectal cancer], and so any treatment for these patients is overtreatment,” they wrote. “Consequently, there is a major unmet need for accurate cancer risk stratification in colitis patients with LGD.”

For this study, Graham and colleagues used 270 low-grade dysplasia samples from 122 patients with ulcerative colitis, comprising a discovery cohort of 67 patients and a validation cohort of 55 patients. The researchers extracted DNA from baseline low-grade dysplasia lesions, and low-coverage whole genome sequencing was performed to detect CNAs. A survival analysis was conducted to evaluate CNAs as predictors of advanced neoplasia risk.

Patients were designated progressors if they had a diagnosis of advanced neoplasia in the approximate 5 years following diagnosis of low-grade dysplasia or non-progressors if they remained free of advanced neoplasia during follow-up.

Of the progressors, median age was 58 in the discovery cohort and 60 in the validation cohort; 59% and 72% were men. Of the non-progressors, median age was 60 and 62, respectively; 73% and 76% were men.

The discovery cohort consisted of patients exclusively from St. Mark’s Hospital in London, a specialist tertiary referral center with more complex and high-risk cases. The validation cohort was drawn from other major centers in the U.K. and also likely had more high-risk cases. Therefore, using the CNA biomarker in the general, lower-risk surveillance population might require further refinement, Graham and colleagues said.

Another study limitation was the fact that the dataset did not include information on family history, a recognized (although weak) predictor of colitis-associated colorectal cancer. Future work to include this factor may further improve risk prediction, the researchers noted.

Please enable JavaScript to view the

comments powered by Disqus.