Public Health Challenge
Colorectal Cancer (CRC) goes through a very recognized, multi-step pathway-both genetically and clinically. If adenomas are caught and removed early, a cancer can be prevented. However, once a cancer develops there is significant morbidity or if it progresses to a late stage cancer, cure is nearly impossible.  The goal of any screening test is to capture the disease before cancer develops or at a preclinical, early stage and prior to any symptoms.  Current screening methodologies used to detect CRC are blood in stool tests (FOBT), colonoscopy, and sigmoidoscopy . For any of the  three screening methods, effectiveness is limited however because of low compliance in patient preparation.   

Research Findings

The objective of Dr. Diaz and his lab, is to develop a simple biomarker, a blood test, that can improve chances for detecting CRC or its preclinical stage. The foundation for the biomarkers is in the molecular genetics of CRC. In theory the development and progression of CRC can be characterized molecularly by the mutations and chromosomal aberrations of the colon cancer genome.  With this in mind, Dr. Diaz answers the next question in detecting CRC: “Would genetic changes serve as good biomarkers for even the early stages of cancer and how?”   Three points suggest that molecular genetic changes could serve as a biomarker:

-          Key genetic alterations are cumulative and occur in a predictable sequence,

-          The spectrum of mutations is sufficient so that at least one known mutation can be found in every tumor, and

-          Genetic alterations are only found in pre-malignant or malignant tissue and NOT normal tissues.
These genetic alterations can be accessed by capturing the cancer cell through DNA fragments circulating in the blood.  However, normal DNA must be distinguished from mutant DNA (DNA containing cancer cells), which can be done by amplifying the target gene. 

Because the current level of detection is very specific, that is good at identifying those without cancer, this blood test so far appears to enable clinicians to detect minimal residual disease in patients undergoing surgery. Those who have evidence of residual tumor by ctDNA – would receive adjuvant therapy and, those without evidence of residual tumor would avoid it.

Possible Directions

Digital analysis of the biomarkers is expected to make the blood test more sensitive (better at detecting positives). This will lead the way to improvement of this tool as a public health screening test, which averts the distasteful preparation or stool collection necessary for current methods.  Dr. Diaz will be examining this prospect in two population-based studies among those with and without cancer.

Future Research Opportunities

Examine Stool and Blood Test – RCT (Randomized Controlled Trials) in a large as yet unscreened population using multiple mutations and digital sequencing technology.  Develop the Minimal Residual Disease testing further in larger studies to assess the effectiveness of curative therapies. Other opportunities for improvement include advancement of the measurement technologies, biologic sensitivity and quantifying costs for the new screenings.