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A novel risk-assessment method for colorectal cancer and prostate cancer

(FCCC Ref. No. 312-GE)

Background

One person in 20 in the U.S. currently develops colorectal cancer. About 30% of these cancers arise within families that are predisposed to the disease. Thus, about 4 to 5 million individuals are at risk for Familial Colorectal Carcinoma (FCRC) which is characterized by early disease onset and/or occurrence of CRC in multiple family members. The molecular cause is unknown for about ~20-25% of FCRC. Within affected families, about half of the members are expected to be at risk, but we cannot identify them. The standard of care is for all of them to undergo early and more frequent colon cancer screening by colonoscopy. Our goal is to improve risk prediction for inherited predisposition to FCRC.

Summary

The goal of this project was to improve risk prediction for inherited predisposition to cancer. We have assayed germline DNA and primary peripheral blood lymphocytes (the cells most readily available) from FCRC patients. On whole exome sequencing, we found that these patients had germline variants in pathways that maintain genome stability (DNA replication, DNA repair and checkpoint proteins etc.).

We found that the majority of FCRC patients compared to age-and sex-matched cancer free controls, exhibit elevated levels of the DNA double strand break (DSB) marker, γH2AX, in primary T-lymphocytes following treatment with low doses of DNA damaging agents, suggesting the basis of a simple screening test for inherited predisposition to cancer.

Thus, the product of this invention would represent a blood test that can detect individuals with a predisposition to develop CRC. The product will most likely include a fluorescence-based high throughput-assay that will detect activation of a DNA damage response in patient primary lymphocytes. Thus, a blood sample will be centrifuged; the 'buffy coat' layer of white cells will be extracted and samples will be cultured and treated to low-doses of DNA damaging agents. We estimate that the test may detect up to 20-25% of familial colon cancer (FCRC). This test could be applied to other members of the family at risk. Therefore, we propose to develop a simple blood test, easy for the patient, reliable, and verifiable by follow-up tests. Moreover, the product would detect risk for tumor development, guiding timing of colonoscopy, dietary, and chemo-preventive interventions. Thus, the patients could plan their care years in advance.

We have advanced these studies and observed similar results in familial prostate cancers (PCa). Over 220,000 new cases and 27,500 deaths from PCa are anticipated in the United States in 2015, with men facing a 1 in 7 lifetime risk of PCa. A large subset of PCa is thought to involve inherited factors compromising DNA damage response (DDR). While germline mutations in BRCA1/2 and a small number of other genes have been linked to PCa risk in up to 10% of families, most cases remain genetically undefined. This situation leaves individuals from high-risk families in peril from both underscreening and overscreening. In our work, we identified germline variants relevant to defective DDR pathways and showed the prevalence of increased markers of DNA DSBs in cases versus matched controls. These results suggest that this work has a strong potential to become a tool for screening to improve assessment of familial cancer risk (including FCRC and PCa) and suggest new directions that improve clinical care.

IP Status: US Patent No. 9,157,124 issued Oct 13, 2015. Additional patent applications are pending.

Partnering: Looking for potential licensee and/or industry collaboration partner

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