Research to identify inborn genetic susceptibility to colon cancer metastasis

Team examines the paradigm of metastatic spread in the second leading cause of cancer deaths

A prestigious National Institutes of Health (NIH) Transformative R01 Program grant for $4.9 million has been awarded to Case Western Reserve University School of Medicine. The five-year grant will fund research to identify patients' inborn genetic susceptibility to the development of colon cancer metastasis. Case Western Reserve was one of only 42 recipients of this competitive new grant designed to support exceptionally innovative, high risk, original and/or unconventional research projects that have the potential to create or overturn fundamental paradigms.

"The distinction of being selected for this award reflects the leading role played by Case Western Reserve University School of Medicine and the University Hospitals Ireland Cancer Center at the national level," says Sanford Markowitz, M.D., Ph.D., the study's principal investigator and the Markowitz-Ingalls Professor of Cancer Genetics.

Colon cancer is the second leading cause of cancer deaths in the United States. One third of individuals with colon cancer die of a metastatic spread of the disease. The School of Medicine team proposes there is a new paradigm in colon cancer metastasis, which has historically thought to be due to the accumulation of multiple gene mutations in the cancer cell. Dr. Markowitz and team hypothesize that cancer metastasis is not due to new "metastasis-causing" genetic mutations in the cancers, but rather is crucially dependent on inborn genetic susceptibility factors. This proposal is based on the team's prior research studies showing that no new mutations acquired in a colon cancer metastases are any different from the preceding primary colon cancer tumor. These findings directly challenge the paradigm that has dominated cancer genetics for more than two decades.

Specifically, the team will identify these susceptibility genetic markers using the technique of a whole genome association study to compare the frequency of more than one million genetic variants between individuals whose colon cancers never metastasized, versus those whose colon cancers were metastatic at the time of diagnosis, and versus individuals whose colon cancers relapsed and metastasized following initial complete surgical resections. By identifying genetic markers that track with individuals who have developed cancer metastases, the team will seek to hone in on and identify the underlying metastasis susceptibility genes; identify the causative metastasis susceptibility variants present in these genes among different ethnic groups; determine if these variants or genes also impart susceptibility to metastasis in other common solid tumors; and determine the biologic pathways by which these susceptibility alleles promote cancer metastasis.

Acceptance of this paradigm will result in the identification of entirely new biological pathways that will be key to the management and prognosis of colon cancer, and to developing new and more effective anti-cancer therapies.

Source: Case Western Reserve University