Earlier diagnosis in Cowden syndrome patients predisposed to breast and kidney cancer

Research allows early detection of tumors

Researchers at Cleveland Clinic's Genomic Medicine Institute have revealed multiple genetic discoveries that may permit easier diagnosis and disease management for Cowden syndrome patients who are predisposed to breast and kidney cancer.

The research, which could allow for earlier discovery of cancerous tumors, is published in the Dec. 22 issue of the Journal of the American Medical Association (JAMA).

Charis Eng, M.D., Ph.D, Chair of the Genomic Medicine Institute at Cleveland Clinic, led the research. It revealed KILLIN as a novel predisposition gene for Cowden syndrome (CS) and Cowden-like syndrome (CLS) features in individuals without germline PTEN mutations, which also plays a role in cancer risk.

According to Dr. Eng, "CLS is at least 10 times more common than CS, but the genetic alteration responsible for CLS and its cancers has eluded the scientific community for more than a decade. From our research, we now know that KILLIN accounts for almost half of CLS, making diagnosis much more accurate."

Mutations in the PTEN gene are the foundation of Cowden syndrome. PTEN is a tumor suppressor gene, helping to direct the growth and division of cells. Inherited mutations in the PTEN gene have been found in approximately 80 percent of Cowden syndrome patients. These mutations prevent the PTEN protein from effectively regulating cell survival and division, which can lead to the formation of tumors.

However, not all CS and CLS patients carry mutated PTEN. In fact, in CLS, less than 10 percent have PTEN mutations, yet they develop cancers just like CS. In those patients without the PTEN mutation, 42 percent of Cowden syndrome patients and 33 percent of Cowden-like syndrome patients have low levels of KILLIN tumor suppressor gene.

"We know that 80 percent of Cowden patients carry the PTEN mutation and half of the remaining 20 percent carry the inactive KILLIN gene," Dr. Eng said. "What that means is that altogether PTEN and KILLIN should account for 90 percent of all cases of classic Cowden syndrome, a huge step forward in diagnosing an often overlooked disease. More importantly, KILLIN and PTEN should account for almost half of CLS individuals."

This study shows that CS/CLS individuals with KILLIN promoter methylation, which switches the KILLIN gene off, have a threefold greater risk of breast cancer, and a twofold greater risk of kidney cancer, compared to those with mutant PTEN. Having the ability to identify these individuals will allow for more proactive management of their health, such as more careful screening and shared best practices among physicians who treat them.

Findings from this study indicate that individuals with classic Cowden syndrome should be offered PTEN testing first; those found not to have PTEN mutations should then be screened for the inactivated KILLIN gene and offered genetic counseling. Those patients who carry neither the PTEN mutation nor the inactive KILLIN gene should be offered additional/alternative genetic testing and importantly, encouraged to participate in research.

Source: Cleveland Clinic Foundation