Study Finds Link Between MUTYH Gene And Development Of Solid Tumors

A recent study linked a gene related to colorectal cancer which appeared to have a hand in the development of other solid tumors.

Researchers from the Johns Hopkins Kimmel Cancer Centre, the Johns Hopkins Bloomberg School of Public Health, and Foundation Medicine conducted a study on more than 350,000 patient biopsy samples.

Scientists have been aware since the early 2000s that having two mutated copies of the MUTYH gene significantly raises the likelihood of developing colorectal cancer, making it a major contributor to the disease in individuals below the age of 55. The most recent study, published on February 23 in JCO Precision Oncology, is the largest investigation conducted so far to examine whether possessing just one mutated copy of the MUTYH gene affects a person's susceptibility to cancer.

"We know two missing copies of MUTYH greatly increases the risk of colon cancer, and now it appears that having only one missing copy may lead to a small increased risk of other cancer types," says the study's lead author, Channing Paller, M.D., director of prostate cancer clinical research and an associate professor of oncology at the Johns Hopkins University School of Medicine.

She collaborated with Emmanuel Antonarakis, M.D., who is the associate director of translational research at the Masonic Cancer Center and holds the Clark Endowed Professor of Medicine position at the University of Minnesota Medical School. It is worth mentioning that he was affiliated with Johns Hopkins University during the time the research was carried out.

The MUTYH gene is responsible for producing an important enzyme that plays a crucial role in repairing DNA damage in human cells through the base excision repair (BER) pathway. If the BER pathway is not functioning properly, regular DNA damage remains unrepaired, resulting in more DNA mutations or even cell death.

Starting from 2021, Paller has been one of the leaders of PROMISE, a genetic database that focuses on individuals with inherited genetic mutations related to prostate cancer. Paller explains that when a patient of hers inquired about the impact of his specific MUTYH mutation (where he only had one faulty copy instead of two) on his aggressive prostate cancer, there was insufficient information available regarding MUTYH variations to provide a clear answer. Previous research studies have yielded contradictory findings on whether having a single, heterozygous MUTYH mutation might make someone more susceptible to developing cancer.

To find a solution, Paller contacted Foundation Medicine, a company in Massachusetts that specializes in genomic profiling and has a vast cancer genomic database. Paller collaborated with researchers from Foundation Medicine, including Alexandra Maertens, Ph.D. from the Center for Alternatives to Animal Testing at the Bloomberg School of Public Health, and others. Together, they used a sophisticated algorithm to examine the genetic information of 354,366 solid tumor biopsies that were stored in the Foundation database.

In the population of tumor samples, 5,991 samples were found to have both a functioning and mutated version of the MUTYH gene. Out of these, 738 samples (approximately 12 per cent) had lost the functioning copy of the gene, leaving only the mutated version. These individuals with a single mutated copy of MUTYH exhibited a distinct genetic pattern characterized by additional genetic mutations and a faulty BER pathway. This genetic signature was associated with a slight increase in susceptibility to certain types of solid tumors, such as adrenal gland cancers and pancreatic islet cell tumors. However, there was no heightened risk of breast or prostate cancer, thus addressing the original concern raised by the patient.

According to Paller, the findings indicated that MUTYH mutations could potentially play a role in a wider array of cancer types than previously recognized.

"The next question is whether this finding has therapeutic implications," she said. "Can we target the BER pathway for possible drug sensitivities?" If so, doctors might be able to add a new therapeutic approach to their arsenal of tools against solid cancers.