Study finds how colorectal cancer gene is associated in broad range of solid tumors

Washington: A gene linked to colorectal cancer appears to play a role in the development of other solid tumours, according to a study. A study of over 350,000 patient biopsy samples conducted by researchers from the Johns Hopkins Kimmel Cancer Centre, the Johns Hopkins Bloomberg School of Public Health, and Foundation Medicine.

PlayUnmute Fullscreen Scientists have known since the early 2000s that inheriting two mutant copies of the gene MUTYH increases the risk of colorectal cancer by 93 times and is a leading cause of the disease in people under the age of 55 years.

The current study, published online February 23 in JCO Precision Oncology, is the largest to date to look into whether a single mutant copy of MUTYH influences one's risk of acquiring 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 co-led the work with Emmanuel Antonarakis, M.D., associate director of translational research at the Masonic Cancer Center and Clark Endowed Professor of Medicine at the University of Minnesota Medical School. He was at Johns Hopkins at the time the research was conducted. The gene MUTYH encodes a critical enzyme in the base excision repair (BER) pathway, which fixes DNA damage in human cells.

When the BER pathway isn't working, routine DNA damage is not repaired, leading to additional DNA mutations or cell death. Paller has co-led PROMISE, a genetic registry of patients with inherited mutations in prostate cancer.

When one of her patients asked whether his MUTYH mutation, for which he had one defective copy rather than two, affected his aggressive prostate cancer, there was not enough data on MUTYH variants to answer the question, says Paller.

Past studies reached conflicting results about whether a single, heterozygous mutation of MUTYH might predispose a person to cancer. In pursuit of an answer, Paller reached out to Foundation Medicine, a Massachusetts-based genomic profiling company that maintains one of the world's largest cancer genomic databases.

With researchers at Foundation Medicine; Alexandra Maertens, Ph.D., of the Center for Alternatives to Animal Testing at the Bloomberg School of Public Health; and others, the team applied an advanced algorithm to analyze the genetic data of 354,366 solid tumor biopsies stored in the Foundation database.

Within that population of tumor samples, 5,991 had one working version and one mutated version of MUTYH. Of those, 738 (about 12%) had lost their working copy of the gene, leaving them with just the mutated copy.

Those with a single, mutated copy of MUTYH showed a genetic signature, like a fingerprint, of additional genetic mutations and a defective BER pathway. Individuals with that genetic signature had a modest increase in susceptibility to a subset of solid tumors, including adrenal gland cancers and pancreatic islet cell tumors. However, they did not have an increased risk for breast or prostate cancer, resolving the original patient's question.

The results suggested that MUTYH variants might be involved in a broader range of cancers than previously known, Paller said. "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.