A single mutation in MUTYH, a gene known to cause colorectal cancer, may cause other solid tumors, according to a study of over 350,000 patient biopsy samples conducted by researchers at the Johns Hopkins Kimmel Cancer Center, the Johns Hopkins Bloomberg School of Public Health, and Foundation Medicine.
Their findings are important not only because MUTYH could be a PAN cancer gene, but because the gene is linked to colorectal cancer in young men, which is increasing.
In addition, the researchers say this is the largest analysis to date of whether a single mutated copy of MUTYH affects cancer risk. It is well known that inheriting two mutated copies of the gene leads to a 93-fold increased risk of colorectal cancer and is a major cause of that cancer in people younger than 55. But past studies have reached conflicting results about whether a single, heterozygous MUTYH mutation predisposes a person to any cancer.
This study was published last month in JCO Precision Oncology. The lead author is Channing Paller, MD, director of prostate cancer clinical research at Johns Hopkins.
“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,” said Paller.
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.
Since 2021, 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, said Paller.
So she contacted Foundation Medicine, which maintains one of the world’s largest cancer genomic databases. With researchers at Foundation Medicine; Alexandra Maertens, PhD, 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.
Of those samples, 5,991 had one working version and one mutated version of MUTYH. They found 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 that was modestly elevated in some cancer types, including adrenal gland cancers, pancreatic islet cell tumors, non-glioma CNS tumors, GI stromal tumors, and thyroid cancers.
The results suggest 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.
