Chemotherapy’s Potential Mutagenic Effects on Sperm DNA: Sylvester and Desai Sethi Research Published in Nature Reviews

While chemotherapy is a mainstay of cancer treatment for many malignancies, little is known about how it might change sperm DNA, which is important information for cancer patients planning to start families after treatment.

“Knowing there is a mutagenic effect of therapy is very important for the individual patient,” said C. Ola Landgren, M.D., Ph.D., a researcher at Sylvester Comprehensive Cancer Center at  the University of Miami Miller School of Medicine and author of “Mutagenic effect of chemotherapy on sperm DNA and implications for family planning,” published in Nature Reviews Urology. “Physicians have to counsel patients on this, but it isn’t easy because currently there are only limited universally accepted guidelines on best practices for men diagnosed with cancer attempting to start a family after having chemotherapy.”

Whether a man will recover spermatogenesis after chemotherapy treatment, and to what degree, is hard to predict. It is also unclear whether men who recover spermatogenesis post chemotherapy will have sperm suitable for conception and what genetic risks the sperm may carry, according to Dr. Landgren, who is chief of the Myeloma Division, leader of the Translational and Clinical Oncology Program, and Paul J. DiMare Endowed Chair in Immunotherapy at Sylvester, and professor of medicine at the Miller School.

Questions surrounding chemotherapy’s potential mutagenic effect on sperm DNA apply to a range of treatments for cancers, including not only those known to affect younger men but also cancers with a higher age of onset.

“In our research on multiple myeloma, which has an average age of onset around 70 years, about 5% of all cases are diagnosed in the 30s and 40s — ages when men often consider having families,” Dr. Landgren said. “Currently, over 10,000 men in their 30s and 40s are living with multiple myeloma in the U.S.”

Mutational Signatures

Researchers have identified mutational signatures, or changes, caused by exposure to chemotherapy types, including platinum-based chemotherapy agents. But most of the research is in cancer cells, not healthy cells. Researchers have also found mutagenic effects of chemotherapy on the germline, where spermatogenesis is recovered after treatment, but the sperm are impaired from exposure to the toxic agents used to treat the cancer, according to the paper.

The authors also point to research looking at whole genome sequencing of children born two to five years after paternal chemotherapy treatment, showing an increase in DNA mutations compared to siblings born before paternal cancer treatment.

Based on available data, medical societies and associations make recommendations on how long after cancer treatment men should wait to start or grow their families.

Guidelines and Remaining Questions

For example, the American Urological Association guidelines recommend that clinicians inform patients undergoing chemotherapy and/or radiotherapy to avoid pregnancy for a period of at least one year after completion of treatment, according to co-author of the Nature Reviews paper Emad Ibrahim, M.D., assistant professor of urology and director of the clinical andrology lab at the Desai Sethi Urology Institute at the Miller School.

Dr. Ibrahim referred to the American Society for Reproductive Medicine Practice Committee’s opinion, which states, “Patients preparing to undergo gonadotoxic medical therapy, radiation therapy, or gonadectomy should be provided with prompt counseling regarding available options for fertility preservation for iatrogenic infertility.”

While these are helpful guidelines for men undergoing cancer treatment, scientists are trying to answer important questions that remain for patients and their providers who counsel them.

“The extent of damage caused by multiple chemotherapy agents is not well known or studied,” Dr. Ibrahim said. “We are currently collaborating with Dr. Landgren and his distinguished team in a research project to study these effects by collecting semen specimens from men before, during, and after completion of chemotherapy. These specimens will undergo whole genome sequencing to reveal and quantify the mutagenic impact of different chemotherapies on the sperm DNA.”

“The current observations that chemotherapy causes mutations detectable in sperms is consistent with recent observations we have done when we have investigated the impact of high-dose melphalan chemotherapy followed by autologous stem cell transplant, also referred to as bone marrow transplant,” said Dr. Landgren.

“In 2020, we discovered that high-dose melphalan chemotherapy causes a unique genomic signature called SBS-MM1, which can be tracked in patients after bone marrow transplant. In fact, our team found that high-dose melphalan increases the burden of mutations by more than 20%,” he said. “These important discoveries have already been validated by other groups, such as the Dana-Farber Myeloma Program. As the field is moving forward into the era of immunotherapies,  we will likely see less of these chemotherapy-induced mutational signatures.”

Being published in a high-impact journal like one in the Nature family confirms the clinical importance of how chemotherapy can affect sperm DNA, as well as the quality of research at Sylvester and the Desai Sethi Urology Institute.

“The scientific content of these journals follows a well-established and strict peer review system,” Dr. Ibrahim said. “Researchers and medical professionals very often review, trust, and cite the publications published in a high-impact journal. These publications confirm the scientific quality of research and researchers in any institution, in this case the Desai Sethi Urology Institute.”

Tags: American Urological Association, chemotherapy, Department of Urology, Desai Sethi Urology Institute, Dr. Emad Ibrahim, Dr. Ola Landgren, Miller School of Medicine, multiple myeloma, Nature Reviews Urology, Sylvester Comprehensive Cancer Center