Picciotto Shany, Arenas-Gallo Camilo, Toren Amos, Mehrian-Shai Ruty, Daly Bryan, Rhodes Stephen, Prunty Megan, Liu Ruolin, Bohorquez Anyull, Grońska-Pęski Marta, Melanaphy Shana, Callum Pamela, Lassen Emilie, Skytte Anne-Bine, Obeng Rebecca C, Barbieri Christopher, Gallogly Molly, Cooper Brenda, Daunov Katherine, Beard Lydia, van Besien Koen, Halpern Joshua, Pan Quintin, Evrony Gilad D, Adalsteinsson Viktor A, Shoag Jonathan E
Department of Urology, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Pediatric Hemato-Oncology, Sheba Medical Center, Ramat Gan, Israel.
JCI Insight. 2025 May 13;10(12). doi: 10.1172/jci.insight.188175. eCollection 2025 Jun 23.
Many chemotherapeutic agents impair cancer growth by inducing DNA damage. The impact of these agents on mutagenesis in normal cells, including sperm, is largely unknown. Here, we applied high-fidelity duplex sequencing to 94 samples from 36 individuals exposed to diverse chemotherapies and 32 controls. We found that in many of the sperm samples from men exposed to chemotherapy, the mutation burden was elevated as compared with controls and the expected burden based on trio studies, with 1 patient having a more than 10-fold increase over that expected for age. Saliva from this same individual also had a markedly higher mutation burden. We then validated this finding using other tissues, also finding an increased mutation burden in the blood and liver of many patients exposed to chemotherapy as compared with unexposed controls. Similarly, mice treated with 3 cycles of cisplatin had an increased mutation burden in sperm but also in the liver and hematopoietic progenitor cells. These results suggest an association between cancer therapies and mutation burden, with implications for counseling patients with cancer considering banking sperm before therapy and for cancer survivors considering the trade-offs of using banked sperm as compared with conceiving naturally.
许多化疗药物通过诱导DNA损伤来抑制癌症生长。这些药物对包括精子在内的正常细胞诱变的影响在很大程度上尚不清楚。在此，我们对来自36名接受不同化疗的个体和32名对照的94个样本进行了高保真双链测序。我们发现，在许多接受化疗男性的精子样本中，与对照组以及基于三联体研究预期的负担相比，突变负担有所升高，有1名患者的突变负担比预期年龄的负担高出10倍以上。该个体的唾液突变负担也明显更高。然后，我们使用其他组织验证了这一发现，同样发现与未接受化疗的对照组相比，许多接受化疗患者的血液和肝脏中的突变负担增加。同样，接受3个周期顺铂治疗的小鼠精子中的突变负担增加，肝脏和造血祖细胞中的突变负担也增加。这些结果表明癌症治疗与突变负担之间存在关联，这对于为考虑在治疗前储存精子的癌症患者提供咨询以及对于考虑与自然受孕相比使用储存精子的利弊的癌症幸存者具有重要意义。
