Genetic Effect of Chemotherapy Exposure in Children of Testicular Cancer Survivors

Abstract

Background Cancer survivors express anxiety that chemotherapy exposure may lead to transmissible genetic damage in post-treatment children. Preclinical models suggest chemotherapy exposure may result in considerable genomic alterations in post-exposure progeny. Epidemiological studies have not demonstrated a significant increase in congenital abnormalities in post-treatment children of cancer survivors, but the inherited genome-wide effect of chemotherapy exposure in humans is unknown. Methods Two testicular cancer survivors cured with chemotherapy who had children pre- and post-exposure without sperm banking were identified. Familial germline whole genome sequencing (WGS) was performed for these families, and analytical methods were utilized to identify de novo alterations, including mutations, recombinations, and structural rearrangements in the pre- and post-exposure offspring. Results No increase in de novo germline mutations in post-exposure children compared to their pre-exposure siblings. Furthermore, there was no increased short insertion/deletions, recombination frequency or structural rearrangements in these post-exposure children. Conclusions In two families of male cancer survivors, there was no transmissible genomic impact of significant mutagenic exposure in post-exposure children. This study may provide possible reassuring evidence for patients undergoing chemotherapy who are unable to have pre-treatment sperm cryopreservation. Expanded cohorts that utilize WGS to identify environmental exposure effects on the inherited genome may inform the generalizability of these results.

Exposure to Chemotherapy During Childhood or Adulthood and Consequences on Spermatogenesis and Male Fertility

“…FSH: follicle stimulating hormone, LH: luteinizing hormone, SSC: spermatogonial stem cell. [24][25][26][27][28][29][30]77,81,83], spermatogonia and spermatocytes [24,43,[46][47][48]52,53,55,89,[96][97][98], spermatozoa [56,62,98,[108][109][110][111]125,126,[129][130][131]135,136] and progeny [55,[109][110][111][143][144][145][146][147][148][149]151] following chemotherapy administration during childhood and adulthood. Animal species and the age at which the chemotherapy treatments achieved are specified in parentheses.…”

“…It seemed that no increased risk of congenital anomalies has been observed among children parented by male cancer survivors in comparison with the offspring born from parents with no history of cancer [142]. Moreover, whole genome sequencing of germline, used to identify de novo alterations, reported no increase in de novo genetic events in children born after or before paternal exposure to chemotherapy [143]. However, this study is limited to two families, and thus needs to be confirmed on a larger cohort of patients.…”

Risks of genetic damage in offspring conceived using spermatozoa produced during chemotherapy or radiotherapy

“…Mutations do not necessarily cause genetic disease, as they may be recessive, conservative, in non‐coding regions, or in redundant genes. However, mutations that do not cause genetic disease can still be used to identify cancer therapies that will also cause harmful mutations , …”

“…Mutations in non‐coding regions are less likely than those in coding regions to have a phenotype but may affect gene regulation or non‐coding RNA function. Base‐change mutations have traditionally been identified only when they had a known phenotype, but now mutations without a phenotype can be identified using whole‐genome DNA sequencing . However, care must be exercised because the error rates of these techniques may be higher than the very low spontaneous mutation frequencies.…”

“…Some key studies include the offspring of male survivors of atomic bomb radiation in Japan and the offspring of survivors of childhood cancer treated with radiation and/or potentially mutagenic chemotherapy (alkylating agents) . In addition, whole‐genome sequencing of children conceived 2‐5 years after their fathers underwent chemotherapy showed no increase in DNA sequence mutations relative to their siblings conceived before their father's exposure . Although there are studies indicating possible risk of congenital abnormalities, the increased risk is very low.…”