M2: Cancer treatment and genetic instability in relation to the health of the offspring

This study is performed by Yahia Al-Jebari at Reproductive Medicine, Lund University, Sweden.

Background
Testicular germ cell cancer (TGCC) is the most common neoplasm in men aged 25-40 years. The incidence of TGCC has increased by a factor of 3-4 the past 50 years. Generally, there is a concern that children fathered by men treated for cancer might have an increased risk of congenital malformations, due to the mutagenicity of radio- and chemotherapy. It has previously been published – based on Swedish and Danish registry data including almost 1 800 000 births – that children of male cancer survivors, conceived after the cancer diagnosis was made, had 20% higher risk for major congenital abnormalities than the offspring of fathers with no history of cancer. The study only showed the relation but nothing about the mechanism(s) behind the findings. One hypothesis could be that both the paternal cancer and child defect are due to a constitutional genetic instability in the male. Another explanation might be that the genetic alternations passed on to the offspring are induced by cancer treatment administered to the father.

Results from the epidemiological part
We investigated the risk associated with the fathers’ cancer by examining the risk of congenital malformation in children born before the fathers’ cancer diagnosis, and therefore prior to the fathers’ cancer treatment. We obtained data on around 2M children and their 1M fathers through high quality Swedish national registries. We found that children conceived before paternal cancer had a statistically significantly increased risk of birth defects. As the children were born before paternal cancer therapy, the increased risk of birth anomalies among these children is not due to cancer therapy and implicates cancer itself or another underlying paternal factor. It is, however, important to mention that the risk of having a child with malformations is, despite the increase, very low and there is no reason for concern or avoid having children.

Publication: Al-Jebari Y, Rylander L, Ståhl O, Giwercman A. Risk of congenital malformations in children born before paternal cancer. JNCI Cancer Spectrum 2018;2.

The molecular part
In order to better understand the underlying mechanisms, molecular studies are planned for in order to answer the following:

  1. Is the prevalence of genetic aberrations increased in leukocytes of men treated for childhood or testicular cancer?
  2. Is the ratio of genetic abnormalities higher, as compared to leukocytes, in the spermatozoa of testicular and childhood cancer survivors?
  3. Is the frequency of genetic anomalies seen in leukocytes or in spermatozoa related to cancer type or treatment protocol?

The biological material is already collected and stored in the biobank in Malmö (leukocyte and sperm DNA) from more than 300 testicular cancer and 150 childhood cancer survivors as well as from healthy controls will be used.

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