The Role of Parental and Grandparental Epigenetic Alterations in Familial Cancer Risk

Some epigenetic alterations that influence cancer risk are inherited through the germline from the DES-exposed to offspring and are observed in multiple DES generations of victims

2008 Study Abstract

Epigenetic alterations of the genome such as DNA promoter methylation and chromatin remodeling play an important role in tumorigenesis. These modifications take place throughout development with subsequent events occurring later in adulthood. Recent studies, however, suggest that some epigenetic alterations that influence cancer risk are inherited through the germline from parent to child and are observed in multiple generations. Epigenetic changes may be inherited as Mendelian, non-Mendelian, or environmentally induced traits. Here, we will discuss Mendelian, non-Mendelian, and environmentally induced patterns of multigenerational epigenetic alterations as well as some possible mechanisms for how these events may be occurring.

Diethylstilbestrol

One example of multiple generations in families showing effects of an environmental agent are daughters of mothers who were exposed to diethylstilbestrol (DES) during the first trimester.

The daughters show developmental abnormalities and an increased risk of developing a rare type of clear-cell adenocarcinoma. DES daughters also show a 2.5-fold increase in breast cancer risk after 40 years of age. To prove that this indeed is an inherited transgenerational effect, granddaughters and great granddaughters of the exposed mothers will need to show a DES phenotype. This analysis has not yet been completed.

Mouse studies have shown that the F2 generation from a DES-exposed pregnant female had strikingly similar effects as the F1 generation, including abnormal uterine development and uterine cancer. The proposed mechanism of action of DES is aberrant CpG methylation of key uterine cancer genes. The changes in CpG methylation may be stable throughout gametogenesis, providing insight into the transgenerational effects of DES.

Sources and more information
  • Full study (free access) : The Role of Parental and Grandparental Epigenetic Alterations in Familial Cancer Risk, Perspectives in Cancer Research, NCBI PubMed PMC4423451, 2008 Nov.
  • Epigenetics featured image credit NestleNutritionInstitute.
DES DIETHYLSTILBESTROL RESOURCES

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