Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance

Abstract

Gene-environment interactions are important determinants of cancer risk. Traditionally, gene-environment interactions are thought to contribute to tumor-suppressor-gene penetrance by facilitating or inhibiting the acquisition of additional somatic mutations required for tumorigenesis. Here, we demonstrate that a distinctive type of gene-environment interaction can occur during development to enhance the penetrance of a tumorsuppressor-gene defect in the adult. Using rats carrying a germ-line defect in the tuberous sclerosis complex 2 (Tsc-2) tumor-suppressor gene predisposed to uterine leiomyomas, we show that an earlylife exposure to diethylstilbestrol during development of the uterus increased tumor-suppressor-gene penetrance from 65% to >90% and tumor multiplicity and size in genetically predisposed animals, but it failed to induce tumors in wild-type rats. This exposure was shown to impart a hormonal imprint on the developing uterine myometrium, causing an increase in expression of estrogen-responsive genes before the onset of tumors. Loss of function of the normal Tsc-2 allele remained the rate-limiting event for tumorigenesis; however, tumors that developed in exposed animals displayed an enhanced proliferative response to steroid hormones relative to tumors that developed in unexposed animals. These data suggest that exposure to environmental factors during development can permanently reprogram normal physiological tissue responses and thus lead to increased tumor-suppressor-gene penetrance in genetically susceptible individuals.developmental programming ͉ gene-environment interaction ͉ Eker rat ͉ uterine leiomyoma ͉ Tsc-2 I nheritance of a defect in a tumor-suppressor gene confers a high risk for developing cancer. However, defects in these genes are rarely 100% penetrant, and, even in families harboring the same genetic mutation, the penetrance of the tumor-suppressor-gene defect can vary significantly (1-4). The importance of geneenvironment interactions in contributing to individual differences in tumor-suppressor-gene penetrance was recently highlighted in the New York Breast Cancer Study, which evaluated the breast and ovarian cancer risk in female relatives harboring mutations in the BRCA1 and BRCA2 tumor-suppressor genes. The magnitude of increase in breast cancer risk in the birth cohort born after 1940 was substantially greater than in those born before 1940 (5). These data suggest that additional factors, such as diet, exercise, hormonal milieu, and environmental exposures, can significantly modify cancer risk in the presence of an inherited cancer-susceptibility gene.Traditionally, gene-environment interactions that influence cancer risk are thought to occur over an individual's lifetime by facilitating or inhibiting acquisition of the multiple somatic mutations required for tumorigenesis (6). However, for some diseases, such as cardiovascular disease and adult-onset diabetes, a developmental programming hypothesis is proposed as an alternative mechanism for modulating adult disease. This hypo...

Do septins have a role in cancer?

“…However, genes whose protein products appear, at least in some tumour types, to contribute to the neoplastic phenotype continue to be identified. While it is the case that mutations are crucial to the role of many oncogenes and tumour suppressor genes in neoplasia, it is becoming increasingly apparent that the neoplastic phenotype can be a consequence of alterations in gene expression, with haploinsufficiency being an increasingly common theme (Mao et al, 2004), coupled with environmental factors, often having a multifaceted spatial (Orimo et al, 2005) and temporal interplay (Cook et al, 2005). Furthermore, the surprising revelation of how relatively few genes we have in the human genome and the extent of alternate splicing that exists, highlights the possibility that the range of genes whose products will have a role in neoplasia will continue to grow as we develop a more detailed understanding of the molecular events that regulate cells.…”

Urogenital Carcinogenesis in Female CD1 Mice Induced by In utero Arsenic Exposure Is Exacerbated by Postnatal Diethylstilbestrol Treatment

“…Thus, functional ER-a overexpression seems to be associated with the carcinogenicity of arsenic in several tissues. Based on these data, we hypothesize that arsenic in utero may attack a critical pool of progenitor cells in urogenital system and induce aberrant genetic ''reprograming'' as part of its carcinogenic mechanism, in a fashion similar to that thought to occur in early life exposure to diethylstilbestrol (36). An intrauterine component of estrogen carcinogenesis involving stem cells has been long suspected (37).…”

Epigenetics, brain, behavior, and the environment

“…For example, Eker rats carry a germ line defect in the tuberous sclerosis complex 2 tumor-suppressor gene and approximately 65% develop hormone-dependent uterine leiomyomas. 52 Exposure of females to DES on days 3-5 after birth increases the tumor-suppressor-gene penetrance to more than 90%. In principle, stress, which has been shown to have organizational actions of behavior in rats via an effect on the HPA, could have a similar potentiating effect on epigenetically induced transgenerational imprints as well as on genetic predisposition to develop disease.…”