Penetrance of Mutations in the Familial Wilms Tumor Gene FWT1

Rahman, Nazneen; Arbour, Laura; Houlston, Richard S.; Bonaïti‐Pellié, Catherine; Abidi, Fatima; Tranchemontagne, Julie; Ford, D; Narod, Steven A.; Pritchard‐Jones, Kathy; Foulkes, William D.; Schwartz, Charles; Stratton, Michael R.

doi:10.1093/jnci/92.8.650

Cited by 16 publications

(8 citation statements)

References 7 publications

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“…At the earliest time point examined (10 mo of age), there was no significant difference in tumor incidence between neoDES and neoVEH carriers (10% vs. 23%). However, even at 10 mo, the earliest time at which grossly observable tumors were seen, tumors were larger in the neoDES vs. neoVEH animals (0.16 vs. 0.01 cm 3 ), and this trend continued in the 13-mo-old females (13.70 vs. 1.10 cm 3 ) and became significant by 16 mo (P Ͻ 0.05, Table 1). Therefore, consistent with previous studies in this model, loss of function of the remaining wild-type allele appeared to be a rate-limiting event for tumorigenesis.…”

Section: Fig 2 Des-induced Developmental Programming Alters Steroidmentioning

confidence: 94%

“…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)(2)(3)(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.…”

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confidence: 99%

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

Cook

Davis

Cai

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

101

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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...

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Section: Fig 2 Des-induced Developmental Programming Alters Steroidmentioning

confidence: 94%

mentioning

confidence: 99%

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

Cook

Davis

Cai

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

101

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“…However, the penetrance of FWT1 at least appears to be low, of the order of 15-30%. 15 It is therefore possible that a substantial proportion of apparently sporadic cases of Wilms' tumour carry a constitutional mutation in a low penetrance familial Wilms' tumour gene.…”

Section: Familial Wilms' Tumourmentioning

confidence: 99%

Controversies and advances in the management of Wilms' tumour

Pritchard‐Jones

2002

Archives of Disease in Childhood

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“…Breslow et al have shown that 1% -3% of cases of Wilms tumor are familial and that a predisposition to Wilms tumor is most likely caused by rare germline mutations acting in a dominant fashion [13]. Constitutional mutations in the WT1 gene on chromosome 11p13 predispose an individual to Wilms tumor and are associated with genitourinary abnormalities [4]. Several genetic syndromes (e.g., Denys-Drash syndrome) have been correlated with intragenic WT1 mutations [12].…”

Section: Discussionmentioning

confidence: 99%

“…Several genetic loci have been shown to be associated with tumor formation, including WT1 on chromosome 11p13, WT2 on chromosome 11p15, FWT1 on chromosome 17q12-q21, and FWT2 on 19q [3,4]. WT1 is the first and most important gene to be isolated [5].…”

Section: Introductionmentioning

confidence: 99%

Identification of a constitutional mutation in the WT1 gene in Taiwanese patients with Wilms tumor

Lu¹,

Wang²,

Lin³

et al. 2014

ABB

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The overall frequency of WT1 gene alterations in Wilms tumor is still unclear in Taiwan. Here we conducted molecular genetic analysis of the WT1 gene in Taiwanese patients with Wilms tumor. Polymerase chain reaction and direct sequencing were performed on DNA samples from blood and paraffin-embedded tumor specimens. A constitutional mutation in the WT1 gene was found in one DNA sample from peripheral blood lymphocytes. The remaining DNA samples from peripheral blood lymphocytes and paraffin-embedded tumor specimens were tested negative for both constitutional mutations and somatic mutations. Thus, mutations at other Wilms tumor loci may play an important role in Wilms tumor development.

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Penetrance of Mutations in the Familial Wilms Tumor Gene FWT1

Cited by 16 publications

References 7 publications

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

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

Controversies and advances in the management of Wilms' tumour

Identification of a constitutional mutation in the WT1 gene in Taiwanese patients with Wilms tumor

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