Highly penetrant hereditary cancer syndromes

Nagy, Rebecca; Sweet, Kevin; Eng, Charis

doi:10.1038/sj.onc.1207714

Cited by 317 publications

(268 citation statements)

References 292 publications

(269 reference statements)

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“…What makes the case even more interesting it is that the tumor type of neoplasms appearing in WS patients is remarkably different from that observed in people who do not have the syndrome: the ratio of mesenchymal:epithelial cancers is 1:1, as compared with 1:10 in the normal aging population (12,32). Thus, it seems that the accelerated aging process in WS patients contributes to the higher incidence of tumors, but the specific loss of the WRN gene confers a particular tumor-type prone phenotype, in a similar fashion to what has been observed with other familial tumor-suppressor genes with DNA-repair function, such as hMLH1 or BRCA1 (33). Our observation that the WRN gene undergoes epigenetic inactivation by CpG island promoter hypermethylation in various tumor types of both mesenchymal and epithelial origin, including those commonly observed in WRN patients (such as osteosarcoma, thyroid, and gastric tumors) (34), may provide further insight into the WRN protein's contribution to the tumorigenic process.…”

Section: Discussionmentioning

confidence: 50%

Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer

Agrelo

Cheng

Setién

et al. 2006

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

242

227

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Werner syndrome (WS) is an inherited disorder characterized by premature onset of aging, genomic instability, and increased cancer incidence. The disease is caused by loss of function mutations of the WRN gene, a RecQ family member with both helicase and exonuclease activities. However, despite its putative tumorsuppressor function, little is known about the contribution of WRN to human sporadic malignancies. Here, we report that WRN function is abrogated in human cancer cells by transcriptional silencing associated with CpG island-promoter hypermethylation. We also show that, at the biochemical and cellular levels, the epigenetic inactivation of WRN leads to the loss of WRN-associated exonuclease activity and increased chromosomal instability and apoptosis induced by topoisomerase inhibitors. The described phenotype is reversed by the use of a DNA-demethylating agent or by the reintroduction of WRN into cancer cells displaying methylationdependent silencing of WRN. Furthermore, the restoration of WRN expression induces tumor-suppressor-like features, such as reduced colony formation density and inhibition of tumor growth in nude mouse xenograft models. Screening a large collection of human primary tumors (n ‫؍‬ 630) from different cell types revealed that WRN CpG island hypermethylation was a common event in epithelial and mesenchymal tumorigenesis. Most importantly, WRN hypermethylation in colorectal tumors was a predictor of good clinical response to the camptothecin analogue irinotecan, a topoisomerase inhibitor commonly used in the clinical setting for the treatment of this tumor type. These findings highlight the importance of WRN epigenetic inactivation in human cancer, leading to enhanced chromosomal instability and hypersensitivity to chemotherapeutic drugs. DNA methylationW erner syndrome (WS) is an autosomal recessive disease characterized by premature aging and a high incidence of malignant neoplasms (1, 2). Mutations in the WS gene (WRN) are found in patients exhibiting the clinical symptoms of WS (3-5). The vast majority of WRN mutations result in loss of function of the WRN protein (6). The WRN protein has been demonstrated to possess helicase and exonuclease activities (7-9), and cultures of WS cells show increased chromosomal instability, with abundant deletions, reciprocal translocations, and inversions (10, 11).WRN belong to the RecQ family of helicases, which are highly conserved from bacteria to human, and whose members are thought to be essential caretakers of the genome (11,12). In addition to WRN, germline mutations of two other RecQ helicases, BLM in Bloom syndrome and RECQL4 in Rothmund-Thomson syndrome, are also associated with an elevated incidence of cancer (12). Because patients with WRN germline mutations develop a broad spectrum of epithelial and mesenchymal tumors, which is one of the main causes of their death before the age of 50, a tumorsuppressor function for WRN has been proposed. This putative role is also supported by a very high rate of loss of heterozygosity at the chrom...

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Section: Discussionmentioning

confidence: 50%

Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer

Agrelo

Cheng

Setién

et al. 2006

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

242

227

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“…Approximately 5-10% of all cancers are caused by inherited mutations in cancer predisposing genes. [1][2][3] Preimplantation genetic diagnosis (PGD) is a procedure used to test embryos for genetic disorders before uterine implantation. [4][5][6][7] PGD has been used to avoid both the potential risks of miscarriage associated with amniocentesis and chorionic villus sampling and decisions about pregnancy termination if the fetus is found to be affected following prenatal diagnosis.…”

Section: Introductionmentioning

confidence: 99%

High-risk consumers’ perceptions of preimplantation genetic diagnosis for hereditary cancers: a systematic review and meta-analysis

Quinn

Pal

Murphy

et al. 2012

Genetics in Medicine

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Individuals carrying deleterious germline mutations placing them at increased risk for hereditary cancer syndromes (high-risk consumers) often have a great deal of fear and concern over transmitting mutations to their offspring, particularly conditions which are autosomal dominant. Preimplantation genetic diagnosis (PGD) is a procedure that can detect certain germline cancer predisposing mutations present in embryos. The objective of this review was to assess high-risk consumers' knowledge and perceptions of PGD for hereditary cancers. A systematic literature review was conducted through PubMed, Wiley Interscience, PsychInfo, and Cochrane Library databases to identify all articles assessing consumer knowledge and attitudes of PGD for hereditary cancer syndromes. We assessed heterogeneity and the robustness of findings through additional analyses according to study location, hereditary cancer type, and sample size. Thirteen articles remained eligible after the application of specific criteria. Results show a general low level of knowledge about PGD for hereditary cancers, moderate rates of acceptability among high-risk groups, and high levels of need for information about PGD. Individuals in specific risk groups such as those with a personal or family history of hereditary breast and ovarian cancer (HBOC) syndrome or familial adenomatous polyposis (FAP) may benefit from educational information from healthcare professionals about the use of PGD. 2012:14(2):191-200 Genet Med

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“…Sporadic MTC forms are related to somatic mutations in the RET gene in 30-50% of these tumors (Uchino et al 1999), while the vast majority of FMTC forms carry inherited mutations of RET (Schuffenecker et al 1998, Randolph & Maniar 2000, Nagy et al 2004. These are gainof-function mutations and activate the kinase activity of RET, which provides mitogenic and survival signals to the calcitonin-producing C-cells.…”

Section: Introductionmentioning

confidence: 99%

Overexpression and activation of EGFR and VEGFR2 in medullary thyroid carcinomas is related to metastasis

Rodríguez‐Antona

Pallarés²,

Montero‐Conde³

et al. 2010

Endocrine-Related Cancer

120

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Therapeutic options for patients with metastatic medullary thyroid carcinoma (MTC) are limited due to lack of effective treatments. Thus, there is a need to thoroughly characterize the pathways of molecular pathogenesis and to identify potential targets for therapy in MTC. Since epidermal growth factor receptor (EGFR) seems to play a crucial role for RET activation, a key feature of MTCs, and several promising EGFR/vascular endothelial growth factor receptor 2 (VEGFR2)-targeted drugs have been developed, the present study was designed to investigate whether these proteins are altered in MTCs. We used a well-characterized series of 153 MTCs to evaluate EGFR activation by sequencing and FISH analysis, and to perform EGFR and VEGFR2 immunohistochemistry. EGFR tyrosine kinase domain mutations were not a feature of MTCs; however, EGFR polysomy and a strong EGFR expression were detected in 15 and 13% of the tumors respectively. Interestingly, EGFR was significantly overexpressed in metastases compared with primary tumors (35 vs 9%, PZ0.002). We also studied whether specific RET mutations were associated with EGFR status, and found a decrease in EGFR polysomies (PZ0.006) and a tendency towards lower EGFR expression for the most aggressive RET mutations (918, 883). Concerning VEGFR2, metastasis showed a higher expression than primary tumors (PZ2.8!10 K8 ). In this first study investigating the relationship between EGFR, RET, and VEGFR2 in a large MTC series, we found an activation of EGFR and VEGFR2 in metastasis, using both independent and matched primary/metastasis samples. This suggests that some MTC patients may benefit from existing anti-EGFR/VEFGR2 therapies, although additional preclinical and clinical evidence is needed.

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Highly penetrant hereditary cancer syndromes

Cited by 317 publications

References 292 publications

Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer

Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer

High-risk consumers’ perceptions of preimplantation genetic diagnosis for hereditary cancers: a systematic review and meta-analysis

Overexpression and activation of EGFR and VEGFR2 in medullary thyroid carcinomas is related to metastasis

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