High cumulative risks of cancer in patients with<i>PTEN</i>hamartoma tumour syndrome

Bubien, Virginie; Bonnet, Françoise; Brouste, Véronique; Hoppe, Stéphanie; Barouk-Simonet, Emmanuelle; David, Albert; Edery, Patrick; Bottani, Armand; Layet, Valérie; Caron, Olivier; Gilbert‐Dussardier, Brigitte; Delnatte, Capucine; Dugast, Catherine; Fricker, Jean-Pierre; Bonneau, Dominique; Sévenet, Nicolas; Longy, Michel; Caux, F.

doi:10.1136/jmedgenet-2012-101339

Cited by 317 publications

(264 citation statements)

References 27 publications

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“…9 Moreover, in patients with Cowden Syndrome, which are highly susceptible to breast and thyroid cancer, 80% of their total mutations are germline C-terminus PTEN truncations. 25 Therefore, using the overexpression of satellite DNAs as a reporter of disrupted heterochromatin, we conducted a knockdown-and-mutant-rescue experiment to examine the function of various cancer-associated PTEN mutants in heterochromatin. As determined by RT-qPCR, WT PTEN successfully suppressed satellite DNA overexpression (Fig.…”

Section: Resultsmentioning

confidence: 99%

Nuclear PTEN tumor-suppressor functions through maintaining heterochromatin structure

et al. 2015

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The tumor suppressor, PTEN, is one of the most commonly mutated genes in cancer. Recently, PTEN has been shown to localize in the nucleus and is required to maintain genomic stability. Here, we show that nuclear PTEN, independent of its phosphatase activity, is essential for maintaining heterochromatin structure. Depletion of PTEN leads to loss of heterochromatic foci, decreased chromatin compaction, overexpression of heterochromatic genes, and reduced protein stability of heterochromatin protein 1 a. We found that the C-terminus of PTEN is required to maintain heterochromatin structure. Additionally, cancer-associated PTEN mutants lost their tumor-suppressor function when their heterochromatin structure was compromised. We propose that this novel role of PTEN accounts for its function in guarding genomic stability and suppressing tumor development.

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Section: Resultsmentioning

confidence: 99%

Nuclear PTEN tumor-suppressor functions through maintaining heterochromatin structure

et al. 2015

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“…Numerous other genes have been shown to be involved in the genetic determinism of breast or ovarian cancers, but their respective contribution and the penetrance of their mutations remain, for most of them, to be characterized. Mutations within TP53, PTEN, STK11 and CDH1 resulting in Li Fraumeni (LFS), Cowden, Peutz-Jeghers syndrome and hereditary diffuse gastric cancer, respectively, are associated to an increased risk of breast cancer; [12][13][14][15] mutations within RAD51 paralogs, such as RAD51C, confer an increased risk of ovarian cancer; 16 and variations within ATM, BRIP1, PALB2 and CHEK2 have been shown to be associated with a moderate increase of breast cancer. 17 Next-generation sequencing (NGS), based on massively parallel sequencing after clonal amplification of DNA templates in emulsion PCR or solid phase, allows molecular diagnostic laboratories to increase their throughput, to reduce the delay of analysis and to analyze simultaneously the different genes involved in a specific disease or a group of diseases.…”

Section: Introductionmentioning

confidence: 99%

Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes

et al. 2014

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To optimize the molecular diagnosis of hereditary breast and ovarian cancer (HBOC), we developed a next-generation sequencing (NGS)-based screening based on the capture of a panel of genes involved, or suspected to be involved in HBOC, on pooling of indexed DNA and on paired-end sequencing in an Illumina GAIIx platform, followed by confirmation by Sanger sequencing or MLPA/QMPSF. The bioinformatic pipeline included CASAVA, NextGENe, CNVseq and Alamut-HT. We validated this procedure by the analysis of 59 patients' DNAs harbouring SNVs, indels or large genomic rearrangements of BRCA1 or BRCA2. We also conducted a blind study in 168 patients comparing NGS versus Sanger sequencing or MLPA analyses of BRCA1 and BRCA2. All mutations detected by conventional procedures were detected by NGS. We then screened, using three different versions of the capture set, a large series of 708 consecutive patients. We detected in these patients 69 germline deleterious alterations within BRCA1 and BRCA2, and 4 TP53 mutations in 468 patients also tested for this gene. We also found 36 variations inducing either a premature codon stop or a splicing defect among other genes: 5/708 in CHEK2, 3/708 in RAD51C, 1/708 in RAD50, 7/708 in PALB2, 3/708 in MRE11A, 5/708 in ATM, 3/708 in NBS1, 1/708 in CDH1, 3/468 in MSH2, 2/468 in PMS2, 1/708 in BARD1, 1/468 in PMS1 and 1/468 in MLH3. These results demonstrate the efficiency of NGS in performing molecular diagnosis of HBOC. Detection of mutations within other genes than BRCA1 and BRCA2 highlights the genetic heterogeneity of HBOC. In BRCA1 and BRCA2 mutation carriers, the cumulative risk of breast cancer at 70 years has been estimated to 65 and 45%, respectively, and the risk of ovarian cancer to 39 and 10%, respectively. 3 The identification of a deleterious BRCA1/BRCA2 mutation within a family is crucial for the medical follow-up, as mutation carriers should be offered annual MRI or, alternatively, prophylactic mastectomy and prophylactic salpingooophorectomy. Furthermore, in a breast cancer patient, the detection of a germline BRCA1 or BRCA2 mutation may have important therapeutic consequences: complete mastectomy instead of partial mastectomy and, in the future, the prescription of specific targeted therapies, such as PARP inhibitors. 4,5 Considering the medical consequences of the identification of a germline BRCA1 or BRCA2 mutation and the frequency of mutation carriers, which has

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“…[24][25][26][27][28] Clinical diagnostic criteria involve combinations of major and minor criteria 29 ( Table 4). We recommend referral for anyone meeting any three criteria from the major or minor diagnostic criteria.…”

Section: Cowden Syndrome Also Known As Pten Hamartoma Tumor Syndromementioning

confidence: 99%

A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment

Hampel

Bennett

Buchanan

et al. 2015

Genetics in Medicine

468

326

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Cancer genetic consultation services include the evaluation of patients' personal and family history for concerning features of hereditary cancer predisposition syndromes, development of a differential diagnosis for one or more possible hereditary cancer syndromes, genetic testing if indicated and available, recommendations for management, cancer surveillance and prevention, and information regarding genetic counseling and genetic testing for at-risk relatives. This counseling is informed by the genetic Cancer genetic consultation is an important aspect of the care of individuals at increased risk of a hereditary cancer syndrome. Yet several patient, clinician, and system-level barriers hinder identification of individuals appropriate for cancer genetics referral. Thus, the purpose of this practice guideline is to present a single set of comprehensive personal and family history criteria to facilitate identification and maximize appropriate referral of at-risk individuals for cancer genetic consultation. To develop this guideline, a literature search for hereditary cancer susceptibility syndromes was conducted using PubMed. In addition, GeneReviews and the National Comprehensive Cancer Network guidelines were reviewed when applicable. When conflicting guidelines were identified, the evidence was ranked as follows: position papers from national and professional organizations ranked highest, followed by consortium guidelines, and then peerreviewed publications from single institutions. The criteria for cancer genetic consultation referral are provided in two formats: (i) tables that list the tumor type along with the criteria that, if met, would warrant a referral for a cancer genetic consultation and (ii) an alphabetical list of the syndromes, including a brief summary of each and the rationale for the referral criteria that were selected. Consider referral for a cancer genetic consultation if your patient or any of their firstdegree relatives meet any of these referral criteria.

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High cumulative risks of cancer in patients withPTENhamartoma tumour syndrome

Abstract: This study shows a considerably high cumulative risk of cancer for patients with PHTS, mainly in women without clear genotype-phenotype correlation for this cancer risk. New recommendations for the management of PHTS patients are proposed.

Cited by 317 publications

References 27 publications

Nuclear PTEN tumor-suppressor functions through maintaining heterochromatin structure

Nuclear PTEN tumor-suppressor functions through maintaining heterochromatin structure

Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes

A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment

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