A mosaic PTEN mutation causing Cowden syndrome identified by deep sequencing

Pritchard, Colin C.; Smith, Christina; Marushchak, Tatyana; Koehler, Karen M.; Holmes, Heidi H.; Raskind, Wendy H.; Walsh, Tom; Bennett, Robin L.

doi:10.1038/gim.2013.51

Cited by 33 publications

(23 citation statements)

References 19 publications

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“…Somatic mosaicism cannot be completely ruled out but is unlikely as ColoSeq can detect mutations in as little as 2% of DNA. 16 In the three cases that are possibly explained in our study, it was difficult to determine whether the mutations were associated with LOH. In all three cases, the tumors accumulated frequent mutations (range 38–126 per Mb) supporting the notion that the MMR gene mutations were pathogenic.…”

Section: Discussionmentioning

confidence: 76%

“…Mosaic mutations are detectable by this methodology when present in as little as 2% of the DNA. 16 Single nucleotide variant and indel calling was performed through the GATK Universal Genotyper using default parameters and using VarScan v2.3.2. 17 Deletion/duplication analysis was performed using CONTRA v2.0.3 18 with customized scripts to allow accurate detection of events at exon-level resolution.…”

Section: Methodsmentioning

confidence: 99%

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Colon and Endometrial Cancers With Mismatch Repair Deficiency Can Arise From Somatic, Rather Than Germline, Mutations

et al. 2014

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Background & Aims Patients with Lynch syndrome carry germline mutations in single alleles of genes encoding the MMR proteins MLH1, MSH2, MSH6 and PMS2; when the second allele becomes mutated, cancer can develop. Increased screening for Lynch syndrome has identified patients with tumors that have deficiency in MMR, but no germline mutations in genes encoding MMR proteins. We investigated whether tumors with deficient MMR had acquired somatic mutations in patients without germline mutations in MMR genes using next-generation sequencing. Methods We analyzed blood and tumor samples from 32 patients with colorectal or endometrial cancer who participated in Lynch syndrome screening studies in Ohio and were found to have tumors with MMR deficiency (based on microsatellite instability and/or absence of MMR proteins in immunohistochemical analysis, without hypermethylation of MLH1), but no germline mutations in MMR genes. Tumor DNA was sequenced for MLH1, MSH2, MSH6, PMS2, EPCAM, POLE and POLD1 with ColoSeq and mutation frequencies were established. Results Twenty-two of 32 patients (69%) were found to have two somatic (tumor) mutations in MMR genes encoding proteins that were lost from tumor samples, based on immunohistochemistry. Of the 10 tumors without somatic mutations in MMR genes, 3 had somatic mutations with possible loss of heterozygosity that could lead to MMR deficiency, 6 were found to be false-positive results (19%), and 1 had no mutations known to be associated with MMR deficiency. All of the tumors found to have somatic MMR mutations were of the hypermutated phenotype (>12 mutations/Mb); 6 had mutation frequencies >200 per Mb, and 5 of these had somatic mutations in POLE, which encodes a DNA polymerase. Conclusions Some patients are found to have tumors with MMR deficiency during screening for Lynch syndrome, yet have no identifiable germline mutations in MMR genes. We found that almost 70% of these patients acquire somatic mutations in MMR genes, leading to a hypermutated phenotype of tumor cells. Patients with colon or endometrial cancers with MMR deficiency not explained by germline mutations might undergo analysis for tumor mutations in MMR genes, to guide future surveillance guidelines.

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Section: Discussionmentioning

confidence: 76%

Section: Methodsmentioning

confidence: 99%

Colon and Endometrial Cancers With Mismatch Repair Deficiency Can Arise From Somatic, Rather Than Germline, Mutations

et al. 2014

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“…Most patients with PS harbor somatic mutations in the AKT1 gene, and all cases with mutations in this gene display the same recurrent gain-of-function missense mutation, p.E17K, in exon 1, which is present only in the affected overgrowth tissue in a mosaic pattern but not in normal tissue or in blood cells (Lindhurst et al, 2011). However, patients with PS-like findings have also been reported to have loss-of-function mutations, some of them being germline mutations with very severe phenotype, in the PTEN gene ( Table 2) Multiple organ involvement or congenital tissue-limited asymmetrical overgrowth syndrome See Table 2 Germline; gain of function Pritchard et al, 2013;Salo-Mullen et al, 2014;Schmid et al, 2014). In addition, both somatic and germline loss-of-function mutations have been disclosed in the PTEN gene in patients with the Cowden syndrome characterized by soft-tissue overgrowth commonly found in the skin and mucous membranes, but which can also affect the intestine and other parts of the body (Tan et al, 2011).…”

Section: Molecular Basis Of Tissue Overgrowth Syndromesmentioning

confidence: 97%

Molecular Genetics of the PI3K-AKT-mTOR Pathway in Genodermatoses: Diagnostic Implications and Treatment Opportunities

Vahidnezhad

Youssefian

Uitto

2016

Journal of Investigative Dermatology

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A number of critical signaling pathways are required for homeostatic regulation of cell survival, differentiation, and proliferation during organogenesis. One of them is the PI3K-AKT-mTOR pathway consisting of a cascade of inhibitor/activator molecules. Recently, a number of heritable diseases with skin involvement, manifesting particularly with tissue overgrowth, have been shown to result from mutations in the genes in the PI3K-AKT-mTOR and interacting intracellular pathways. Many of these conditions represent an overlapping spectrum of phenotypic manifestations forming a basis for novel, unifying classiﬁcations. Identiﬁcation of the mutant genes and speciﬁc mutations in these patients has implications for diagnostics and genetic counseling and provides a rational basis for the development of novel treatment modalities for this currently intractable group of disorders.

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“…We propose that considering the diagnostic or screening context of genomic testing and evaluating variants in different contexts using different pre-test probabilities will bend the linear relationship between amount of DNA sequenced and number of variants reported to patients (Outstanding Questions Box). The combinations of relatively rapid functional assays, such as assays for potential splice altering variants with family follow-up, are powerful, and when used well have allowed identification of new types of disease causing variants (Pritchard et al, 2013, Shirts et al, 2014). Given the ubiquity of family-specific variants, personalized medicine will necessarily lead to personalized research.…”

Section: Discussionmentioning

confidence: 99%

Family-Specific Variants and the Limits of Human Genetics

Shirts

Pritchard

Walsh

2016

Trends in Molecular Medicine

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Every single nucleotide change compatible with life is present in the human population today. Understanding these rare human variants defines an extraordinary challenge for genetics and medicine. The new clinical practice of sequencing many genes for hereditary cancer risk has illustrated the utility of clinical next-generation sequencing in adults, identifying more medically actionable variants than single gene testing. However, it has also revealed a linear relationship between length of DNA evaluated and number of rare “variants of uncertain significance” reported. We propose that careful approaches to phenotype-genotype inference, distinguishing between diagnostic and screening intent, and expanded use of family-scale genetics studies as a source of information on family-specific variants will reduce variants of uncertain significance reported to patients.

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A mosaic PTEN mutation causing Cowden syndrome identified by deep sequencing

Cited by 33 publications

References 19 publications

Colon and Endometrial Cancers With Mismatch Repair Deficiency Can Arise From Somatic, Rather Than Germline, Mutations

Colon and Endometrial Cancers With Mismatch Repair Deficiency Can Arise From Somatic, Rather Than Germline, Mutations

Molecular Genetics of the PI3K-AKT-mTOR Pathway in Genodermatoses: Diagnostic Implications and Treatment Opportunities

Family-Specific Variants and the Limits of Human Genetics

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