Publications by authors named "Jessica L Mester"

24 Publications

  • Page 1 of 1

Apparently Heterozygous TP53 Pathogenic Variants May Be Blood Limited in Patients Undergoing Hereditary Cancer Panel Testing.

J Mol Diagn 2020 03 24;22(3):396-404. Epub 2019 Dec 24.

Inherited Cancer Program, GeneDx, Inc., Gaithersburg, Maryland.

Heterozygous (HET) TP53 pathogenic variants (PVs) are associated with Li-Fraumeni syndrome (LFS), a dominantly inherited condition causing high risk for sarcoma, breast, and other cancers. Recent reports describe patients without features of LFS and apparently HET TP53 PVs in blood cells but not fibroblasts (FBs), suggesting the variant occurred sporadically during hematopoiesis and rose to high allele fraction through clonal expansion. To explore possible clonal hematopoiesis in patients undergoing hereditary cancer testing, FB testing was performed for patients with apparently HET or mosaic TP53 PVs identified in blood, oral rinse, or buccal specimens via next-generation sequencing panels. Among 291 individuals with TP53 PVs, 146 (50.2%) appeared HET and 145 (49.8%) were mosaic. Twenty-eight HET cases were proven constitutional through familial testing. FB testing was completed for 17 apparently HET and 36 mosaic patients. FB testing was positive in 11 of 17 (64.7%) apparently HET patients, only one of whom met Chompret criteria. Of 36 mosaic patients, 5 (13.9%) were also mosaic in FBs, indicating constitutional mosaicism. Breast cancers in patients with constitutional TP53 PVs were diagnosed at younger ages (P < 0.0001) and more likely to demonstrate human epidermal growth factor receptor 2 overexpression (P = 0.0003). These results demonstrate the utility of cultured FB testing to clarify constitutional status for TP53 PVs identified on next-generation sequencing panels, particularly for patients not meeting LFS or Chompret criteria.
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http://dx.doi.org/10.1016/j.jmoldx.2019.12.003DOI Listing
March 2020

ClinGen Variant Curation Expert Panel experiences and standardized processes for disease and gene-level specification of the ACMG/AMP guidelines for sequence variant interpretation.

Hum Mutat 2018 11;39(11):1614-1622

Department of Genetics, University of North Carolina, Chapel Hill, North Carolina.

Genome-scale sequencing creates vast amounts of genomic data, increasing the challenge of clinical sequence variant interpretation. The demand for high-quality interpretation requires multiple specialties to join forces to accelerate the interpretation of sequence variant pathogenicity. With over 600 international members including clinicians, researchers, and laboratory diagnosticians, the Clinical Genome Resource (ClinGen), funded by the National Institutes of Health, is forming expert groups to systematically evaluate variants in clinically relevant genes. Here, we describe the first ClinGen variant curation expert panels (VCEPs), development of consistent and streamlined processes for establishing new VCEPs, and creation of standard operating procedures for VCEPs to define application of the ACMG/AMP guidelines for sequence variant interpretation in specific genes or diseases. Additionally, ClinGen has created user interfaces to enhance reliability of curation and a Sequence Variant Interpretation Working Group (SVI WG) to harmonize guideline specifications and ensure consistency between groups. The expansion of VCEPs represents the primary mechanism by which curation of a substantial fraction of genomic variants can be accelerated and ultimately undertaken systematically and comprehensively. We welcome groups to utilize our resources and become involved in our effort to create a publicly accessible, centralized resource for clinically relevant genes and variants.
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http://dx.doi.org/10.1002/humu.23645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225902PMC
November 2018

Gene-specific criteria for PTEN variant curation: Recommendations from the ClinGen PTEN Expert Panel.

Hum Mutat 2018 11;39(11):1581-1592

Case Comprehensive Cancer Center, Cleveland, Ohio.

The ClinGen PTEN Expert Panel was organized by the ClinGen Hereditary Cancer Clinical Domain Working Group to assemble clinicians, researchers, and molecular diagnosticians with PTEN expertise to develop specifications to the 2015 ACMG/AMP Sequence Variant Interpretation Guidelines for PTEN variant interpretation. We describe finalized PTEN-specific variant classification criteria and outcomes from pilot testing of 42 variants with benign/likely benign (BEN/LBEN), pathogenic/likely pathogenic (PATH/LPATH), uncertain significance (VUS), and conflicting (CONF) ClinVar assertions. Utilizing these rules, classifications concordant with ClinVar assertions were achieved for 14/15 (93.3%) BEN/LBEN and 16/16 (100%) PATH/LPATH ClinVar consensus variants for an overall concordance of 96.8% (30/31). The variant where agreement was not reached was a synonymous variant near a splice donor with noncanonical sequence for which in silico models cannot predict the native site. Applying these rules to six VUS and five CONF variants, adding shared internal laboratory data enabled one VUS to be classified as LBEN and two CONF variants to be as classified as PATH and LPATH. This study highlights the benefit of gene-specific criteria and the value of sharing internal laboratory data for variant interpretation. Our PTEN-specific criteria and expertly reviewed assertions should prove helpful for laboratories and others curating PTEN variants.
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http://dx.doi.org/10.1002/humu.23636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329583PMC
November 2018

Utility of Expedited Hereditary Cancer Testing in the Surgical Management of Patients with a New Breast Cancer Diagnosis.

Ann Surg Oncol 2018 Nov 30;25(12):3556-3562. Epub 2018 Aug 30.

GeneDx, Gaithersburg, MD, USA.

Background: Knowledge of a germline pathogenic/likely pathogenic variant (PV) may inform breast cancer management. BRCA1/2 PV often impact surgical decisions, but data for multi-gene panel testing are lacking. Expedited genetic testing reduces turn-around times based on request for treatment-related decision making. This report aims to describe the clinical utility of expedited multi-gene panel testing for patients with newly diagnosed breast cancer.

Methods: Clinical and demographic information were reviewed for patients with newly diagnosed female breast cancer undergoing expedited panel testing between 2013 and 2017. The National Comprehensive Cancer Network guidelines (NCCN, version 1.2018) were evaluated in terms of published management recommendations for the genes in which PVs were identified.

Results: The overall PV yield was 9.5% (678/7127) for women undergoing expedited panel testing, with 700 PVs identified among 678 women. PVs were identified in genes other than BRCA1/2 in 55.9% (391/700) of cases. The NCCN guidelines recommend management for the genes in which 96.6% (676/700) of PVs are identified. The NCCN guidelines also recommend risk-reducing mastectomy for 46.0% (322/700) of PVs identified. An additional 45.6% (319/700) of PVs were identified in genes for which NCCN recommends mastectomy based on family history. In addition, 49.9% (349/700) of PVs were in genes with NCCN guidelines recommending prophylactic surgery for tissues other than breast.

Conclusion: A majority of the patients with newly diagnosed breast cancer were candidates for surgical intervention according to the NCCN guidelines, and half of these patients would have been missed if only BRCA1/2 testing had been ordered. Expedited multi-gene hereditary cancer panel testing should be considered as a first-line approach to provide comprehensive information for breast cancer management.
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http://dx.doi.org/10.1245/s10434-018-6581-8DOI Listing
November 2018

Exome sequencing reveals germline gain-of-function mutation in an adult with Lhermitte-Duclos disease.

Cold Spring Harb Mol Case Stud 2016 11;2(6):a001230

Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA;; Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA;; Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA;; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA;; CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA;; Germline High Risk Focus Group, CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA.

Lhermitte-Duclos disease (LDD) is a rare cerebellar disorder believed to be pathognomonic for Cowden syndrome. Presently, the only known etiology is germline mutation. We report a 41-yr-old white female diagnosed with LDD and wild-type for . Exome sequencing revealed a germline heterozygous mutation that breaks a disulfide bond in the receptor's extracellular domain, resulting in constitutive activation. Functional studies demonstrate activation of ERK/AKT signaling pathways, mimicking loss-of-function downstream effects. The identification of as a candidate LDD susceptibility gene contributes to advancement of molecular diagnosis and targeted therapy for this rare condition with limited treatment options.
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http://dx.doi.org/10.1101/mcs.a001230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5111001PMC
November 2016

Germline PARP4 mutations in patients with primary thyroid and breast cancers.

Endocr Relat Cancer 2016 Mar 23;23(3):171-9. Epub 2015 Dec 23.

Section of Hematology/OncologyDepartment of Medicine, The University of Chicago, Chicago, Illinois 60637, USAGenomic Medicine InstituteCleveland Clinic, Cleveland, Ohio 44195, USADepartment of Genetics and Genome SciencesComprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USAEndocrine Surgery Research ProgramSection of General Surgery, Department of Surgery, The University of Chicago, 5841 S Maryland Avenue, Chicago, Illinois 60637, USA

Germline mutations in the PTEN gene, which cause Cowden syndrome, are known to be one of the genetic factors for primary thyroid and breast cancers; however, PTEN mutations are found in only a small subset of research participants with non-syndrome breast and thyroid cancers. In this study, we aimed to identify germline variants that may be related to genetic risk of primary thyroid and breast cancers. Genomic DNAs extracted from peripheral blood of 14 PTEN WT female research participants with primary thyroid and breast cancers were analyzed by whole-exome sequencing. Gene-based case-control association analysis using the information of 406 Europeans obtained from the 1000 Genomes Project database identified 34 genes possibly associated with the phenotype with P < 1.0 × 10(-3). Among them, rare variants in the PARP4 gene were detected at significant high frequency (odds ratio = 5.2; P = 1.0 × 10(-5)). The variants, G496V and T1170I, were found in six of the 14 study participants (43%) while their frequencies were only 0.5% in controls. Functional analysis using HCC1143 cell line showed that knockdown of PARP4 with siRNA significantly enhanced the cell proliferation, compared with the cells transfected with siControl (P = 0.02). Kaplan-Meier analysis using Gene Expression Omnibus (GEO), European Genome-phenome Archive (EGA) and The Cancer Genome Atlas (TCGA) datasets showed poor relapse-free survival (P < 0.001, Hazard ratio 1.27) and overall survival (P = 0.006, Hazard ratio 1.41) in a PARP4 low-expression group, suggesting that PARP4 may function as a tumor suppressor. In conclusion, we identified PARP4 as a possible susceptibility gene of primary thyroid and breast cancer.
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http://dx.doi.org/10.1530/ERC-15-0359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5152685PMC
March 2016

Germline Heterozygous Variants in SEC23B Are Associated with Cowden Syndrome and Enriched in Apparently Sporadic Thyroid Cancer.

Am J Hum Genet 2015 Nov 29;97(5):661-76. Epub 2015 Oct 29.

Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address:

Cancer-predisposing genes associated with inherited cancer syndromes help explain mechanisms of sporadic carcinogenesis and often inform normal development. Cowden syndrome (CS) is an autosomal-dominant disorder characterized by high lifetime risks of epithelial cancers, such that ∼50% of affected individuals are wild-type for known cancer-predisposing genes. Using whole-exome and Sanger sequencing of a multi-generation CS family affected by thyroid and other cancers, we identified a pathogenic missense heterozygous SEC23B variant (c.1781T>G [p.Val594Gly]) that segregates with the phenotype. We also found germline heterozygous SEC23B variants in 3/96 (3%) unrelated mutation-negative CS probands with thyroid cancer and in The Cancer Genome Atlas (TCGA), representing apparently sporadic cancers. We note that the TCGA thyroid cancer dataset is enriched with unique germline deleterious SEC23B variants associated with a significantly younger age of onset. SEC23B encodes Sec23 homolog B (S. cerevisiae), a component of coat protein complex II (COPII), which transports proteins from the endoplasmic reticulum (ER) to the Golgi apparatus. Interestingly, germline homozygous or compound-heterozygous SEC23B mutations cause an unrelated disorder, congenital dyserythropoietic anemia type II, and SEC23B-deficient mice suffer from secretory organ degeneration due to ER-stress-associated apoptosis. By characterizing the p.Val594Gly variant in a normal thyroid cell line, we show that it is a functional alteration that results in ER-stress-mediated cell-colony formation and survival, growth, and invasion, which reflect aspects of a cancer phenotype. Our findings suggest a different role for SEC23B, whereby germline heterozygous variants associate with cancer predisposition potentially mediated by ER stress "addiction."
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http://dx.doi.org/10.1016/j.ajhg.2015.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667132PMC
November 2015

KLLN epigenotype-phenotype associations in Cowden syndrome.

Eur J Hum Genet 2015 Nov 11;23(11):1538-43. Epub 2015 Feb 11.

Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.

Germline KLLN promoter hypermethylation was recently identified as a potential genetic etiology of the cancer predisposition syndrome, Cowden syndrome (CS), when no causal PTEN gene mutation was found. We screened for KLLN promoter methylation in a large prospective series of CS patients and determined the risk of benign and malignant CS features in patients with increased methylation both with and without a PTEN mutation/variant of unknown significance. In all, 1012 CS patients meeting relaxed International Cowden Consortium criteria including 261 PTEN mutation-positive CS patients, 187 PTEN variant-positive CS patients and 564 PTEN mutation-negative CS patients, as well as 111 population controls were assessed for germline KLLN promoter methylation by MassARRAY EpiTYPER analysis. KLLN promoter methylation was analyzed both as a continuous and a dichotomous variable in the calculation of phenotypic risks by stepwise logistic regression and Kaplan-Meier/standardized incidence ratio methods, respectively. Significantly increased KLLN promoter methylation was seen in CS individuals with and without a PTEN mutation/VUS compared with controls (P<0.001). Patients with high KLLN promoter methylation have increased risks of all CS-associated malignancies compared with the general population. Interestingly, KLLN-associated risk of thyroid cancer appears to be gender and PTEN status dependent. KLLN promoter methylation associated with different benign phenotypes dependent on PTEN status. Furthermore, increasing KLLN promoter methylation is associated with a greater phenotype burden in mutation-negative CS patients. Germline promoter hypermethylation of KLLN is associated with particular malignant and benign CS features, which is dependent on the PTEN mutation status.
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http://dx.doi.org/10.1038/ejhg.2015.8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613489PMC
November 2015

Communicating with biobank participants: preferences for receiving and providing updates to researchers.

Cancer Epidemiol Biomarkers Prev 2015 Apr 18;24(4):708-12. Epub 2015 Jan 18.

Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio. Department of Bioethics, Cleveland Clinic, Cleveland, Ohio. Department of Bioethics, Case Western Reserve University, Cleveland, Ohio. Center for Clinical Investigation, Case Western Reserve University, Cleveland, Ohio. Biomedical Ethics Program, Mayo Clinic, Rochester, Minnesota.

Background: Research biobanks collect biologic samples and health information. Previous work shows that biobank participants desire general study updates, but preferences about the method or frequency of these communications have not been explored. Thus, we surveyed participants in a long-standing research biobank.

Methods: Eligible participants were drawn from a study of patients with personal/family history suggestive of Cowden syndrome, a poorly recognized inherited cancer syndrome. Participants gave blood samples and access to medical records and received individual results but had no other study interactions. The biobank had 3,618 participants at sampling. Survey eligibility included age ≥18 years, enrollment within the biobank's first 5 years, normal PTEN analysis, and contiguous U.S. address. Multivariate logistic regression analyses identified predictors of participant interest in Internet-based versus offline methods and methods allowing participant-researcher interaction versus one-way communication. Independent variables were narrowed by independent Pearson correlations by cutoff P < 0.2, with P < 0.02 considered significant.

Results: Surveys were returned from 840 of 1,267 (66%) eligible subjects. Most (97%) wanted study updates, with 92% wanting updates at least once a year. Participants preferred paper (66%) or emailed (62%) newsletter methods, with 95% selecting one of these. Older, less-educated, and lower-income respondents strongly preferred offline approaches (P < 0.001). Most (93%) had no concerns about receiving updates and 97% were willing to provide health updates to researchers.

Conclusion: Most participants were comfortable receiving and providing updated information. Demographic factors predicted communication preferences.

Impact: Researchers should make plans for ongoing communication early in study development and funders should support the necessary infrastructure for these efforts.
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http://dx.doi.org/10.1158/1055-9965.EPI-13-1375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383666PMC
April 2015

Germline PTEN, SDHB-D, and KLLN alterations in endometrial cancer patients with Cowden and Cowden-like syndromes: an international, multicenter, prospective study.

Cancer 2015 Mar 5;121(5):688-96. Epub 2014 Nov 5.

Section of Gynecologic Oncology/ObGyn and Women's Health Institute, Cleveland Clinic, Cleveland, Ohio.

Background: Endometrial cancer has been recognized only recently as a major component of Cowden syndrome (CS). Germline alterations in phosphatase and tensin homolog (PTEN; PTEN_mut+), succinate dehydrogenase B/C/D (SDHB-D; SDHx_var+), and killin (KLLN_Me+) cause CS and Cowden syndrome-like (CSL) phenotypes. This study was aimed at identifying the prevalence and clinicopathologic predictors of germline PTEN_mut+, SDHx_var+, and KLLN_Me+ in CS/CSL patients presenting with endometrial cancer.

Methods: PTEN and SDHB-D mutation and KLLN promoter methylation analyses were performed for 371 prospectively enrolled patients (2005-2011). PTEN protein was analyzed from patient-derived lymphoblast lines. The PTEN Cleveland Clinic (CC) score is a weighted, regression-based risk calculator giving the a priori risk for PTEN_mut+. Demographic and clinicopathologic features were correlated with the specific gene.

Results: Germline PTEN_mut+, SDHx_var+, and KLLN_Me+ were found in 7%, 9.8%, and 10.5% of informative samples, respectively. Predictors of PTEN_mut+ included an age ≤ 50 years (odds ratio [OR] for an age < 30 years, 6.1 [P = .015]; OR for an age of 30-50 years, 4.4 [P = .001]), macrocephaly (OR, 14.4; P < .001), a higher CC score (OR for a 1-U increment, 1.35; P < .001), a PTEN protein level within the lowest quartile (OR, 5.1; P = .039), and coexisting renal cancer (OR, 5.7; P = .002). KLLN_Me+ patients were on average 8 years younger than KLLN_Me- patients (44 vs 52 years, P = .018). Predictors of KLLN_Me+ were a younger age and a higher CC score. On the other hand, no clinical predictors of SDH_var+ were found.

Conclusions: Clinical predictors of PTEN and KLLN alterations, but not SDHx_var+, were identified. These predictors should alert the treating physician to potential heritable risk and the need for referral to genetic professionals. High-risk cancer surveillance and prophylactic surgery of the uterus may be considered for KLLN_Me+ patients similarly to PTEN_mut+ patients.
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http://dx.doi.org/10.1002/cncr.29106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4339629PMC
March 2015

Second malignant neoplasms in patients with Cowden syndrome with underlying germline PTEN mutations.

J Clin Oncol 2014 Jun 28;32(17):1818-24. Epub 2014 Apr 28.

Joanne Ngeow, Kim Stanuch, Jessica L. Mester, and Charis Eng, Cleveland Clinic; and Jill S. Barnholtz-Sloan and Charis Eng, Case Western Reserve University, Cleveland, OH.

Purpose: Patients with Cowden syndrome (CS) with underlying germline PTEN mutations are at increased risk of breast, thyroid, endometrial, and renal cancers. To our knowledge, risk of subsequent cancers in these patients has not been previously explored or quantified.

Patients And Methods: We conducted a 7-year multicenter prospective study (2005 to 2012) of patients with CS or CS-like disease, all of whom underwent comprehensive PTEN mutational analysis. Second malignant neoplasms (SMNs) were ascertained by medical records and confirmed by pathology reports. Standardized incidence ratios (SIRs) for all SMNs combined and for breast, thyroid, endometrial, and renal cancers were calculated.

Results: Of the 2,912 adult patients included in our analysis, 2,024 had an invasive cancer history. Germline pathogenic PTEN mutations (PTEN mutation positive) were identified in 114 patients (5.6%). Of these 114 patients, 46 (40%) had an SMN. Median age of SMN diagnosis was 50 years (range, 21 to 71 years). Median interval between primary cancer and SMN was 5 years (range, <1 to 35 years). Of the 51 PTEN mutation-positive patients who presented with primary breast cancer, 11 (22%) had a subsequent new primary breast cancer and 10-year second breast cancer cumulative risk of 29% (95% CI, 15.3 to 43.7). Risk of SMNs compared with that of the general population was significantly elevated for all cancers (SIR, 7.74; 95% CI, 5.84 to 10.07), specifically for breast (SIR, 8.92; 95% CI, 5.85 to 13.07), thyroid (SIR, 5.83; 95% CI, 3.01 to 10.18), and endometrial SMNs (SIR, 14.08.07; 95% CI, 7.10 to 27.21).

Conclusion: Patients with CS with germline PTEN mutations are at higher risk for SMNs compared with the general population. Prophylactic mastectomy should be considered on an individual basis given the significant risk of subsequent breast cancer.
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http://dx.doi.org/10.1200/JCO.2013.53.6656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039869PMC
June 2014

PTEN germline mutations in patients initially tested for other hereditary cancer syndromes: would use of risk assessment tools reduce genetic testing?

Oncologist 2013 13;18(10):1083-90. Epub 2013 Sep 13.

Genomic Medicine Institute.

Purpose: PTEN Hamartoma Tumor syndrome (PHTS) includes patients with Cowden syndrome or other syndromes with germline mutation of the PTEN tumor suppressor gene. The risk for breast, colorectal, and endometrial cancer and polyposis is increased, creating clinical overlap with hereditary breast and ovarian cancer (HBOC), Lynch syndrome (LS), and adenomatous polyposis syndromes (APS). We reviewed our series of patients with PHTS to determine how often testing criteria for these syndromes were met and how often other-gene testing was ordered before testing PTEN.

Patients And Methods: Patients were prospectively recruited by relaxed International Cowden Consortium criteria or presence of known germline PTEN mutation. Mutations were identified by mutation scanning/multiplex ligation-dependent probe amplification analysis and confirmed by sequencing/quantitative polymerase chain reaction. Patients were excluded if they were adopted, were <18 years of age, or if they were diagnosed with Cowden syndrome before 1998. Standard risk-assessment models were applied to determine whether patients met HBOC testing criteria, LS-relevant Amsterdam II/Bethesda 2004 criteria, or had adenomatous polyps. Prior probability of PTEN mutation was estimated with the Cleveland Clinic PTEN risk calculator.

Results: Of 137 PTEN mutation-positive adult probands, 59 (43.1%) met testing criteria for HBOC or LS. Of these, 45 (32.8%) were first offered HBOC, LS, or APS testing. Of those who underwent APS testing, none of the six patients met criteria. Initial risk assessment by a genetics specialist was significantly associated with immediate PTEN testing in patients also meeting HBOC testing criteria. Using this PTEN risk assessment tool could have spared gene testing for 22 unlikely syndromes, at a total cost of $66,080.

Conclusion: PHTS is an important differential diagnosis for patients referred for HBOC, LS, or APS. Risk assessment tools may help focus genetic analysis and aid in the interpretation of multiplex testing.
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http://dx.doi.org/10.1634/theoncologist.2013-0174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3805149PMC
May 2014

A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma.

Mol Cancer Res 2013 Sep 24;11(9):1061-1071. Epub 2013 May 24.

Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Unlabelled: Renal cell carcinoma (RCC) clusters in some families. Familial RCC arises from mutations in several genes, including the von Hippel-Lindau (VHL) tumor suppressor, which is also mutated in sporadic RCC. However, a significant percentage of familial RCC remains unexplained. Recently, we discovered that the BRCA1-associated protein-1 (BAP1) gene is mutated in sporadic RCC. The BAP1 gene encodes a nuclear deubiquitinase and appears to be a classic two-hit tumor suppressor gene. Somatic BAP1 mutations are associated with high-grade, clear-cell RCC (ccRCC) and poor patient outcomes. To determine whether BAP1 predisposes to familial RCC, the BAP1 gene was sequenced in 83 unrelated probands with unexplained familial RCC. Interestingly, a novel variant (c.41T>A; p.L14H) was uncovered that cosegregated with the RCC phenotype. The p.L14H variant targets a highly conserved residue in the catalytic domain, which is frequently targeted by missense mutations. The family with the novel BAP1 variant was characterized by early-onset ccRCC, occasionally of high Fuhrman grade, and lacked other features that typify VHL syndrome. These findings suggest that BAP1 is an early-onset familial RCC predisposing gene.

Implications: BAP1 mutations may drive tumor development in a subset of patients with inherited renal cell cancer.
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http://dx.doi.org/10.1158/1541-7786.MCR-13-0111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4211292PMC
September 2013

Biochemical screening and PTEN mutation analysis in individuals with autism spectrum disorders and macrocephaly.

Eur J Hum Genet 2014 Feb 22;22(2):273-6. Epub 2013 May 22.

1] Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA [2] Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA [3] Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA [4] CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Unlike some other childhood neurodevelopmental disorders, no diagnostic biochemical marker has been identified in all individuals with an autism spectrum disorder (ASD). This deficit likely results from genetic heterogeneity among the population. Therefore, we evaluated a subset of individuals with ASDs, specifically, individuals with or without macrocephaly in the presence or absence of PTEN mutations. We sought to determine if amino or organic acid markers could be used to identify individuals with ASDs with or without macrocephaly in the presence or absence of PTEN mutations, and to establish the degree of macrocephaly in individuals with ASDs and PTEN mutation. Urine, blood and occipital-frontal circumference (OFC) measurements were collected from 69 individuals meeting DSM-IV-TR criteria. Urine and plasma samples were subjected to amino and organic acid analyses. PTEN was Sanger-sequenced from germline genomic DNA. Germline PTEN mutations were identified in 27% (6/22) of the macrocephalic ASD population. All six PTEN mutation-positive individuals were macrocephalic with average OFC+4.35 standard deviations (SDs) above the mean. No common biochemical abnormalities were identified in macrocephalic ASD individuals with or without PTEN mutations. In contrast, among the collective ASD population, elevation of urine aspartic acid (87%; 54/62), plasma taurine (69%; 46/67) and reduction of plasma cystine (72%; 46/64) were observed. PTEN sequencing should be carried out for all individuals with ASDs and macrocephaly with OFC ≥2SDs above the mean. A proportion of individuals with ASDs may have an underlying disorder in sulfur amino acid metabolism.
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http://dx.doi.org/10.1038/ejhg.2013.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895634PMC
February 2014

Germline and somatic KLLN alterations in breast cancer dysregulate G2 arrest.

Hum Mol Genet 2013 Jun 27;22(12):2451-61. Epub 2013 Feb 27.

Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

PTEN is a well-described predisposition gene for Cowden syndrome (CS), a familial cancer syndrome characterized by a high risk of breast and other cancers. KLLN, which shares a bidirectional promoter with PTEN, causes cell cycle arrest and apoptosis. We previously identified germline hypermethylation of the KLLN promoter in 37% of PTEN mutation-negative CS/CS-like (CSL) patients. Patients with germline KLLN hypermethylation have an increased prevalence of breast and renal cancers when compared with PTEN mutation carriers. We have consequently sought to identify and characterize germline KLLN variants/mutations in CS/CSL and in apparently sporadic breast cancer patients. KLLN variants in CS/CSL patients are rare (1 of 136, 0.007%). Interestingly, among 438 breast cancer patients, 13 (3%) have germline KLLN variants when compared with none in 128 controls (P = 0.049). Patients with KLLN variants have a family history of breast cancer when compared with those without (P = 0.02). We demonstrate that germline KLLN variants dysregulate the cell cycle at G2. Of 24 breast carcinomas analyzed, 3 (13%) have somatic KLLN hemizygous deletions, with somatic loss of the wild-type allele in a patient with germline KLLN p.Leu119Leu. Of 452 breast carcinomas in The Cancer Genome Atlas project, 93 (21%) have KLLN hemizygous or homozygous deletions. This is the first study to associate germline KLLN variants with sporadic breast cancer and to recognize somatic KLLN deletions in breast carcinomas. Our observations suggest that KLLN may be a low penetrance susceptibility factor for apparently sporadic breast cancer.
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http://dx.doi.org/10.1093/hmg/ddt097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858115PMC
June 2013

Prevalence of germline PTEN, BMPR1A, SMAD4, STK11, and ENG mutations in patients with moderate-load colorectal polyps.

Gastroenterology 2013 Jun 8;144(7):1402-9, 1409.e1-5. Epub 2013 Feb 8.

Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.

Background & Aims: Gastrointestinal polyposis is a common clinical problem, yet there is no consensus on how to best manage patients with moderate-load polyposis. Identifying genetic features of this disorder could improve management and especially surveillance of these patients. We sought to determine the prevalence of hamartomatous polyposis-associated mutations in the susceptibility genes PTEN, BMPR1A, SMAD4, ENG, and STK11 in individuals with ≥5 gastrointestinal polyps, including at least 1 hamartomatous or hyperplastic/serrated polyp.

Methods: We performed a prospective, referral-based study of 603 patients (median age: 51 years; range, 2-89 years) enrolled from June 2006 through January 2012. Genomic DNA was extracted from peripheral lymphocytes and analyzed for specific mutations and large rearrangements in PTEN, BMPR1A, SMAD4, and STK11, as well as mutations in ENG. Recursive partitioning analysis was used to determine cutoffs for continuous variables. The prevalence of mutations was compared using Fisher's exact test. Logistic regression analyses were used to determine univariate and multivariate risk factors.

Results: Of 603 patients, 119 (20%) had a personal history of colorectal cancer and most (n = 461 [76%]) had <30 polyps. Seventy-seven patients (13%) were found to have polyposis-associated mutations, including 11 in ENG (1.8%), 13 in PTEN (2.2%), 13 in STK11 (2.2%), 20 in BMPR1A (3.3%), and 21 in SMAD4 (3.5%). Univariate clinical predictors for risk of having these mutations included age at presentation younger than 40 years (19% vs 10%; P = .008), a polyp burden of ≥30 (19% vs 11%; P = .014), and male sex (16% vs 10%; P = .03). Patients who had ≥1 ganglioneuroma (29% vs 2%; P < .001) or presented with polyps of ≥3 histologic types (20% vs 2%; P = .003) were more likely to have germline mutations in PTEN.

Conclusions: Age younger than 40 years, male sex, and specific polyp histologies are significantly associated with risk of germline mutations in hamartomatous-polyposis associated genes. These associations could guide clinical decision making and further investigations.
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http://dx.doi.org/10.1053/j.gastro.2013.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3969031PMC
June 2013

Germline PIK3CA and AKT1 mutations in Cowden and Cowden-like syndromes.

Am J Hum Genet 2013 Jan 13;92(1):76-80. Epub 2012 Dec 13.

Genomic Medicine Institute and Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Cowden syndrome (CS) is a difficult-to-recognize multiple hamartoma syndrome with high risks of breast, thyroid, and other cancers. Germline mutations in PTEN on 10q23 were found to cause 85% of CS when accrued from tertiary academic centers, but prospective accrual from the community over the last 12 years has revealed a 25% PTEN mutation frequency. PTEN is the phosphatase that has been implicated in a heritable cancer syndrome and subsequently in multiple sporadic cancers and developmental processes. PTEN antagonizes the AKT1/PI3K signaling pathway and has roles in cell cycle, migration, cell polarity, and apoptosis. We report that 8 of 91 (8.8%) unrelated CS individuals without germline PTEN mutations carried 10 germline PIK3CA mutations (7 missense, 1 nonsense, and 2 indels) and 2 (2.2%) AKT1 mutations. These mutations result in significantly increased P-Thr308-AKT and increased cellular PIP3. Our observations suggest that PIK3CA and AKT1 are CS susceptibility genes.
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http://dx.doi.org/10.1016/j.ajhg.2012.10.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3542473PMC
January 2013

Utility of PTEN protein dosage in predicting for underlying germline PTEN mutations among patients presenting with thyroid cancer and Cowden-like phenotypes.

J Clin Endocrinol Metab 2012 Dec 12;97(12):E2320-7. Epub 2012 Oct 12.

Genomic Medicine Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.

Context: Thyroid cancer is a major component of Cowden syndrome (CS). CS patients with an underlying PTEN mutation (PTEN(mut+)) have a 70-fold increased risk of developing epithelial thyroid cancer. In contrast, less than 1% of sporadic epithelial thyroid cancer patients carry a germline PTEN mutation. Cost-efficient markers capable of shortlisting thyroid cancers for CS genetic testing would be clinically useful.

Objective: Our objective was to analyze the utility of patient blood phosphate and tensin homolog deleted on chromosome 10 (PTEN) protein levels in predicting germline PTEN mutations.

Design, Setting, And Patients: We conducted a 5-yr, multicenter prospective study of 2792 CS and CS-like patients, all of whom had comprehensive PTEN analysis. Analysis of PTEN and downstream proteins by immunoblotting was performed on total protein lysates from patient-derived lymphoblast lines. We compared blood PTEN protein levels between PTEN(mut+) patients and those with variants of unknown significance or wild-type PTEN (PTEN(wt/vus)).

Main Outcome Measures: We assessed the utility of PTEN protein levels in predicting germline PTEN mutations.

Results: Of 2792 CS/CS-like patients, 721 patients had thyroid cancer; 582 of them (81%) had blood PTEN protein analyzed. PTEN germline pathogenic mutations were present in 27 of 582 patients (4.6%). Ninety-six percent (26 of 27) of PTEN(mut+) patients had blood PTEN protein levels in the lowest quartile as compared with 25% (139 of 555) of PTEN(wt/vus) patients (P < 0.001). Low blood PTEN levels predicted for PTEN(mut+) cases with a 99.76% negative predictive value (95% confidence interval = 98.67-99.96) and a positive test likelihood ratio of 3.84 (95% confidence interval = 3.27-4.52).

Conclusions: Our study shows that low blood PTEN protein expression could serve as a screening molecular correlate to predict for germline PTEN mutation in CS and CS-like presentations of thyroid cancer.
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http://dx.doi.org/10.1210/jc.2012-2944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3513537PMC
December 2012

Genetic counselors: your partners in clinical practice.

Cleve Clin J Med 2012 Aug;79(8):560-8

Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

As our understanding of the human genome has grown, so too has the need for health care providers who can help patients and families understand the implications of these new discoveries for their health care. Increasingly, genetic counselors are working in partnership with physicians to provide a continuum of care from risk assessment to diagnosis. In this article, we explain the process of genetic counseling and its value for patients who have a personal or family history of a hereditary condition.
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http://dx.doi.org/10.3949/ccjm.79a.11091DOI Listing
August 2012

Papillary renal cell carcinoma is associated with PTEN hamartoma tumor syndrome.

Urology 2012 May 3;79(5):1187.e1-7. Epub 2012 Mar 3.

Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.

Objective: To formally study the prevalence and histologic classification of renal cell carcinoma (RCC) in a series of patients with PTEN hamartoma tumor syndrome (PHTS).

Methods: We evaluated prevalence of RCC within a prospectively-accrued series of 219 patients found to have pathogenic germline PTEN mutations. Clinical data including pathology reports were requested for all participants. Slides and tumor blocks were requested for central pathology re-review and immunohistochemistry (IHC) analysis.

Results: Nine patients were identified with RCC. Based on Surveillance Epidemiology and End Results (SEER) data 0.28 RCC cases were expected for the group, giving an overall age-adjusted Standardized Incidence Ratio (SIR) of 31.7 (95% CI 15.4-58.1, P < 0.001) with a higher sex-adjusted SIR for females (46.7 vs 21.6 for males). Reported histology of each mutation positive patient's RCC was variable. However, on central pathology re-review of eight patients, six examined lesions were determined to be of papillary subhistology (pRCC), with the other two patients' tumors consistent with the initial report of chromophobe RCC (chRCC). IHC demonstrated complete loss of PTEN protein in all PTEN mutation positive patients' pRCCs and patchy positivity in one chRCC.

Conclusion: PHTS is a hereditary syndrome newly associated with pRCC, and PTEN IHC may be a helpful screening tool to identify pRCC patients with PHTS. Physicians caring for PHTS patients should note the >31-fold increased risk for RCC and have a low threshold for investigating possible RCC in patients with relevant complaints. Renal ultrasound is not sensitive for detecting pRCC and so PHTS patients should have alternate renal imaging (CT or MRI).
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http://dx.doi.org/10.1016/j.urology.2011.12.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341468PMC
May 2012

Elevated plasma succinate in PTEN, SDHB, and SDHD mutation-positive individuals.

Genet Med 2012 Jun 26;14(6):616-9. Epub 2012 Jan 26.

Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

Purpose: Cowden syndrome results from germline mutations in the gene for phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and from variants in succinate dehydrogenase B and D subunits. We hypothesized that succinate accumulation may be common among individuals with SDH variants/mutations and those with PTEN mutations.

Methods: Urine and blood were collected from individuals meeting full or partial Cowden syndrome diagnostic criteria or those with paraganglioma (PGL) or a known susceptibility paraganglioma-associated gene mutation, and succinate was measured. PTEN, SDHB, SDHC, and SDHD genes were sequenced from genomic DNA.

Results: Elevated plasma succinate was observed in 13/21 (62%) individuals with germline PTEN, SDHB, or SDHD mutations as compared with 5/32 (16%) controls (P < 0.001), in 10/15 (67%) individuals with pathogenic PTEN mutations but in <20% of mutation-negative individuals meeting identical criteria, and in individuals with mutations in SDHB (1/1, 100%) and SDHD (2/5, 40%).

Conclusion: Our data suggest that mutations in PTEN, SDHB, and SDHD reduce catalytic activity of succinate dehydrogenase, resulting in succinate accumulation, and identify a common biochemical alteration in these two patient populations (PTEN and SDHx mutation positive individuals). Plasma organic acid analysis may provide an effective and inexpensive screening method to determine when more expensive gene sequencing of PTEN and SDH genes is warranted.
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http://dx.doi.org/10.1038/gim.2011.63DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019996PMC
June 2012

Lifetime cancer risks in individuals with germline PTEN mutations.

Clin Cancer Res 2012 Jan;18(2):400-7

Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, OH 44195, USA.

Purpose: Age-adjusted cancer incidence and age-related penetrance studies have helped guide cancer risk assessment and management. PTEN hamartoma tumor syndrome (PHTS) is a term encompassing subsets of several clinical syndromes with germline mutations in the PTEN tumor suppressor gene. We conducted the first prospective study to clarify corresponding cancer risks to shed biologic insights on human germline PTEN mutations, and to better inform current surveillance recommendations on the basis of expert opinion.

Experimental Design: A series of 3,399 individuals meeting relaxed International Cowden Consortium PHTS criteria were prospectively recruited; 368 individuals were found to have deleterious germline PTEN mutations. Age-adjusted standardized incidence ratio (SIR) calculations and genotype-phenotype analyses were carried out.

Results: Elevated SIRs were found for carcinomas of the breast [25.4, 95% confidence interval (CI), 19.8-32.0], thyroid (51.1, 38.1-67.1), endometrium (42.9, 28.1-62.8), colorectum (10.3, 5.6-17.4), kidney (30.6, 17.8-49.4), and melanoma (8.5, 4.1-15.6). Estimated lifetime risks were, respectively, 85.2% (95% CI, 71.4%-99.1%), 35.2% (19.7%-50.7%), 28.2% (17.1%-39.3%), 9.0% (3.8%-14.1%), 33.6% (10.4%-56.9%), and 6% (1.6%-9.4%). Promoter mutations were associated with breast cancer, whereas colorectal cancer was associated with nonsense mutations.

Conclusion: Lifetime risks for a variety of cancers, now extending to colorectal cancer, kidney cancer, and melanoma, are increased in patients with PTEN mutations. The genotype-phenotype associations here may provide new insights on PTEN structure and function. We propose a comprehensive approach to surveillance of patients with PTEN mutations.
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http://dx.doi.org/10.1158/1078-0432.CCR-11-2283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3261579PMC
January 2012

Analysis of prevalence and degree of macrocephaly in patients with germline PTEN mutations and of brain weight in Pten knock-in murine model.

Eur J Hum Genet 2011 Jul 23;19(7):763-8. Epub 2011 Feb 23.

Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

PTEN Hamartoma Tumour Syndrome (PHTS) includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), and other conditions resulting from germline mutation of the PTEN tumour suppressor gene. Although macrocephaly, presumably due to megencephaly, is found in both CS and BRRS, the prevalence and degree have not been formally assessed in PHTS. We evaluated head size in a prospective nested series of 181 patients found to have pathogenic germline PTEN mutations. Clinical data including occipital-frontal circumference (OFC) measurement were requested for all participants. Macrocephaly was present in 94% of 161 evaluable PHTS individuals. In patients ≤ 18 years, mean OFC was +4.89 standard deviations (SD) above the population mean with no difference between genders (P = 0.7). Among patients >18 years, average OFC was 60.0 cm in females and 62.8 cm in males (P < 0.0001). To systematically determine whether macrocephaly was due to megencephaly, we examined Pten(M3M4) missense mutant mice generated and maintained on mixed backgrounds. Mice were killed at various ages, brains were dissected out and weighed. Average brain weight for Pten(M3M4) homozygous mice (N = 15) was 1.02 g compared with 0.57 g for heterozygous mice (N = 29) and 0.49 g for wild-type littermates (N = 24) (P < 0.0001). Macrocephaly, secondary to megencephaly, is an important component of PHTS and more prevalent than previously appreciated. Patients with PHTS have increased risks for breast and thyroid cancers, and early diagnosis is key to initiating timely screening to reduce patient morbidity and mortality. Clinicians should consider germline PTEN testing at an early point in the diagnostic work-up for patients with extreme macrocephaly.
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http://dx.doi.org/10.1038/ejhg.2011.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137495PMC
July 2011

Perceptions of licensure: a survey of Michigan genetic counselors.

J Genet Couns 2009 Aug 19;18(4):357-65. Epub 2009 May 19.

Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

This study by the Michigan Genetic Counselor Licensure Committee is the first known published documentation of genetic counselors' beliefs and attitudes about licensure. The response rate from genetic counselors in Michigan was 66% (41/62). Ninety-five percent of respondents were supportive of licensure. Respondents believed licensure would legitimize genetic counseling as a distinct allied healthcare profession (97.5%), increase the public's protection (75%), and allow genetic counselors to practice independently (67%). While 45% felt licensure would increase counselor involvement in lawsuits, this did not impact licensure support (p = 0.744). Opinions were split regarding physician supervision and ordering tests. Even though 28% favored physician supervision, there was overwhelming support for genetic counselors performing some components of genetic testing (95%) and ordering some types of genetic tests (82%) independent of a physician. Use of this survey may be helpful in other states to assess genetic counselors' interest in licensure and for drafting legislation.
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http://dx.doi.org/10.1007/s10897-009-9225-0DOI Listing
August 2009