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Article ; Online: Risk assessment and genetic testing for ovarian cancer.

Gulden, Cassandra / Olopade, Olufunmilayo I

2010 Volume 194, Issue 2, Page(s) 309–310

Abstract: Objective: Prevention of ovarian cancer starts with identifying women at high risk for this deadly disease. Once identified, these women can be offered risk-reducing options such as oral contraceptives and bilateral salpingo-oophorectomy. In this review, ...

Abstract	Objective: Prevention of ovarian cancer starts with identifying women at high risk for this deadly disease. Once identified, these women can be offered risk-reducing options such as oral contraceptives and bilateral salpingo-oophorectomy. In this review, strategies for identifying high-risk individuals and the clinical utility of genetic testing for BRCA1 and BRCA2 will be discussed. Conclusion: To offer potentially life-saving interventions for at-risk family members, we propose that every woman newly diagnosed with ovarian cancer be offered genetic testing for BRCA1 and BRCA2 genes because mutations in these genes are the strongest known predictors of ovarian cancer risk.
MeSH term(s)	Female ; Genes, BRCA1 ; Genes, BRCA2 ; Genetic Testing ; Humans ; Mutation ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/prevention & control ; Risk Assessment/methods
Language	English
Publishing date	2010-02
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	82076-3
ISSN	1546-3141 ; 0361-803X ; 0092-5381
ISSN (online)	1546-3141
ISSN	0361-803X ; 0092-5381
DOI	10.2214/AJR.09.3999
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Article ; Online: Racial differences in a high-risk colorectal cancer referral population

Gulden Cassandra / Moss Tovah / Olopade Olufunmilayo I / Kupfer Sonia

Hereditary Cancer in Clinical Practice , Vol 9, Iss Suppl 1, p P

a single-center experience

2011 Volume 15

Keywords	Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Oncology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Language	English
Publishing date	2011-03-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Longitudinal follow-up after telephone disclosure in the randomized COGENT study.

Kilbride, Madison K / Egleston, Brian L / Hall, Michael J / Patrick-Miller, Linda J / Daly, Mary B / Ganschow, Pamela / Grana, Generosa / Olopade, Olufunmilayo I / Fetzer, Dominique / Brandt, Amanda / Chambers, Rachelle / Clark, Dana F / Forman, Andrea / Gaber, Rikki / Gulden, Cassandra / Horte, Janice / Long, Jessica M / Lucas, Terra / Madaan, Shreshtha /

Mattie, Kristin / McKenna, Danielle / Montgomery, Susan / Nielsen, Sarah / Powers, Jacquelyn / Rainey, Kim / Rybak, Christina / Savage, Michelle / Seelaus, Christina / Stoll, Jessica / Stopfer, Jill E / Yao, Xinxin Shirley / Domchek, Susan M / Bradbury, Angela R

Genetics in medicine : official journal of the American College of Medical Genetics

2020 Volume 22, Issue 8, Page(s) 1401–1406

Abstract: Purpose: To better understand the longitudinal risks and benefits of telephone disclosure of genetic test results in the era of multigene panel testing.: Methods: Adults who were proceeding with germline cancer genetic testing were randomized to ... ...

Abstract	Purpose: To better understand the longitudinal risks and benefits of telephone disclosure of genetic test results in the era of multigene panel testing. Methods: Adults who were proceeding with germline cancer genetic testing were randomized to telephone disclosure (TD) with a genetic counselor or in-person disclosure (IPD) (i.e., usual care) of test results. All participants who received TD were recommended to return to meet with a physician to discuss medical management recommendations. Results: Four hundred seventy-three participants were randomized to TD and 497 to IPD. There were no differences between arms for any cognitive, affective, or behavioral outcomes at 6 and 12 months. Only 50% of participants in the TD arm returned for the medical follow-up appointment. Returning was associated with site (p < 0.0001), being female (p = 0.047), and not having a true negative result (p < 0.002). Mammography was lower at 12 months among those who had TD and did not return for medical follow-up (70%) compared with those who had TD and returned (86%) and those who had IPD (87%, adjusted p < 0.01). Conclusion: Telephone disclosure of genetic test results is a reasonable alternative to in-person disclosure, but attention to medical follow-up may remain important for optimizing appropriate use of genetic results.
MeSH term(s)	Adult ; Disclosure ; Female ; Follow-Up Studies ; Genetic Counseling ; Genetic Predisposition to Disease ; Genetic Testing ; Humans ; Telephone
Language	English
Publishing date	2020-05-07
Publishing country	United States
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural
ZDB-ID	1455352-1
ISSN	1530-0366 ; 1098-3600
ISSN (online)	1530-0366
ISSN	1098-3600
DOI	10.1038/s41436-020-0808-3
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Article ; Online: Performance of Lynch syndrome predictive models in a multi-center US referral population.

Khan, Omar / Blanco, Amie / Conrad, Peggy / Gulden, Cassandra / Moss, Tovah Z / Olopade, Olufunmilayo I / Kupfer, Sonia S / Terdiman, Jonathan

The American journal of gastroenterology

2011 Volume 106, Issue 10, Page(s) 1822–7; quiz 1828

Abstract: Objectives: Lynch syndrome is the most common cause of inherited colorectal cancer (CRC) and is due to germline mutations in mismatch repair (MMR) genes. Early Lynch syndrome diagnosis and appropriate CRC surveillance improves mortality. Traditional ... ...

Abstract	Objectives: Lynch syndrome is the most common cause of inherited colorectal cancer (CRC) and is due to germline mutations in mismatch repair (MMR) genes. Early Lynch syndrome diagnosis and appropriate CRC surveillance improves mortality. Traditional qualitative clinical criteria including Amsterdam and Bethesda guidelines may miss mutation carriers. Recently, quantitative predictive models including MMRPredict, PREMM(1,2,6), and MMRPro were developed to facilitate diagnosis. However, these models remain to be externally validated in the United States. Therefore, we evaluated the test characteristics of Lynch syndrome predictive models in a tertiary referral group at two US academic centers. Methods: We retrospectively collected data on 230 consecutive individuals who underwent genetic testing for MMR gene mutations at the University of Chicago and University of California at San Francisco's Cancer Risk Clinics. Each individual's risk of mutation was examined using MMRPredict, PREMM(1,2,6), and MMRPro. Amsterdam and Bethesda criteria were also determined. Testing characteristics were calculated for each of the models. Results: We included 230 individuals in the combined cohort. In all, 113 (49%) probands were MMR mutation carriers. Areas under the receiver operator characteristic curves were 0.76, 0.78, and 0.82 for MMRPredict, PREMM(1,2,6), and MMRPro, respectively. While similar in overall performance, our study highlights unique test characteristics of these three quantitative models including comparisons of sensitivity and specificity. Moreover, we identify characteristics of mutation carriers who were missed by each model. Conclusions: Overall, all three Lynch syndrome predictive models performed comparably in our multi-center US referral population. These results suggest that Lynch syndrome predictive models can be used to screen for MMR mutation carriers and can provide improved test characteristics compared with traditional clinical criteria. Identification of MMR mutation carriers is paramount as appropriate screening can prevent CRC mortality in this high-risk group.
MeSH term(s)	Adult ; Aged ; Cohort Studies ; Colorectal Neoplasms/epidemiology ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis ; Colorectal Neoplasms, Hereditary Nonpolyposis/epidemiology ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics ; DNA Mismatch Repair/genetics ; Female ; Genetic Testing ; Germ-Line Mutation ; Heterozygote ; Humans ; Male ; Middle Aged ; Predictive Value of Tests ; ROC Curve ; Research Design ; Retrospective Studies ; Sensitivity and Specificity ; United States/epidemiology
Language	English
Publishing date	2011-07-12
Publishing country	United States
Document type	Journal Article ; Multicenter Study ; Research Support, N.I.H., Extramural
ZDB-ID	390122-1
ISSN	1572-0241 ; 0002-9270
ISSN (online)	1572-0241
ISSN	0002-9270
DOI	10.1038/ajg.2011.200
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Article ; Online: Tumor genome analysis includes germline genome: are we ready for surprises?

Catenacci, Daniel V T / Amico, Andrea L / Nielsen, Sarah M / Geynisman, Daniel M / Rambo, Brittany / Carey, George B / Gulden, Cassandra / Fackenthal, Jim / Marsh, Robert D / Kindler, Hedy L / Olopade, Olufunmilayo I

International journal of cancer

2014 Volume 136, Issue 7, Page(s) 1559–1567

Abstract: We sought to describe the spectrum of potential and confirmed germline genomic events incidentally identified during routine medium-throughput somatic tumor DNA sequencing, and to provide a framework for pre- and post-test consent and counseling for ... ...

Abstract	We sought to describe the spectrum of potential and confirmed germline genomic events incidentally identified during routine medium-throughput somatic tumor DNA sequencing, and to provide a framework for pre- and post-test consent and counseling for patients and families. Targeted tumor-only next-generation sequencing (NGS) had been used to evaluate for possible druggable genomic events obtained from consecutive new patients with metastatic gastroesophageal, hepatobiliary or colorectal cancer seen at the University of Chicago. A panel of medical oncologists, cancer geneticists and genetic counselors retrospectively grouped these patients (N = 111) based on probability of possessing a potentially inherited mutation in a cancer susceptibility gene, both prior to and after incorporating tumor-only NGS results. High-risk patients (determined from NGS results) were contacted and counseled in person by a genetic counselor (N = 21). When possible and indicated, germline genetic testing was offered. Of 8 evaluable high-risk patients, 7 underwent germline testing. Three (37.5%) had confirmed actionable germline mutations (all in the BRCA2 gene). NGS offers promise, but poses significant challenges for oncologists who are ill prepared to handle incidental findings that have clinical implications for at risk family members. In this relatively small cohort of patients undergoing tumor genomic testing for gastrointestinal malignancies, we incidentally identified 3 BRCA2 mutations carriers. This report underscores the need for oncologists to develop a framework for pre- and post-test communication of risks to patients undergoing routine tumor-only sequencing.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Chromosome Aberrations ; Early Detection of Cancer ; Family ; Female ; Genetic Counseling ; Genetic Testing ; Genomics ; Germ Cells/metabolism ; Germ-Line Mutation ; High-Throughput Nucleotide Sequencing ; Humans ; Male ; Middle Aged ; Neoplasms/diagnosis ; Neoplasms/genetics ; Retrospective Studies
Language	English
Publishing date	2014-08-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218257-9
ISSN	1097-0215 ; 0020-7136
ISSN (online)	1097-0215
ISSN	0020-7136
DOI	10.1002/ijc.29128
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Article: Use and Patient-Reported Outcomes of Clinical Multigene Panel Testing for Cancer Susceptibility in the Multicenter Communication of Genetic Test Results by Telephone Study.

Hall, Michael J / Patrick-Miller, Linda J / Egleston, Brian L / Domchek, Susan M / Daly, Mary B / Ganschow, Pamela / Grana, Generosa / Olopade, Olufunmilayo I / Fetzer, Dominique / Brandt, Amanda / Chambers, Rachelle / Clark, Dana F / Forman, Andrea / Gaber, Rikki / Gulden, Cassandra / Horte, Janice / Long, Jessica M / Lucas, Terra / Madaan, Shreshtha /

JCO precision oncology

2018 Volume 2

Abstract: Purpose: Multigene panels (MGPs) are increasingly being used despite questions regarding their clinical utility and no standard approach to genetic counseling. How frequently genetic providers use MGP testing and how patient-reported outcomes (PROs) ... ...

Abstract	Purpose: Multigene panels (MGPs) are increasingly being used despite questions regarding their clinical utility and no standard approach to genetic counseling. How frequently genetic providers use MGP testing and how patient-reported outcomes (PROs) differ from targeted testing (eg, Methods: We evaluated use of MGP testing and PROs in participants undergoing cancer genetic testing in the multicenter Communication of Genetic Test Results by Telephone study (ClinicalTrials.gov identifier: ), a randomized study of telephone versus in-person disclosure of genetic test results. PROs included genetic knowledge, general and state anxiety, depression, cancer-specific distress, uncertainty, and satisfaction. Genetic providers offered targeted or MGP testing based on clinical assessment. Results: Since the inclusion of MGP testing in 2014, 395 patients (66%) were offered MGP testing. MGP testing increased over time from 57% in 2014 to 66% in 2015 ( Conclusion: MGP testing was more frequently offered to patients with lower anxiety, depression, and uncertainty and was associated with favorable outcomes, with the exception of a greater increase in uncertainty compared with patients who had targeted testing. Addressing uncertainty may be important as MGP testing is increasingly adopted.
Language	English
Publishing date	2018-12-18
Publishing country	United States
Document type	Journal Article
ISSN	2473-4284
ISSN	2473-4284
DOI	10.1200/PO.18.00199
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Article ; Online: Randomized Noninferiority Trial of Telephone vs In-Person Disclosure of Germline Cancer Genetic Test Results.

Bradbury, Angela R / Patrick-Miller, Linda J / Egleston, Brian L / Hall, Michael J / Domchek, Susan M / Daly, Mary B / Ganschow, Pamela / Grana, Generosa / Olopade, Olufunmilayo I / Fetzer, Dominique / Brandt, Amanda / Chambers, Rachelle / Clark, Dana F / Forman, Andrea / Gaber, Rikki / Gulden, Cassandra / Horte, Janice / Long, Jessica M / Lucas, Terra /

Madaan, Shreshtha / Mattie, Kristin / McKenna, Danielle / Montgomery, Susan / Nielsen, Sarah / Powers, Jacquelyn / Rainey, Kim / Rybak, Christina / Savage, Michelle / Seelaus, Christina / Stoll, Jessica / Stopfer, Jill E / Yao, Xinxin Shirley

Journal of the National Cancer Institute

2018 Volume 110, Issue 9, Page(s) 985–993

Abstract: Background: Germline genetic testing is standard practice in oncology. Outcomes of telephone disclosure of a wide range of cancer genetic test results, including multigene panel testing (MGPT) are unknown.: Methods: Patients undergoing cancer genetic ...

Abstract	Background: Germline genetic testing is standard practice in oncology. Outcomes of telephone disclosure of a wide range of cancer genetic test results, including multigene panel testing (MGPT) are unknown. Methods: Patients undergoing cancer genetic testing were recruited to a multicenter, randomized, noninferiority trial (NCT01736345) comparing telephone disclosure (TD) of genetic test results with usual care, in-person disclosure (IPD) after tiered-binned in-person pretest counseling. Primary noninferiority outcomes included change in knowledge, state anxiety, and general anxiety. Secondary outcomes included cancer-specific distress, depression, uncertainty, satisfaction, and screening and risk-reducing surgery intentions. To declare noninferiority, we calculated the 98.3% one-sided confidence interval of the standardized effect; t tests were used for secondary subgroup analyses. Only noninferiority tests were one-sided, others were two-sided. Results: A total of 1178 patients enrolled in the study. Two hundred eight (17.7%) participants declined random assignment due to a preference for in-person disclosure; 473 participants were randomly assigned to TD and 497 to IPD; 291 (30.0%) had MGPT. TD was noninferior to IPD for general and state anxiety and all secondary outcomes immediately postdisclosure. TD did not meet the noninferiority threshold for knowledge in the primary analysis, but it did meet the threshold in the multiple imputation analysis. In secondary analyses, there were no statistically significant differences between arms in screening and risk-reducing surgery intentions, and no statistically significant differences in outcomes by arm among those who had MGPT. In subgroup analyses, patients with a positive result had statistically significantly greater decreases in general anxiety with telephone disclosure (TD -0.37 vs IPD +0.87, P = .02). Conclusions: Even in the era of multigene panel testing, these data suggest that telephone disclosure of cancer genetic test results is as an alternative to in-person disclosure for interested patients after in-person pretest counseling with a genetic counselor.
MeSH term(s)	Adult ; Affect ; Biomarkers, Tumor ; Cognition ; Disclosure ; Female ; Genetic Counseling ; Genetic Predisposition to Disease ; Genetic Testing ; Humans ; Interviews as Topic ; Male ; Middle Aged ; Neoplasms, Germ Cell and Embryonal/diagnosis ; Neoplasms, Germ Cell and Embryonal/epidemiology ; Neoplasms, Germ Cell and Embryonal/genetics ; Telephone
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2018-02-28
Publishing country	United States
Document type	Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural
ZDB-ID	2992-0
ISSN	1460-2105 ; 0027-8874 ; 0198-0157
ISSN (online)	1460-2105
ISSN	0027-8874 ; 0198-0157
DOI	10.1093/jnci/djy015
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Article ; Online: Preferences for in-person disclosure: Patients declining telephone disclosure characteristics and outcomes in the multicenter Communication Of GENetic Test Results by Telephone study.

Beri, Nina / Patrick-Miller, Linda J / Egleston, Brian L / Hall, Michael J / Domchek, Susan M / Daly, Mary B / Ganschow, Pamela / Grana, Generosa / Olopade, Olufunmilayo I / Fetzer, Dominique / Brandt, Amanda / Chambers, Rachelle / Clark, Dana F / Forman, Andrea / Gaber, Rikki / Gulden, Cassandra / Horte, Janice / Long, Jessica / Lucas, Terra /

Clinical genetics

2018 Volume 95, Issue 2, Page(s) 293–301

Abstract: Telephone disclosure of cancer genetic test results is noninferior to in-person disclosure. However, how patients who prefer in-person communication of results differ from those who agree to telephone disclosure is unclear but important when considering ... ...

Abstract	Telephone disclosure of cancer genetic test results is noninferior to in-person disclosure. However, how patients who prefer in-person communication of results differ from those who agree to telephone disclosure is unclear but important when considering delivery models for genetic medicine. Patients undergoing cancer genetic testing were recruited to a multicenter, randomized, noninferiority trial (NCT01736345) comparing telephone to in-person disclosure of genetic test results. We evaluated preferences for in-person disclosure, factors associated with this preference and outcomes compared to those who agreed to randomization. Among 1178 enrolled patients, 208 (18%) declined randomization, largely given a preference for in-person disclosure. These patients were more likely to be older (P = 0.007) and to have had multigene panel testing (P < 0.001). General anxiety (P = 0.007), state anxiety (P = 0.008), depression (P = 0.011), cancer-specific distress (P = 0.021) and uncertainty (P = 0.03) were higher after pretest counseling. After disclosure of results, they also had higher general anxiety (P = 0.003), depression (P = 0.002) and cancer-specific distress (P = 0.043). While telephone disclosure is a reasonable alternative to in-person disclosure in most patients, some patients have a strong preference for in-person communication. Patient age, distress and complexity of testing are important factors to consider and requests for in-person disclosure should be honored when possible.
MeSH term(s)	Adult ; Aged ; Biomarkers, Tumor ; Communication ; Female ; Genetic Counseling/ethics ; Genetic Counseling/methods ; Genetic Predisposition to Disease ; Genetic Testing/ethics ; Hereditary Breast and Ovarian Cancer Syndrome/diagnosis ; Hereditary Breast and Ovarian Cancer Syndrome/epidemiology ; Hereditary Breast and Ovarian Cancer Syndrome/genetics ; Humans ; Male ; Middle Aged ; Neoplastic Syndromes, Hereditary/diagnosis ; Neoplastic Syndromes, Hereditary/epidemiology ; Neoplastic Syndromes, Hereditary/genetics ; Outcome Assessment, Health Care ; Patient Compliance ; Patient Preference ; Telephone ; Truth Disclosure
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2018-12-07
Publishing country	Denmark
Document type	Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural
ZDB-ID	221209-2
ISSN	1399-0004 ; 0009-9163
ISSN (online)	1399-0004
ISSN	0009-9163
DOI	10.1111/cge.13474
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Article ; Online: Mutation spectrum and risk of colorectal cancer in African American families with Lynch syndrome.

Guindalini, Rodrigo Santa Cruz / Win, Aung Ko / Gulden, Cassandra / Lindor, Noralane M / Newcomb, Polly A / Haile, Robert W / Raymond, Victoria / Stoffel, Elena / Hall, Michael / Llor, Xavier / Ukaegbu, Chinedu I / Solomon, Ilana / Weitzel, Jeffrey / Kalady, Matthew / Blanco, Amie / Terdiman, Jonathan / Shuttlesworth, Gladis A / Lynch, Patrick M / Hampel, Heather /

Lynch, Henry T / Jenkins, Mark A / Olopade, Olufunmilayo I / Kupfer, Sonia S

Gastroenterology

2015 Volume 149, Issue 6, Page(s) 1446–1453

Abstract: Background & aims: African Americans (AAs) have the highest incidence of and mortality resulting from colorectal cancer (CRC) in the United States. Few data are available on genetic and nongenetic risk factors for CRC among AAs. Little is known about ... ...

Abstract	Background & aims: African Americans (AAs) have the highest incidence of and mortality resulting from colorectal cancer (CRC) in the United States. Few data are available on genetic and nongenetic risk factors for CRC among AAs. Little is known about cancer risks and mutations in mismatch repair (MMR) genes in AAs with the most common inherited CRC condition, Lynch syndrome. We aimed to characterize phenotype, mutation spectrum, and risk of CRC in AAs with Lynch syndrome. Methods: We performed a retrospective study of AAs with mutations in MMR genes (MLH1, MSH2, MSH6, and PMS2) using databases from 13 US referral centers. We analyzed data on personal and family histories of cancer. Modified segregation analysis conditioned on ascertainment criteria was used to estimate age- and sex-specific CRC cumulative risk, studying members of the mutation-carrying families. Results: We identified 51 AA families with deleterious mutations that disrupt function of the MMR gene product: 31 in MLH1 (61%), 11 in MSH2 (21%), 3 in MSH6 (6%), and 6 in PMS2 (12%); 8 mutations were detected in more than 1 individual, and 11 have not been previously reported. In the 920 members of the 51 families with deleterious mutations, the cumulative risks of CRC at 80 years of age were estimated to be 36.2% (95% confidence interval [CI], 10.5%-83.9%) for men and 29.7% (95% CI, 8.31%-76.1%) for women. CRC risk was significantly higher among individuals with mutations in MLH1 or MSH2 (hazard ratio, 13.9; 95% CI, 3.44-56.5). Conclusions: We estimate the cumulative risk for CRC in AAs with MMR gene mutations to be similar to that of individuals of European descent with Lynch syndrome. Two-thirds of mutations were found in MLH1, some of which were found in multiple individuals and some that have not been previously reported. Differences in mutation spectrum are likely to reflect the genetic diversity of this population.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adenosine Triphosphatases/genetics ; Adult ; African Americans/genetics ; Age Factors ; Aged ; Aged, 80 and over ; Colorectal Neoplasms/epidemiology ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms, Hereditary Nonpolyposis/epidemiology ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics ; DNA Mismatch Repair/genetics ; DNA Repair Enzymes/genetics ; DNA-Binding Proteins/genetics ; Family ; Female ; Humans ; Incidence ; Male ; Middle Aged ; Mismatch Repair Endonuclease PMS2 ; MutL Protein Homolog 1 ; MutS Homolog 2 Protein/genetics ; Mutation ; Nuclear Proteins/genetics ; Retrospective Studies ; Risk Factors ; Sex Factors
Chemical Substances	Adaptor Proteins, Signal Transducing ; DNA-Binding Proteins ; G-T mismatch-binding protein ; MLH1 protein, human ; Nuclear Proteins ; Adenosine Triphosphatases (EC 3.6.1.-) ; PMS2 protein, human (EC 3.6.1.-) ; MSH2 protein, human (EC 3.6.1.3) ; Mismatch Repair Endonuclease PMS2 (EC 3.6.1.3) ; MutL Protein Homolog 1 (EC 3.6.1.3) ; MutS Homolog 2 Protein (EC 3.6.1.3) ; DNA Repair Enzymes (EC 6.5.1.-)
Language	English
Publishing date	2015-08-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80112-4
ISSN	1528-0012 ; 0016-5085
ISSN (online)	1528-0012
ISSN	0016-5085
DOI	10.1053/j.gastro.2015.07.052
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Article ; Online: ColoSeq provides comprehensive lynch and polyposis syndrome mutational analysis using massively parallel sequencing.

Pritchard, Colin C / Smith, Christina / Salipante, Stephen J / Lee, Ming K / Thornton, Anne M / Nord, Alex S / Gulden, Cassandra / Kupfer, Sonia S / Swisher, Elizabeth M / Bennett, Robin L / Novetsky, Akiva P / Jarvik, Gail P / Olopade, Olufunmilayo I / Goodfellow, Paul J / King, Mary-Claire / Tait, Jonathan F / Walsh, Tom

The Journal of molecular diagnostics : JMD

2012 Volume 14, Issue 4, Page(s) 357–366

Abstract: Lynch syndrome (hereditary nonpolyposis colon cancer) and adenomatous polyposis syndromes frequently have overlapping clinical features. Current approaches for molecular genetic testing are often stepwise, taking a best-candidate gene approach with ... ...

Abstract	Lynch syndrome (hereditary nonpolyposis colon cancer) and adenomatous polyposis syndromes frequently have overlapping clinical features. Current approaches for molecular genetic testing are often stepwise, taking a best-candidate gene approach with testing of additional genes if initial results are negative. We report a comprehensive assay called ColoSeq that detects all classes of mutations in Lynch and polyposis syndrome genes using targeted capture and massively parallel next-generation sequencing on the Illumina HiSeq2000 instrument. In blinded specimens and colon cancer cell lines with defined mutations, ColoSeq correctly identified 28/28 (100%) pathogenic mutations in MLH1, MSH2, MSH6, PMS2, EPCAM, APC, and MUTYH, including single nucleotide variants (SNVs), small insertions and deletions, and large copy number variants. There was 100% reproducibility of detection mutation between independent runs. The assay correctly identified 222 of 224 heterozygous SNVs (99.4%) in HapMap samples, demonstrating high sensitivity of calling all variants across each captured gene. Average coverage was greater than 320 reads per base pair when the maximum of 96 index samples with barcodes were pooled. In a specificity study of 19 control patients without cancer from different ethnic backgrounds, we did not find any pathogenic mutations but detected two variants of uncertain significance. ColoSeq offers a powerful, cost-effective means of genetic testing for Lynch and polyposis syndromes that eliminates the need for stepwise testing and multiple follow-up clinical visits.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adenomatous Polyposis Coli/genetics ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics ; DNA Glycosylases/genetics ; DNA Mutational Analysis/methods ; DNA-Binding Proteins/genetics ; Humans ; MutL Protein Homolog 1 ; MutS Homolog 2 Protein/genetics ; Nuclear Proteins/genetics
Chemical Substances	Adaptor Proteins, Signal Transducing ; DNA-Binding Proteins ; G-T mismatch-binding protein ; MLH1 protein, human ; Nuclear Proteins ; DNA Glycosylases (EC 3.2.2.-) ; mutY adenine glycosylase (EC 3.2.2.-) ; MSH2 protein, human (EC 3.6.1.3) ; MutL Protein Homolog 1 (EC 3.6.1.3) ; MutS Homolog 2 Protein (EC 3.6.1.3)
Language	English
Publishing date	2012-05-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2000060-1
ISSN	1943-7811 ; 1525-1578
ISSN (online)	1943-7811
ISSN	1525-1578
DOI	10.1016/j.jmoldx.2012.03.002
Database	MEDical Literature Analysis and Retrieval System OnLINE

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