Dataset Information

Clinical Validity of Next-Generation Sequencing Multi-Gene Panel Testing for Detecting Pathogenic Variants in Patients With Hereditary Breast-Ovarian Cancer Syndrome.

ABSTRACT: BACKGROUND:Hereditary breast and ovarian cancer syndrome (HBOC) is caused by pathogenic variants in BRCA and other cancer-related genes. We analyzed variants in BRCA gene and other cancer-related genes in HBOC patients to evaluate the clinical validity of next-generation sequencing (NGS) multi-gene panel testing. METHODS:The BRCA1/2 NGS testing was conducted for 262 HBOC patients. Multiplex ligation-dependent probe amplification and direct Sanger sequencing were performed for confirmation. Multi-gene panel testing was conducted for 120 patients who did not possess BRCA1/2 pathogenic variants but met the National Comprehensive Cancer Network criteria. RESULTS:Pathogenic variants in BRCA1/2 were detected in 30 HBOC patients (11.5%). Additionally, four out of the 120 patients possessed pathogenic variants by multi-gene panel testing (3.3%): MSH2 (c.256G>T, p.Glu86*), PMS2 (c.1687C>T, p.Arg563*), CHEK2 (c.546C>A, p.Tyr182*), and PALB2 (c.3351-1G>C). All the four patients had a family history of cancer. CONCLUSIONS:Multi-gene panel testing could be a significant screening tool for HBOC patients, especially for those with a family history of cancer.

SUBMITTER: Yoo J

PROVIDER: S-EPMC6822011 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

Clinical Validity of Next-Generation Sequencing Multi-Gene Panel Testing for Detecting Pathogenic Variants in Patients With Hereditary Breast-Ovarian Cancer Syndrome.

Yoo Jaeeun J Lee Gun Dong GD Kim Jee Hae JH Lee Seung Nam SN Chae Hyojin H Han Eunhee E Kim Yonggoo Y Kim Myungshin M

Annals of laboratory medicine 20200301 2

<h4>Background</h4>Hereditary breast and ovarian cancer syndrome (HBOC) is caused by pathogenic variants in <i>BRCA</i> and other cancer-related genes. We analyzed variants in <i>BRCA</i> gene and other cancer-related genes in HBOC patients to evaluate the clinical validity of next-generation sequencing (NGS) multi-gene panel testing.<h4>Methods</h4>The <i>BRCA1/2</i> NGS testing was conducted for 262 HBOC patients. Multiplex ligation-dependent probe amplification and direct Sanger sequencing we ...[more]

PMID: 31650731

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Project description:Background:Understanding the genetic basis of cancer risk is a major international endeavor. The emergence of next-generation sequencing (NGS) in late 2000's has further accelerated the discovery of many cancer susceptibility genes. The use of targeted NGS-based multigene testing panels to provide comprehensive analysis of cancer susceptible genes has proven to be a viable option, with the accurate and robust detection of a wide range of clinically relevant variants in the targeted genes being crucial. Methods:We have developed and validated a targeted NGS-based test for hereditary cancer risk assessment using Illumina's NGS platform by analyzing the protein-coding regions of 35 hereditary cancer genes with a bioinformatics pipeline that utilizes standard practices in the field. This 35-gene hereditary cancer panel is designed to identify germline cancer-causing mutations for 8 different cancers: breast, ovarian, prostate, uterine, colorectal, pancreatic, stomach cancers and melanoma. The panel was validated using well-characterized DNA specimens [NIGMS Human Genetic Cell Repository], where DNA had been extracted using blood of individuals whose genetic variants had been previously characterized by the 1000 Genome Project and the Coriell Catalog. Results:The 35-gene hereditary cancer panel shows high sensitivity (99.9%) and specificity (100%) across 4820 variants including single nucleotide variants (SNVs) and small insertions and deletions (indel; up to 25?bp). The reproducibility and repeatability are 99.8 and 100%, respectively. Conclusions:The use of targeted NGS-based multigene testing panels to provide comprehensive analysis of cancer susceptible genes has been considered a viable option. In the present study, we developed and validated a 35-gene panel for testing 8 common cancers using next-generation sequencing (NGS). The performance of our hereditary cancer panel is assessed across a board range of variants in the 35 genes to support clinical use.

Project description:Recent advances in next generation sequencing have enabled panel gene testing, or simultaneous testing for mutations in multiple genes for a clinical condition. With more extensive and widespread genetic testing, there will be increased detection of genes with moderate penetrance without established clinical guidelines and of variants of uncertain significance (VUS), or genetic variants unknown to either be disease-causing or benign. This study surveyed 232 patients who underwent genetic counseling for hereditary breast and ovarian cancer to examine the impact of panel gene testing on psychological outcomes, patient understanding, and utilization of genetic information. The survey used standardized instruments including the Impact of Event Scale (IES), Multidimensional Impact of Cancer Risk Assessment (MICRA), Satisfaction with Decision Instrument (SWD), Ambiguity Tolerance Scale (AT-20), genetics knowledge, and utilization of genetic test results. Study results suggested that unaffected individuals with a family history of breast or ovarian cancer who received positive results were most significantly impacted by intrusive thoughts, avoidance, and distress. However, scores were also modestly elevated among unaffected patients with a family history of breast and ovarian cancer who received VUS, highlighting the impact of ambiguous results that are frequent among patients undergoing genetic testing with large panels of genes. Potential risk factors for increased genetic testing-specific distress in this study included younger age, black or African American race, Hispanic origin, lower education level, and lower genetic knowledge and highlight the need for developing strategies to provide effective counseling and education to these communities, particularly when genetic testing utilizes gene panels that more commonly return VUS. More detailed pre-test education and counseling may help patients appreciate the probability of various types of test results and how results would be used clinically, and allow them to make more informed decisions about the type of genetic testing to select.

Dataset Information

Clinical Validity of Next-Generation Sequencing Multi-Gene Panel Testing for Detecting Pathogenic Variants in Patients With Hereditary Breast-Ovarian Cancer Syndrome.

Publications

Clinical Validity of Next-Generation Sequencing Multi-Gene Panel Testing for Detecting Pathogenic Variants in Patients With Hereditary Breast-Ovarian Cancer Syndrome.

Similar Datasets

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