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      Inherited breast cancer predisposition in Asians: multigene panel testing outcomes from Singapore

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          Abstract

          Genetic testing for germline mutations in breast cancer predisposition genes can potentially identify individuals at a high risk of developing breast and/or ovarian cancer. There is a paucity of such mutational information for Asians. Panel testing of 25 cancer susceptibility genes and BRCA1/2 deletion/duplication analysis was performed for 220 Asian breast cancer patients or their family members referred for genetics risk assessment. All 220 participants had at least one high-risk feature: having a family history of breast and/or ovarian cancer in first- and/or second-degree relatives; having breast and ovarian cancer in the same individual or bilateral breast cancer; having early-onset breast cancer or ovarian cancer (⩽40 years of age). We identified 67 pathogenic variants in 66 (30.0%) patients. Of these, 19 (28.3%) occurred in BRCA1, 16 (23.9%) in BRCA2, 7 (10.4%) in PALB2, 6 (9.0%) in TP53, 2 (3.0%) in PTEN, 2 (3.0%) in CDH1 and 15 (22.4%) in other predisposition genes. Notably, 47.8% of pathogenic variants were in non- BRCA1/2 genes. Of the 66 patients with pathogenic mutations, 63.6% (42/66) were under the age of 40 years. Family history of breast and/or ovarian cancer is enriched in patients with BRCA1/2 pathogenic variants but less predictive for non- BRCA1/2 related pathogenic variations. We detected a median of three variants of unknown significance (VUS) per gene (range 0–21). Custom gene panel testing is feasible and useful for the detection of pathogenic mutations and should be done in the setting of a formal clinical cancer genetics service given the rate of VUS.

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          Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results.

          Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic testing may detect changes that are clearly pathogenic, clearly neutral, or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based genetic testing, describe other standardized reporting systems used in oncology, and propose a standardized classification system for application to sequence-based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines. The international adoption of a standardized reporting system should improve the clinical utility of sequence-based genetic tests to predict cancer risk. (c) 2008 Wiley-Liss, Inc.
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            Realizing the promise of cancer predisposition genes.

            Genes in which germline mutations confer highly or moderately increased risks of cancer are called cancer predisposition genes. More than 100 of these genes have been identified, providing important scientific insights in many areas, particularly the mechanisms of cancer causation. Moreover, clinical utilization of cancer predisposition genes has had a substantial impact on diagnosis, optimized management and prevention of cancer. The recent transformative advances in DNA sequencing hold the promise of many more cancer predisposition gene discoveries, and greater and broader clinical applications. However, there is also considerable potential for incorrect inferences and inappropriate clinical applications. Realizing the promise of cancer predisposition genes for science and medicine will thus require careful navigation.
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              Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment.

              Multiple-gene sequencing is entering practice, but its clinical value is unknown. We evaluated the performance of a customized germline-DNA sequencing panel for cancer-risk assessment in a representative clinical sample. Patients referred for clinical BRCA1/2 testing from 2002 to 2012 were invited to donate a research blood sample. Samples were frozen at -80° C, and DNA was extracted from them after 1 to 10 years. The entire coding region, exon-intron boundaries, and all known pathogenic variants in other regions were sequenced for 42 genes that had cancer risk associations. Potentially actionable results were disclosed to participants. In total, 198 women participated in the study: 174 had breast cancer and 57 carried germline BRCA1/2 mutations. BRCA1/2 analysis was fully concordant with prior testing. Sixteen pathogenic variants were identified in ATM, BLM, CDH1, CDKN2A, MUTYH, MLH1, NBN, PRSS1, and SLX4 among 141 women without BRCA1/2 mutations. Fourteen participants carried 15 pathogenic variants, warranting a possible change in care; they were invited for targeted screening recommendations, enabling early detection and removal of a tubular adenoma by colonoscopy. Participants carried an average of 2.1 variants of uncertain significance among 42 genes. Among women testing negative for BRCA1/2 mutations, multiple-gene sequencing identified 16 potentially pathogenic mutations in other genes (11.4%; 95% CI, 7.0% to 17.7%), of which 15 (10.6%; 95% CI, 6.5% to 16.9%) prompted consideration of a change in care, enabling early detection of a precancerous colon polyp. Additional studies are required to quantify the penetrance of identified mutations and determine clinical utility. However, these results suggest that multiple-gene sequencing may benefit appropriately selected patients. © 2014 by American Society of Clinical Oncology.
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                Author and article information

                Journal
                NPJ Genom Med
                NPJ Genom Med
                NPJ Genomic Medicine
                Nature Publishing Group
                2056-7944
                13 January 2016
                2016
                : 1
                : 15003
                Affiliations
                [1 ] Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre , Singapore, Singapore
                [2 ] Division of Medical Oncology, National Cancer Centre Singapore , Singapore, Singapore
                [3 ] Oncology Academic Clinical Program, Duke-NUS Graduate Medical School , Singapore, Singapore
                [4 ] Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore
                [5 ] Centre for Computational Biology, Duke-NUS Graduate Medical School , Singapore, Singapore
                [6 ] Division of Biodevices and Diagnostics, Institute for Bioengineering and Nanotechnology , Singapore, Singapore
                [7 ] OncoCare Cancer Centre, Mount Elizabeth Novena Specialist Centre , Singapore, Singapore
                [8 ] Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore
                [9 ] Office of Clinical & Academic Faculty Affairs, Duke-NUS Graduate Medical School , Singapore, Singapore
                Author notes
                [10]

                These authors contributed equally to this work.

                [11]

                Joint Senior Authors.

                AL, YSY and PA conceived the study. AL and JN designed the study. PA and MHT provided genetic counselling and accrued participants for the study. EW, CC and MS contributed to acquisition of data. EW, SS, MM, CC, MS, SR, JN and AL contributed to data analysis and interpretation of data. All authors contributed to manuscript writing and approved the final version of the article. JN and AL are the guarantors of this manuscript.

                Article
                npjgenmed20153
                10.1038/npjgenmed.2015.3
                5685290
                29263802
                c2ac5e47-17d6-48b5-9b1a-ed8ec6a3807c
                Copyright © 2016 Center of Excellence in Genomic Medicine Research/Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 21 August 2015
                : 12 October 2015
                : 14 October 2015
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