Detection of Germline Mutations in Patients with Epithelial Ovarian Cancer Using Multi-gene Panels: Beyond BRCA1/2
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Purpose Next-generation sequencing (NGS) allows simultaneous sequencing of multiple cancer susceptibility genes and may represent a more efficient and less expensive approach than sequential testing. We assessed the frequency of germline mutations in individuals with epithelial ovarian cancer (EOC), using multi-gene panels and NGS. Materials and Methods Patients with EOC (n=117) with/without a family history of breast or ovarian cancer were recruited consecutively, from March 2016 to December 2016. Germline DNA was sequenced using 35-gene NGS panel, in order to identify mutations. Upon the detection of a genetic alteration using the panel, results were cross-validated using direct sequencing. Results Thirty-eight patients (32.5%) had 39 pathogenic or likely pathogenic mutations in eight genes, including BRCA1 (n=21), BRCA2 (n=10), BRIP1 (n=1), CHEK2 (n=2), MSH2 (n=1), POLE (n=1), RAD51C (n=2), and RAD51D (n=2). Among 64 patients with a family history of cancer, 27 (42.2%) had 27 pathogenic or likely pathogenic mutations, and six (9.3%) had mutations in genes other than BRCA1/2, such as CHECK2, MSH2, POLE, and RAD51C. Fifty-five patients (47.0%) were identified to carry only variants of uncertain significance. Conclusion Using the multi-gene panel test, we found that, of all patients included in our study, 32.5% had germline cancer-predisposing mutations. NGS was confirmed to substantially improve the detection rates of a wide spectrum of mutations in EOC patients compared with those obtained with the BRCA1/2 testing alone.
Abstract
Purpose Next-generation sequencing (NGS) allows simultaneous sequencing of multiple cancer susceptibility genes and may represent a more efficient and less expensive approach than sequential testing. We assessed the frequency of germline mutations in individuals with epithelial ovarian cancer (EOC), using multi-gene panels and NGS. Materials and Methods Patients with EOC (n=117) with/without a family history of breast or ovarian cancer were recruited consecutively, from March 2016 to December 2016. Germline DNA was sequenced using 35-gene NGS panel, in order to identify mutations. Upon the detection of a genetic alteration using the panel, results were cross-validated using direct sequencing. Results Thirty-eight patients (32.5%) had 39 pathogenic or likely pathogenic mutations in eight genes, including BRCA1 (n=21), BRCA2 (n=10), BRIP1 (n=1), CHEK2 (n=2), MSH2 (n=1), POLE (n=1), RAD51C (n=2), and RAD51D (n=2). Among 64 patients with a family history of cancer, 27 (42.2%) had 27 pathogenic or likely pathogenic mutations, and six (9.3%) had mutations in genes other than BRCA1/2, such as CHECK2, MSH2, POLE, and RAD51C. Fifty-five patients (47.0%) were identified to carry only variants of uncertain significance. Conclusion Using the multi-gene panel test, we found that, of all patients included in our study, 32.5% had germline cancer-predisposing mutations. NGS was confirmed to substantially improve the detection rates of a wide spectrum of mutations in EOC patients compared with those obtained with the BRCA1/2 testing alone.
참고문헌 (28)
- Chen S, "Meta-analysis of BRCA1 and BRCA2 penetrance", J Clin Oncol, 25, pp.1329~1333 (2007)[DOI]
- van der Kolk DM, "Penetrance of breast cancer, ovarian cancer and contralateral breast cancer in BRCA1 and BRCA2 families: high cancer incidence at older age", Breast Cancer Res Treat, 124, pp.643~651 (2010)[DOI]
- Brose MS, "Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program", J Natl Cancer Inst, 94, pp.1365~1372 (2002)[DOI]
- 어경진, "Comparison of Clinical Outcomes of BRCA1", 2 Pathologic Mutation, Variants of Unknown Significance, or Wild Type Epithelial Ovarian Cancer Patients, 2017, pp.49(2), 408~415[DOI]
- Domchek SM, "Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality", JAMA, 304, pp.967~975 (2010)[DOI]
- Finch AP, "Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation", J Clin Oncol, 32, pp.1547~1553 (2014)[DOI]
- Walsh T, "Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing", Proc Natl Acad Sci U S A, 108, pp.18032~18037 (2011)[DOI]
- Frey MK, "Rescreening for genetic mutations using multi-gene panel testing in patients who previously underwent noninformative genetic screening", Gynecol Oncol, 139, pp.211~215 (2015)[DOI]
- Norquist BM, "Inherited mutations in women with ovarian carcinoma", JAMA Oncol, 2, pp.482~490 (2016)[DOI]
- Richards S, "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology", Genet Med, 17, pp.405~424 (2015)[DOI]
- Pruss D, "Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes", Breast Cancer Res Treat, 147, pp.119~132 (2014)[DOI]
- Eggington JM, "A comprehensive laboratory-based program for classification of variants of uncertain significance in hereditary cancer genes", Clin Genet, 86, pp.229~237 (2014)[DOI]
- De Leeneer K, "Evaluation of RAD51C as cancer susceptibility gene in a large breast-ovarian cancer patient population referred for genetic testing", Breast Cancer Res Treat, 133, pp.393~398 (2012)[DOI]
- Sopik V, "Genetic testing for RAD51C mutations: in the clinic and community", Clin Genet, 88, pp.303~312 (2015)[DOI]
- Song H, "Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population", J Clin Oncol, 33, pp.2901~2907 (2015)[DOI]
- Levitus M, "The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J", Nat Genet, 37, pp.934~935 (2005)[DOI]
- Rafnar T, "Mutations in BRIP1 confer high risk of ovarian cancer", Nat Genet, 43, pp.1104~1107 (2011)[DOI]
- Ramus SJ, "Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer", J Natl Cancer Inst, 107, pp.djv214~ (2015)
- Cai Z, "Structure and activation mechanism of the CHK2 DNA damage checkpoint kinase", Mol Cell, 35, pp.818~829 (2009)[DOI]
- Weischer M, "CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls", J Clin Oncol, 26, pp.542~548 (2008)[DOI]
- Liu Y, "A recurrent CHEK2 p.H371Y mutation is associated with breast cancer risk in Chinese women", Hum Mutat, 32, pp.1000~1003 (2011)[DOI]
- Matulonis UA, "Olaparib maintenance therapy in patients with platinum-sensitive, relapsed serous ovarian cancer and a BRCA mutation: overall survival adjusted for postprogression poly(adenosine diphosphate ribose) polymerase inhibitor therapy", Cancer, 122, pp.1844~1852 (2016)[DOI]
- Matulonis UA, "Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1", 2 mutation: a multistudy analysis of response rates and safety, 2016, pp.27, 1013~1019
- familial high risk assessment: breast and ovarian (version 1.2017), "NCCN clinical practice guidelines in oncology: genetic", pp.2016
- Miesfeldt S, "Management of genetic syndromes predisposing to gynecologic cancers", Curr Treat Options Oncol, 14, pp.34~50 (2013)[DOI]
- Kurian AW, "Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment", J Clin Oncol, 32, pp.2001~2009 (2014)[DOI]
- Elsayed FA, "Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer", Eur J Hum Genet, 23, pp.1080~1084 (2015)[DOI]
- Frank TS, "Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals", J Clin Oncol, 20, pp.1480~1490 (2002)[DOI]