원저 Lab Med Online Vol. 8, No. 3: , July 진단유전학 BRCA1/2 유전자검사의국내시행현황 (2014) Status of BRCA1/2 Genet

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1 원저 Lab Med Online Vol. 8, No. 3: , July 2018 진단유전학 BRCA1/2 유전자검사의국내시행현황 (2014) Status of BRCA1/2 Genetic Testing Practices in Korea (2014) 이경주 1 장자현 2 이승태 3 윤경아 4 이은숙 5,6,7 김종원 8 공선영 5,9 Kyungju Lee 1, Ja-Hyun Jang, M.D. 2, Seung-Tae Lee, M.D. 3, Kyong-Ah Yoon, Ph.D. 4, Eun Sook Lee, M.D. 5,6,7, Jong-Won Kim, M.D. 8, Sun-Young Kong, M.D. 5,9 국립암센터호발암연구과 1, 그린크로스지놈 2, 연세대학교의과대학진단검사의학과 3, 건국대학교수의과대학 4, 국립암센터국제암대학원대학교암관리학과 5, 국립암센터유방암센터 6, 국립암센터면역치료연구과 7, 성균관대학교의과대학삼성서울병원진단검사의학과 8, 국립암센터진단검사의학과 9 Common Cancer Branch 1 Research Institute, National Cancer Center, Goyang; Green Cross Genome 2, Yongin; Department of Laboratory Medicine 3, Yonsei University College of Medicine, Seoul; College of Veterinary Medicine 4, Konkuk University, Seoul; National Cancer Center Graduate School of Cancer Science and Policy 5, National Cancer Center, Goyang; Center for Breast Cancer 6, Hospital, National Cancer Center, Goyang; Immunotherapeutics Branch 7, Research Institute, National Cancer Center, Goyang; Department of Laboratory Medicine & Genetics 8, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; Department of Laboratory Medicine 9, National Cancer Center, Goyang, Korea Background: The aim of this study was to investigate the status of BRCA1/2 genetic testing practices in Korea in Methods: A structured questionnaire was provided to the specialist in charge of BRCA1/2 genetic testing via between 28 July and 10 August A total of 11 genetic testing professionals from 14 organizations responded to the survey that asked about the status of BRCA1/2 genetic testing in the year Results: The average number of BRCA1/2 genetic tests executed was 192; 6 organizations had executed less than 100 tests, and 5 organizations had conducted more than 100 tests. The primary testing method used was Sanger sequencing (100%), and 2 institutes performed multiplex ligation-dependent probe amplification (MLPA). The analysis software differed across the various organizations, with Sequencher (81.81%), Seqscape (27.27%), and Codoncode Aligner (9.09%) reported as utilized. We found that the guidelines for the interpretation of the genetic tests were different at each institution. Conclusions: Although this study only examined the status of the 2014 BRCA1/2 genetic testing practices of 11 institutions, it illustrates the necessity for standardized genetic testing or interpretation guidelines in Korea. Key Words: Genes, BRCA1, BRCA2, Questionnaires and Surveys, Genetic testing, Standardization 서론 우리나라의유방암과난소암발병률이지속적으로증가하고있 는추세에따라 BRCA1/2 유전자검사의수요가점점늘어나고있 다 [1-3]. Corresponding author: Sun-Young Kong Department of Laboratory Medicine, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea Tel: , Fax: , ksy@ncc.re.kr Received: August 28, 2017 Revision received: October 31, 2017 Accepted: December 21, 2017 This article is available from , Laboratory Medicine Online This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 하지만, 국내의 BRCA1/2 유전자검사방법이나분석법에대한현황이파악되어있지않아표준화를위한첫단계로유전자검사기관을대상으로 BRCA1/2 유전자검사방법에대해설문조사를시행하고응답자의답변을평가하였다 [4]. 연구대상및방법 연구대상자는 2014년기준 BRCA1/2 유전자검사시행기관인 15개의기관으로설문을보내고참여의사를확인한후답변하지않은 4개기관을제외하고총 11개기관을대상으로선정하여답변을분석하였다. 설문은각기관의유전자검사담당전문가에게전자메일로전달하여 2015년 7월 28일부터 8월 10일까지온라인설문조사를실시하고답변을받았다. 설문구성은 BRCA1/2 유전자검사방법및해석 (20문항) 과 BRCA1/2 유전자검사가이드라인의규정 (2문항) 에대한평가로 eissn

2 총 22문항으로이루어졌다. 각문항별설문응답빈도를분석하였고, 중복및주관식질문의경우테이블에별도로정리하였다. 결과 설문응답전체결과는 Table 1과같다. 문항 1에서확인한 2014 년도에시행된 BRCA1/2 유전자검사건수는 11개기관전체평균 192건으로 6개의기관은 100건미만 (87, 범위 19 81), 5개의기관은 100건이상 (256, 범위 ) 이었다. 유전자검사를위해가장많이사용하는방법은 Sanger sequencing으로전체기관에서사용하고있었고, 2개의기관에서 Multiplex Ligation-dependent Probe Amplification (MLPA) 을함께사용하고있었다. 유전자검사결과분석시사용하는소프트웨어는 Sequencher (81.81%), Seqscape (27.27%), Codoncode Aligner (9.09%) 순이었다. 각기관에서 2014년도에발견한 pathogenic 및 variation of unknown (VUS) 의비율은 Table 2와같았다. 전체기관의 pathogenic 발견평균은 pathogenic 18.1% ( 범위 ), VUS 20.5% ( 범위 ) 이었다. 이중 3개의기관은 VUS 발견에대한비율이 pathogenic 보다높게나타나나 1개의기관에서 VUS를보고하지않았다. 문항 5에서확인한 BRCA1/2 유전자검사결과해석시따르고있는가이드라인으로한가지가이드라인을사용하는기관은 7기관, 두가지가이드라인을동시에사용하는기관은 4기관이었으며 American College of Medical Genetics (ACMG) 기준을 9개기관 (81.82%) 에서, The International Agency for Research on Cancer (IARC) 기준을 3기관 (27.27%), 기존가이드라인에서일부를차용한기준을각각 3기관 (27.27%) 에서따르고있음을알수있었다. 또한 BRCA1/2 유전자검사결과보고서의염기위치번호는 Human Genome Variation Society (HGVS) nomenclature를 8개의기관 (72.72%) 에서, HGVS nomenclature & Breast cancer Information Core (BIC) nomenclature를 3개의기관 (18.19%) 에서, BIC nomenclature를 1개의기관 (9.09%) 에서따르고있음을알수있었다. 각기관의 BRCA1/2 유전자검사결과에서발견된변이의임상적해석을위하여참고하는데이터베이스는각기관에서평균적으로최소 3가지를이용하는것으로나타났으며가장많이이용하는데이터베이스의종류로는 Human Gene Mutation Database & BIC Code (100%), Clin Var & DbSNP (90.91%), Literature search (72.73%), Leiden Open Variation Database (LOVD)-IARC (63.64%), LOVD (36.36%), 기관내자체데이터 (27.27%), Associated Regional and University Pathologists (ARUP), BRCA1/2 Mutation Database & Korean Breast Cancer Registry Database (18.18%) 순으로나타났다. 문항 8에서는유전자검사결과에서발견된변이의임상적의미에대해모든기관이 3개의카테고리로분류함을알수있었다 (Table 3). 유전자검사결과해석시 4개의기관에서 3가지임상정보를, 3개의기관에서 2가지임상정보를함께참고하였고가족력 (72.73%), 암발병나이 (63.64%), 병리학적소견 (27.27%), 편측성 / 양측성유방암 (9.09%) 순으로나타났으며임상정보를참고하지않는기관은 27.27% 이었다. 유전자검사에서발견된변이에대한인구집단빈도를참고할경우 1000 Genome에서의빈도 [5-7], 인종별빈도, 한국인에서의빈도데이터를각각 6기관 (54.55%) 에서가장많이참고하였고 5기관 (45.45%) 에서 International HapMap Project 빈도 [8] 를참고하였으며 2기관 (18.18%) 에서는인구집단빈도를참고하지않았다. 인구집단빈도를참고하는경우공통 SNP로판정하는기준을대립유전자빈도 1% 로사용하는기관 5곳 (45.45%), dbsnp 의공통SNP로판정됨을기준으로사용하는기관이 3곳 (27.27%), 대립유전자빈도 5% 를사용하는기관이 1곳 (9.09%) 임을알수있으며 2곳은기준이없는것으로확인되었다. 문항 12에서는기존논문에보고되거나 pathogenic 데이터베이스에등재되어있는변이에대해보고하는과정으로, 추가적인검토를하여근거가부족한경우 VUS로분류하는것이 81.82% 로대부분이었으나 18.18% 에서는 pathogenic 로보고하고있음을알수있었다. BRCA1/2 유전자검사결과에따른위험도보고에대해서는 7개의기관에서는보고하지않는것으로나타났고, 4개의기관에서는위험도증가 / 정상인과비슷함으로나누어보고하는것으로나타났다. VUS에대해서 in-silico 분석을시행하는경우사용하는분석도구는 PolyPhen-2 (31.43%) 가가장많이사용되고있었고 [9-12], SIFT [13-17] (28.57%), Align-GVGD [18] (17.14%), splicing analysis (11.43%), mutation taster (8.57%), FATHMN (2.86%) 순으로나타나며문항 15와같이 in silico 분석을시행한후결과보고서에언급을하는기관은 8곳 (72.73%), 언급하지않는기관은 3곳 (27.27%) 으로조사되었다. 유전자검사결과에서관찰된 VUS 중동일변이에대해서는 45.45% 가 VUS로보고하되인구집단빈도, in-silico study, 문헌보고등다른소견들을종합하여 pathogenic 일가능성을판정하고있었고, 27.27% 가 VUS로보고하되 pathogenic 일가능성이낮음을언급하고, 18.18% 가모두음성으로보고하고있었으며, 9.09% 에서 VUS와동일변이의증례가없었던것으로나타났다. 이렇게관찰된 BRCA1/2 유전자검사결과의 VUS 중 missense variation 에대해서는 90.91% 는 VUS로보고하되인구집단 108

3 Table 1. Survey questionnaires and answer frequencies Questionnaires & Answer Options 1 How many BRCA1/2 genetic tests were conducted at your institution in 2014? A. <100 6 (54.55) B (45.45) 2 What method(s) does your organization use to perform genetic testing?* A. Sanger sequencing (direct sequencing of whole exons) 11 (100.00) B. Multiplex ligation-dependent probe amplification (MLPA) 2 (18.18) C. Mutation scanning 0 (0) D. Pyrosequencing 0 (0) 3 What type of software does your organization use to analyze the genetic testing results?* A. Sequencher 9 (81.81) B. Seqscape 3 (27.27) C. Seqscanner 0 (0) D. Mutation surveyor 0 (0) E. GENETYX 0 (0) F. MT Navigator 0 (0) G. CLC Genomics/Main workbench 0 (0) H. Nextgene 0 (0) I. Others (CodonCode Aligner) 1 (9.09) 4 What percentages of BRCA pathogenic s and VUS detection (prevalence) rates did your institution have in 2014?** A. mutation: % 18.1 (mean) B. VUS: % 20.5 (mean) 5 Do you have any criteria for interpreting the results of the BRCA1/2 genetic tests at your institution?* A. ACMG guideline 9 (81.82) B. IARC guideline 3 (27.27) C. Modified version of previous guideline 3 (27.27) D. No 0 (0) 6 What numbering system does your organization follow for the genetic test report? A. HGVS nomenclature 8 (72.72) B. BIC nomenclature 1 (9.09) C. HGVS nomenclature & BIC nomenclature 2 (18.19) 7 What kind of database does your organization utilize for the clinical interpretation of the pathogenic s found from the results of the genetic tests?* A. Human Gene Mutation Database (HGMD) 11 (100.00) B. Breast Cancer Information Code (BIC) 11 (100.00) C. ClinVar 10 (90.91) D. DbSNP 10 (90.91) E. Literature search 8 (72.73) F. LOVD-IARC 7 (63.64) G. Leiden Open Variation Database 4 (36.36) H. Organization s own database 3 (27.27) I. ARUP BRCA1/2 Mutation Database 2 (18.18) J. Korean Breast Cancer Registry Database 2 (18.18) K. BRCA1/2 Share 0 (0) 8 Based on the clinical of the pathogenic s found from your genetic testing results, how many categories do you use and how do you name them?*** A (100.00) B. 5 0 (0) C. 6 0 (0) Answer N (%) (Continued to the next page) 109

4 Table 1. Continued Questionnaires & Answer Options 9 What type of clinical information is referenced when interpreting the genetic testing results?* A. Family history 8 (72.73) B. Age of cancer onset 7 (63.64) C. Pathological result 3 (27.27) D. Do not exploit references 3 (27.27) E. Unilateral/bilateral 1 (9.09) 10 Do you consider the population frequency of the pathogenic s obtained from genetic testing as an important factor? If so, what type of reference method do you use?* A Genome frequency 6 (54.55) B. Racial (ethnicity) frequency 6 (54.55) C. Korean frequency 6 (54.55) D. Hapmap frequency 5 (45.45) E. Not important 2 (18.18) 11 What criterion is used to decide common SNPs, when using the population frequency as a reference? What standard percentage is used for the allele frequency? A. No criteria 2 (18.18) B. DbSNP-common SNP 3 (27.27) C. 1% 5 (45.45) D. 5% 1 (9.09) 12 How do you report pathogenic s that have already been identified in existing papers or listed in the pathogenic database? A. Always report as a pathogenic 2 (18.18) B. Additional review and classified as VUS if unclassified/unclear result 9 (81.82) 13 Do you report the degree of risk based on the genetic testing results? A. No 7 (63.64) B. Increasing risk level/normal range 4 (36.36) C. Calculation of risk value 0 (0) 14 What analytical tool do you use to perform the in-silico analysis regarding a VUS?* A. PolyPhen-2 11 (100.00) B. SIFT 10 (90.91) C. Align-GVGD 6 (54.55) D. Splicing analysis 4 (36.36) E. Mutation Taster 3 (27.27) F. FATHMN 1 (9.09) G. Mutation Assessor 0 (0) H. GERP++ 0 (0) I. No in-silico analysis 0 (0) 15 If you performed an in-silico analysis, do you indicate this method in the results report? A. Yes 8 (72.73) B. No 3 (27.27) 16 How do you interpret the synonymous variation derived from a VUS observed in the genetic test results? A. All negative 2 (18.18) B. All VUS 0 (0) C. VUS and additional statement of a low possibility of a pathogenic 3 (27.27) D. VUS based on population frequency, in-silico study, and references 5 (45.45) E. No case of VUS, synonymous 1 (9.09) 17 How do you interpret the MISSENSE VARIATION derived from a VUS observed in the genetic test results? A. All positive 0 (0) B. All VUS 0 (0) C. VUS based on population frequency, in-silico study, and references 10 (90.91) D. VUS-based, but provide objective evidence, such as population frequency, in-silico study, and literature reports for clinician determination. 1 (9.09) Answer N (%) (Continued to the next page) 110

5 Table 1. Continued Questionnaires & Answer Options 18 How do you interpret INTRONIC VARIATION other than the splice site of VUS observed in the genetic test results? A. All positive 0 (0) B. All VUS 0 (0) C. VUS and additional statement of a low possibility of a pathogenic 5 (45.45) D. VUS based on population frequency, in-silico study, and references 5 (45.45) E. Additional RNA studies 1 (9.09) 19 If you find any pathogenic s that are unclear based on your clinical judgement, do you recommend testing for the patient s family? A. Yes 8 (72.73) B. No 3 (27.27) 20 Do you consider the prerequisite of the 5-step reporting system for a VUS? A. Yes 0 (0) B. Yes, but it is not practical 8 (72.73) C. Yes, if it is necessary in clinical practice 3 (27.27) D. No 0 (0) 21 Are you willing to follow the Korean version of standardization and guidelines for BRCA1/2 genetic testing in the future? A. Yes 6 (54.55) B. Yes, if it is practical in a clinical setting 5 (45.45) C. Not yet 0 (0) 22 What do you think is indispensable for the standardized interpretation of BRCA1/2 genetic test results in Korean clinical practice?* A. Korean polymorphism database 11 (100.00) B. Functional study database 8 (72.73) C. Objective criteria of interpretation 11 (100.00) *Multiple answers possible; **Open-ended answer, the answers are shown in Table 2; ***Open-ended answer, the answers are shown in Table 3. Answer N (%) Table 2. and variation of unknown (VUS) detection rates for each organization in 2014 (%) A B C D E F G H I J K /8.3* VUS *BRCA1/2: 32%, BRCA1/2: 8.3%. Table 3. Category names used for the s in the genetic test results A B C D E F G H I J K 1 Polymorphism 2 Unclassified 3 VOUS* detected VUS* Not detected detected Benign Polymorphism Polymorphism Unclassified sequence Unclassified Detected Benign Benign No pathogenic detected Polymorphism Benign Benign VUS* All of the organizations used 3 categories. *s of unknown (or ). 빈도, in-silico study, 문헌보고등다른소견들을종합하여 pathogenic 일가능성을판정하고있었고, 9.09% 는 VUS로보고하되임상의가판단할수있게인구집단빈도, in-silico study, 문헌보고등의객관적인증거를제시하고있었다. BRCA1/2 유전자검 사결과에서관찰된 VUS 중 splice site 이외에다른 intronic variation에대해서는각각 45.45% 로 VUS로보고하되 pathogenic 일가능성이낮음을언급하거나, VUS로보고하되인구집단빈도, in-silico study, 문헌보고등다른소견들을종합하여 patho

6 genic 일가능성을판정하고있었고, 9.09% 는추가로 RNA study를진행하고있음을알수있었다. 임상적의미가분명하지않은변이인 VUS가발견된경우 8개의기관에서가족에대한검사를권장하고있었고, 3개의기관에서가족에대한검사를권장하지않음을알수있었다. 문항 20에서는 VUS의등급에따른 5단계이상의결과보고체계의필요성에대해질문하였고 8개 (72.73%) 의기관에서결과보고체계가필요하다고생각하나현실적으로어렵다고생각하고있었으며, 3개 (27.27%) 의기관에서임상에서요구할경우고려해보겠다고대답하였다. 또한한국에서 BRCA1/2 유전자검사의해석에있어서표준화및지침작성을진행할경우 54.55% 의기관이표준화지침에따를계획이며 45.45% 는검사실에서현실적으로실행가능하면따를생각이있다고대답하였다. 각기관에서유전자검사의해석표준화에서필요하다고생각하는부분은전체 11개의기관에서한국인고유의다형성데이터베이스축적 (100%) 과해석기준의객관화 (100%) 가필요하다고대답하였고, 8개의기관에서 functional study 데이터의축적 (72.73%) 이필요하다고대답하였다. 기타의견으로는한국인 super-normal control 데이터를생성하였으면하는의견과유전자검사의해석및결과보고에있어표준화된지침이꼭마련되었으면좋겠다는의견이있었다. 고찰 2014년 BRCA1/2 유전자검사시행기관에대한현재상황을이설문을통해확인하였다. BRCA1/2 검사의결과표기, 해석이검사기관에따라서로달랐다. 이것은 BRCA1/2 검사가단순하게환자의유전적원인을규명하는것을넘어 poly ADP ribose polymerase (PARP) inhibitor 가 BRCA1/2 pathogenic 를가지는환자의치료제로서효과를보인다는최근의보고 [19] 등을감안하면, 검사결과의정확성뿐만아니라, 결과표기, 해석등에있어서혼란을최소화하는것이필요하다고판단이된다. BRCA1/2 유전자검사가늘어나는상황에서가장문제가되는것은 VUS의해석으로보인다. 조사결과유전자검사결과에서관찰된 VUS 판정및보고를적용함에있어각기관별다른기준으로판정및보고를하고있었으며, 이를적용하기에현실적인어려움이있어표준화된가이드라인의필요성을알수있었다. 최근 ACMG 가이드라인이새롭게제정이되었고따라서변이에대해 ACMG 가이드라인으로분류하려는시도들이있다 [20, 21]. 그리고, ACMG 지침조차도변이의확신도가 5 95% 까지광범위하게 VUS로판정하고있으므로 [4], VUS를좀더세분화하기위한환자의임상양상, 병리결과, 가족력등의여러인자를포함하는다인 자확률기반해석이더욱필요할것으로예상된다. 그렇지만현재우리나라전체에통용되는표준화가이드라인은없기때문에한국표준화가이드라인제정의필요성이있고, BRCA1/2 유전자검사시행기관에서의유전자검사에대한 2017년도현황조사및전문가들의의견취합이추가로필요하다. 요약 배경 : 2014년국내에서시행했던 BRACA1/2 유전자검사의현황을파악하기위해서진행하였다. 방법 : 각기관의유전자검사담당전문가에게 2015년 7월 28일부터 8월 10일까지전자메일을통해온라인설문조사를시행하여, 15개의기관중답변을한 11개의기관의답변을분석하였다. 결과 : 2014년도에시행된 BRACA1/2 유전자검사건수는 11개기관전체평균 192건으로, 6개의기관은 100건미만, 5개의기관은 100건이상이었다. 유전자검사를위해가장많이사용하는방법은 Sanger sequencing으로전체기관에서사용하고있었고, 2개의기관에서 Multiplex Ligation-dependent Probe Amplification (MLPA) 을함께사용하고있었다. 유전자검사결과분석시사용하는소프트웨어는 Sequencher (81.81%), Seqscape (27.27%), Codoncode Aligner (9.09%) 순이었고각기관마다유전자검사해석시따르고있는가이드라인이달랐다. 결론 : 2014년도에 BRACA1/2 유전자검사를시행한 11개기관만을관찰하였지만, 본연구로국내의표준화된가이드라인이필요함을보여주었다. ACKNOWLEDGMENTS This study was supported by the research fund of national cancer center, Korea (no ). REFERENCES 1. Jung KW, Won YJ, Oh CM, Kong HJ, Lee DH, Lee KH; Community of Population-Based Regional Cancer Registries. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in Cancer Res Treat 2017;49: Kang E, Park SK, Lee JW, Kim Z, Noh WC, Jung Y, et al. KOHBRA BRCA risk calculator (KOHCal): a model for predicting BRCA1 and BRCA2 mutations in Korean breast cancer patients. J Hum Genet 2016; 61: Kang E, Seong MW, Park SK, Lee JW, Lee J, Kim LS, et al.; Korean He

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012임수진 Received : 2012. 11. 27 Reviewed : 2012. 12. 10 Accepted : 2012. 12. 12 A Clinical Study on Effect of Electro-acupuncture Treatment for Low Back Pain and Radicular Pain in Patients Diagnosed with Lumbar