Radiation Oncology Journal

The Korean Society for Radiation Oncology (대한방사선종양학회)
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Is the BRCA Germline Mutation a Prognostic Factor in Korean Patients with Early-onset Breast Carcinomas?

한국의 젊은 여성유방암 환자에서 BRCA 배선유전자 돌연변이는 예후인자인가?

  • Choi Doo Ho (Departments of Radiation Oncology, Soonchunhyang University, College of Medicine) ;
  • Lee Min Hyuk (Departments of Surgery, Soonchunhyang University, College of Medicine) ;
  • Haffty Bruce G. (Department of Therapeutic Radiology, Yale University School of Medicine)
  • 최두호 (순천향대학교 의과대학 방사선종양학교실) ;
  • 이민혁 (순천향대학교 의과대학 외과학교실) ;
  • Published : 2003.06.01
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Abstract

Purpose: The purpose of this study was to determine if there were prognostic differences between BRCA related and BRCA non-related Korean patients with early-onset breast carcinomas. Materials and Methods: Sixty women who had developed breast cancers before the age of 40, and who were treated at the Soonchunhyang University Hospital, were studied independently of their family histories. The age range was 18 to 40 with a median of 34.5 years. Lymphocyte specimens from peripheral blood were studied for the heterozygous mutations of BRCA1 and BRCA2 using direct sequencing methods. Immunohistochemistry was peformed on the paraffin-embedded tissue blocks that were available. Results: Eleven deleterious mutations (18.3%, 6 in BRCA1 and 5 in BRCA2) and 7 missense mutations of unknown significance (11.7%), were found among the 60 patients. More than half of the mutation were novel, and were not reported in the database. Most of the BRCA-associated patients had no history of breast cancer. No treatment related failures were observed in the BRCA carriers, with the exception of one patient that had experienced a new primary tumor of the contralateral breast. The seven year relapse free survival rate were 50 and 79% In the BRCA carrier and BRCA negative patients, respectively. Although the expression of estrogen and progesterone receptors were less common, and histological features more aggressive, in the BRCA associated tumors, the outcome of the patients with BRCA mutations was not poorer than that on the patients without deleterious mutations. Conclusion.: Despite the BRCA mutation carriers having adverse prognostic features, the recurrence rate was relatively lower than that in the BRCA non-carrying Korean patients wi4h early-onset breast carcinomas. In addition, although the prevalence of the BRCA mutation in Korean patients was higher than that in white patients, the penetrance of the cancer seemed to be relatively low in Korean women carrying BRCA mutations. A large population based study of the BRCA mutation, with a long-term follow-up of the study patients will be required to confirm these results.

목적: 한국인 젊은 여성 유방암 환자에서 유방암 유전자 (BRCA)가 예후인자가 될 수 있는지 알아보기 위하여 본 연구를 시행하였다. 대상 및 방법: 대학병원에서 치료를 받은 환자 중에서 유방암이나 난소암의 가족력과 관계없이 40세 이하의 환자를 선택하였다. 환자의 나이는 18~40세이었고 중앙값은 34.5세이었다. 환자의 말초혈액에서 림프구를 모아 DNA를 추출하였으며 BRCA1과 BRCA2의 모든 염기 중에서 기능과 관계 있는 부위의 DNA를 직접염기서열 결정방식으로 검사하였다. 조직표본 검사가 가능한 환자는 면역화학조직검사를 시행하였다. 대상 및 방법: 60명의 환자 중에서 유방암 발생과 직접 관계가 있는 돌연변이가 11개(18.3%) 있었고(BRCA1 6명, BRCA2 5명), 의미를 알기가 곤란한 돌연변이가 7개 있었으며 반 수 이상의 돌연변이는 이제까지 보고되지 않은 것이었다. 그리고 대부분의 돌연변이 환자는 유방암이나 난소암의 가족력이 관찰되지 않았다. 유방암 유전자 돌연변이 환자는 한 명도 치료의 실패가 없었으며 한 면에서 반대측 유방암이 발생하였다. 7년 무병 생존율은 돌연변이 환자에서 50%, 돌연변이와 관계가 없는 환자에서 79%이었고 차이는 없었다. BRCA 관련 종양에서 에스트로젠, 프로제스테론 수용체 음성의 비율이 높았으며 조직학적 분화도가 낮았으나 예후는 비교대상에 비해 나쁘지 않았다. 결론: 한국의 젊은 여성 유방암 환자는 예후가 인자가 있어도 재발률이 낮았으며 유전자 돌연변이 이환율이 높았으나 암의 발현율은 상대적으로 낮은 것으로 추정되었다 이 결과를 확인하기 위해 더 많은 환자 집단과 오랜 추적기간의 연구가 필요하다.

Keywords

References

  1. ParkinDM,WhelanSL, Ferlay J, etal. Cancer incidence in five continents. IARC Scientific Publications No. 143. Lyon: IARC, 1997
  2. Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994;266:66-71 https://doi.org/10.1126/science.7545954
  3. Wooster R, BignellG,Lancaster J, et al. Identification of the breastcancersusceptibilitygeneBRCA2. Nature 1995;378:789-792 https://doi.org/10.1038/378789a0
  4. Shattuck-Eidens D, McClure M, Simard J, et al. A collaborative survey of 80 mutations in BRCA1 breast and ovarian cancer susceptibility gene. J Am Med Assoc 1995; 273:535-541 https://doi.org/10.1001/jama.273.7.535
  5. Struewing JP,HangeP,WacholderS. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 1997:336:1401-1408
  6. Eisinger F, Stoppa-Lyonnet D, Longy M, Kerangueven F , Naguchi T, Baily C. Germline mutation at BRCA1 affects the histologic grade in hereditary breast cancer. Cancer Res 1996;56:471-474
  7. VerhoogLC,BrekelmansCTM,SeynaeveC,etal. Survival and tumor characteristics of Breast cancer patients with germline mutations of BRCA1. Lancet 1998;351:316-321 https://doi.org/10.1016/S0140-6736(97)07065-7
  8. Armes JE, Trute L, White D, et al. Distinct molecular pathogenesis ofearly onset breast cancers in BRCA1 and BRCA2 mutation carriers: A population based study. Cancer Res 1999;59:2011-2017
  9. Clause EB, Schildkraut JM, ThompsonWB. The genetic attributable risk ofbreastand ovariancancer.Cancer 1996; 77:2318-2324 https://doi.org/10.1002/(SICI)1097-0142(19960601)77:11<2318::AID-CNCR21>3.0.CO;2-Z
  10. RobsonM, Gilewski T, Haas B, et al. BRCA-associated breast cancer in young women. J Clin Oncol 1998;16:1642- 1649 https://doi.org/10.1200/JCO.1998.16.5.1642
  11. NoguchiS, Kasugai T,MikiY,FukutomiT,EmiM,Nomizu T. Clinicopathologic analysis of BRCA1- or BRCA2- associated hereditary breast carcinoma in Japanese women. Cancer 1999;85:2200-2205 https://doi.org/10.1002/(SICI)1097-0142(19990515)85:10<2200::AID-CNCR14>3.0.CO;2-S
  12. Sng JH, Chang J, Feroze F, et al. The prevalence of BRCA1 mutations in Chinesen patients with early onset breast cancer and affected relatives. Br J Cancer 2000; 82:538-542 https://doi.org/10.1054/bjoc.1999.0960
  13. Kang HC, KimIJ,ParkJH,etal. Germline mutations of BRCA1 and BRCA2 in Korean breast families. Hum Mutat 2002;20:235-239
  14. Johannson OT, Idvall I, Anderson C, et al. Tumour bilogical features of BRCA1-induced breast and ovarian cancer. Eur J Cancer 1997;33:362-371 https://doi.org/10.1016/S0959-8049(97)89007-7
  15. Abeliovich D, Kaduri L, Lerer I, et al. The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women. Am J Hum Genet 1997;60:505-514
  16. Johannesdottir G, Gudmundsson J, Berthorsson JT, et al. High prevalence of the 999del5 mutations in Icelandic breast and ovarian cancer patients. Cancer Res 1996;56:3663-3665
  17. Thorlacius S,SigurdssonS,BjarnadottirH,etal. Study of a single BRCA2mutation with high carrierfrequency in a small population. Am J Hum Genet 1997;60:1079-1084
  18. Malone KE, Daling JR, Neal C, et al. Frequency of BRCA1/BRCA2 mutations in a population-based sample of young breast carcinoma cases. Cancer 2000;88:1392-1402
  19. Anton-Culver H, Cohen PF, Gildea ME, Ziogas A. Characteristics of BRCA1 mutations in a population-based case series of breast and ovarian cancer. Eur J Cancer 2000;36:1200-1208 https://doi.org/10.1016/S0959-8049(00)00110-6
  20. PetoJ,CollinsN,BarfootR,etal. Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Ins 1999;91:943-949 https://doi.org/10.1093/jnci/91.11.943
  21. Anglish Breast Cancer Group. Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population- based seriesof breastcancer cases. Br J Cancer 2000; 83:1301-1308 https://doi.org/10.1054/bjoc.2000.1407
  22. Papelard H, de BockGH,vanEijkR,etal. Prevalence of BRCA1 in a hospital-based population of Dutch breast cancer patients. Br J Cancer 2000;83:719-724 https://doi.org/10.1054/bjoc.2000.1331
  23. Loman N,Johannson O, Kristoffersson U,OlssonH,Borg A. Family history ofbreast and ovarian cancers and BRCA1 and BRCA2 mutations inapopulation-based series of early-onset breast cancer. J Natl Cancer Ins 2001;93: 1215-1223 https://doi.org/10.1093/jnci/93.16.1215
  24. Southey MC, Tesoriero AA, Anderson CR, et al. BRCA1 mutations and other sequence variations in a population- based sample ofAustralianwomenwith breast cancer. Br J Cancer 1999;79:34-39 https://doi.org/10.1038/sj.bjc.6690008
  25. MatsudaML,LiedeA,KwanE,etal. BRCA1andBRCA2 mutations among breast cancer patients from the Philippines. Int J Cancer 2002;98:596-603 https://doi.org/10.1002/ijc.10194
  26. Chang J, Hilsenbeck SG, Sng JH, Wong J, Ragu GC. Pathologic features and BRCA1 mutation screening in premenopausal breast cancer patients. Clin Cancer Res 2001; 7:1739-1742
  27. Ford D, Easton DF, Stratton M, et al. Genetic heteogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 1998;62:676-689 https://doi.org/10.1086/301749
  28. Roa BB, Boyd AA, Volcik K, Richards CS. Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet 1996;14:185-187 https://doi.org/10.1038/ng1096-185
  29. Oddoux C, Struewing JP, Clayton CM, et al. The carrier frequency of the BRCA2 6174delT mutation among AshkenaziJewishindividual is approximately 1%.Nat Genet 1996;14:188-190 https://doi.org/10.1038/ng1096-188
  30. Eisinger F, Jacquemier J, Charpin C, et al. Mutations at BRCA1: the medullary breast carcinoma revised. Cancer Res 1998;58:1588-1592
  31. Armes JE, Egan AJ, Southey MC, et al. The histologic phenotypes of breastcarcinoma occurringbeforeage 40years inwomen with andwithoutBRCA1 or BRCA2 germline mutations: a population-based study. Cancer 1998;83:2335- 2345 https://doi.org/10.1002/(SICI)1097-0142(19981201)83:11<2335::AID-CNCR13>3.0.CO;2-N
  32. Johannson OT, Ranstam J, Borg A, et al. Survival of BRCA1 breast and ovarian cancer patients: a population- based study from southern Sweden. J Clin Oncol 1998; 16:397-404 https://doi.org/10.1200/JCO.1998.16.2.397
  33. Stoppa-Lyonnet D, Ansquer Y, Dreyfus H, et al. Familial invasive breast cancers: worse outcome related to BRCA1 mutations. J Clin Oncol 2000;18:4053-4059 https://doi.org/10.1200/JCO.2000.18.24.4053
  34. ChabnerE,Nixon A,Gelman R, et al. Familyhistory and treatment outcome in young women after breast-conserving surgery and radiation therapyfor early-stage breast cancer. J Clin Oncol 1998;16:2045-2051 https://doi.org/10.1200/JCO.1998.16.6.2045
  35. Gaffney DK, Brohet RM, Lewis CM, et al. Response to radiation therapy and prognosis in breast cancer patients with BRCA1 and BRCA2 mutations. Radiother Oncol 1998; 47:129-136 https://doi.org/10.1016/S0167-8140(98)00023-1
  36. Rubin SC, Benjamin I, Behbakht K, et al. Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. N Eng J Med 1996;335: 1413-1416 https://doi.org/10.1056/NEJM199611073351901
  37. Verhoog LC, Bern EM,Brekelmans CT, et al. Prognostic significance of germline BRCA2 mutations in hereditary breast cancer patients. J Clin Oncol 2000;18:119-124