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종양유전질환과 검사

고신대 간호학과 종양단기강좌 2007. 종양유전질환과 검사. 손 병 호 울산의대 서울아산병원 외과 , 암센타 유방암클리닉. Contents. Hereditary cancer syndrome? - Colorectal cancer - Hereditary breast / ovarian cancers BRCA mutation in breast / ovarian cancer patients in Korea

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종양유전질환과 검사

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  1. 고신대 간호학과 종양단기강좌 2007 종양유전질환과 검사 손 병 호 울산의대 서울아산병원 외과, 암센타 유방암클리닉

  2. Contents • Hereditary cancer syndrome? - Colorectal cancer - Hereditary breast / ovarian cancers • BRCA mutation in breast / ovarian cancer patients in Korea • Prevention and management of patient with BRCA mutation

  3. Cancer genetics • Becoming a component of standard cancer care • Cancer prevention • Risk assessment, genetic testing and counseling toward risk reduction

  4. 종양유전검사 • 종양유전검사란? - Genetic Predisposition (Susceptibility) Test (질병소질 검사) - 암 환자 및 그 가족들의 유전자 상에 존재하는 돌연변이 혹은 SNP의 유무를 검색함으로써, 특정 질환의유전적 진단 및 발병 가능성의 예측을 목적으로 하는 검사

  5. 일반적인 종양유전검사의 절차 환자 확인 검사 전 상담 검사동의서 작성 적합한 검사 시행 결과 전달 검사 후 상담 및 Follow up

  6. 일반적인 종양유전검사 단계 • 추출 (DNA 등을 시료에서 분리 정제) • 증폭 (PCR 등을 이용 증폭 및 검출前 조작) • 검출 (유전형을 확인)

  7. BRCA/HNPCC 유전자 분석 Flow Chart 게놈 DNA 분리 샘플접수 Multiplex PCR 반응 F-CSGE on ABI377 돌연변이 Peak Exon 검출 돌연변이 Peak 미검출 Sequencing Mutation DB 분석 결과 통보

  8. Genetic Scanning – F-CSGE heteroduplexing 정상 유전자 정상 유전자’ heteroduplexing 돌연변이 유전자 정상 유전자’ 정상 유전자의 경우 돌연변이 유전자의 경우

  9. Genetic Scanning – F-CSGE Sample # : JB0002 Peak Pattern : 11.1-1 Sample # : BB0010 Peak Pattern : 11.1-3 Sample # : JB0002 Peak Pattern : 11.1-1 Sample # : BB0040 Peak Pattern : 11.1-4 T875 Homozygote (Wild Type) Wild Type T875CHeterozygote (SNP) 1041 del AGC, insT (Mutation)

  10. Sequencing

  11. Comparison of “universal cost equivalents” of “prescreening” BRCA1 for mutations Eng et al, J Med Genet 2001

  12. Methods for detecting BRCA1 mutation

  13. Methods for detecting BRCA1 mutation

  14. BRCA 유전검사의 이득 및 제한점 검사의 이득 Benefits위험 및 제한 Risks and Limitations From ASCO

  15. Proportion of Hereditary Cancers Nagy, 2004

  16. Hereditary Cancer Syndrome 이란? • Germline mutations in oncogenes, tumor suppressor genes, mismatch repair genes • Autosomal dominant inheritance • Affects multiple generations • In any generation ~50% inherit the genetic predisposition to cancer

  17. Hereditary Cancer Susceptibility • Two or more relatives with same type of cancer on the same side of family • Several generations affected; AD pattern • Early age of onset • Bilateral cancers in paired organs • Multiple primary cancers • Genetically related cancers in one family • Nonmalignant conditions and cancer in the same person and/or family; eg, polyp • Phenotypic manifestations; eg, genodermatoses • Ethnic origin Nagy, 2004

  18. Highly penetrant cancer syndromes Nagy, Oncogene 2004

  19. Possible inherited predisposition to cancer

  20. Possible inherited predisposition to cancer

  21. Possible inherited predisposition to cancer Daly, 2004

  22. Common Hereditary Cancers Frank, 2001

  23. Causes of colorectal cancer Trimbath, 2004

  24. Genetic causes of HNPCC Sporadic Familial MSH2 ~30% Unknown ~30% HNPCC Rare CRC syndromes FAP MLH1 ~30% MSH6 (rare) PMS1 (rare) Liu B et al. Nat Med 2:169, 1996 PMS2 (rare)

  25. 대장암의 Lifetime Risk Cumulative %

  26. Hereditary non-polyposis colorectal cancer (HNPCC) • AD with no clear clinical signs preceding cancer except for solitary adenoma • Life time risk of cancers - Colorectal and endometrial: 80% & 60% - Gastric, ovarian, urothelial, bile duct, kidney, SI, brain: 2%~13% • Mutation of DNA mismatch-repair genes - MLH1, MSH2 : >90%, MSH6 : 5% • Family history, young age, proximal site of the colon, synchronous (or metachronous) secondary tumors • MSI (microsatellite instability) of DNA is characteristic - 81% in HNPCC by Amsterdam criteria I - But, 15% in sporadic colorectal cancers

  27. Amsterdam criteria for the clinical definition for HNPCC • 가계 내에 3인의 대장암 환자 (Three first degree relatives)* • 2대 이상에 걸쳐서 환자 존재 (Two generations affected with colon cancer) • 50세 이전 발병 환자가 한 명 이상 존재 (One case less than age 50 years of age) • APC 환자가 아닐 것 (Not APC) • * One or more of the extracolonic cancers include cancer of endometrium, upper GI tract, and urinary tract ** Bethesda criteria

  28. Microsatellite instability (MSI) • 10%–15% of sporadic tumors have MSI (MicroSatellite Instability) • 95% of HNPCC tumors have MSI at multiple loci NEJM 2000;342:71

  29. HNPCC의 종양유전검사 Microsatellite Instability Testing Positive Negative: Stop Immuohistochemistry hMLH1 Test hMSH2 Test Sequencing, SSCP, Protein truncation, CSGE+sequencing

  30. Management of patients with HNPCC • Total colectomy with ileosigmoidal anastomosis > hemicolectomy • The remaining colon and rectum: examine every 2-3 years • Prophylactic hysterectomy or surveillance by endometrial aspiration biopsy every 2-3 years

  31. Surveillance and prevention of asymptomatic mutation carriers • Colonoscopic screening with polypectomies : >60% reduction of CRC • Screening for endometrial and ovarian cancer - Endometrial aspiration biopsy and USG every 2-3 years starting from age 30-35 years - Prophylactic hysterectomy, SO, colectomy ; an alternative option • Chemoprevention - COX2I (aspirin) - Oral contraceptives

  32. Genetic testing algorithm for HNPCC Gastroenterology 2001; 121:196

  33. Familial adenomatous polyposis (FAP) • At least 100 adenomatous polyps in the colon and rectum • 1/10000 newborns • APC mutation in 1/3~1/2 of patients with FAP and in ≥2/3 of families. • Cancer development in one or more of the multiple colorectal adenomas at the mean age of 40 years • At diagnosis, 60% of symptomatic FAP patients will have colorectal cancer. • Dx: endoscopy, APC mutation • Fibreoptic sigmoidoscopy from age of 12-15 years for all children of FAP parent. • Prophylactic collectomy

  34. Familial adenomatous polyposis (FAP) • Prophylactic colectomy with ileorectal anastomosis - At the age of 20-25 years - Rectal stump cancer risk; ≥15% within 20-25 years - Proctocolectomy with ileal pouch-anal anastomosis • Early diagnosis and proper prophylactic treatment

  35. APC gene test for FAP • Indications - ≥100 colorectal adenomas - First-degree relatives (10 year or older) of patients with FAP - ≥20 cumulative colorectal adenomas (suspected attenuated FAP) - First-degree relatives of patients with AFAP • Method - Protein truncation - Sequencing - Linkage - Protein truncation+CSGE, SSCP, or sequencing

  36. Proportion(%) of 10 Major Cancers in Korea Source : Korean Central Cancer Registry, 2002 Stomach(24.0) Breast(16.8) Lung(16.0) Stomach(15.3) Liver(15.4) Colorectum(10.7) Colorectum(11.6) Thyroid(9.5) Cervix(9.1) Bladder(3.2) Prostate(3.0) Lung(6.6) Esophagus(2.8) Liver(6.0) Hematopoietic(2.7) Ovary(3.6) Male Female Pancreas(2.5) Hematopoietic(2.5) Kidney(2.0) Pancreas(2.3) %

  37. Proportion of Patients by Risk Factors Korean Breast Cancer Society

  38. How much breast cancer Is explained? Inherited 5~10% Environmental 45-50% unknown • dietary • behavioral • Physico-chemical environment

  39. Hereditary manifestations of breast cancer

  40. Breast Cancer Risk Model • Gail Model (http://brca.nci.nih.gov/brc/):일반여성의 유방암 위험도 - 초경연령, 첫 출산연령, 유방조직검사 횟수, 이형성결과, 1대 가족력 - Nonbiologic variable포함, 세부적인 가족력 결여 - BRCA보인자의 위험성이 낮게 평가될 우려 • Claus Model: 가족력이 있는 여성에게 적합 - 유전적 관계에 기초; 연령, 가족력 관계 - 고위험 가족은 낮게 평가될 가능성 • Pedigree-Based Model : BRCA mutation 가능성 평가 - Prevalence table on website (Myriad Genetic Laboratories) - Computer Model : BRCAPRO

  41. 88 63세에 유방암 진단 80세에 사망 89 89세에 심근경색으로 사망 80세에 사망 남자 여자 유방암 여성 48 55 60 58세에 유방암 진단 18 20 Pedigree constructed on the family

  42. Risk factors for breast cancer (RR > 4.0) • Old Age • BRCA1 and/or BRCA2 mutations • 2 or more first-degree relatives with breast cancer diagnosed at an early age • Personal history of breast cancer • Postmenopausal breast density 2005-2006 ACS, adapted from Hulka, 2001

  43. 첫 유방암 발병유전자 17번 염색체 (17q21) (Hall et al. Science 1990) 22 coding exons, 1,863개의 아미노산 전체 cDNA는 약 5,589 base 돌연변이시 유방암 및 난소암의 발병 위험 증가 13번 염색체 (13q12-13) (Wooster et al. Science 1994) 26 coding exons, 3,418개의 아미노산 cDNA의 길이 10,259 bases 돌연변이시 유방암 (남성 유방암), 난소암, 췌장암, 전립선암, 담낭암, 위암 등의 발병 위험 증가 BRCA 2 BRCA 1

  44. Cancer risks associated with BRCA mutation

  45. DNA 손상과 수리, 암 발생 여러 위험 인자 암 촉진 유전자 유방 세포 DNA 손상 DNA 수리 정상세포 분열 BRCA 암 억제 유전자 비정상세포 분열 암

  46. DNA break BRCA function RNA Pol II ATM p p BRCA1 Gene transcription or Transcription-coupled repair (+) (-) RAD51 BRCA2 RAD51 BRCA2 Caretaker RAD52 BRCA1 RAD52 p Homologous recombination Repair Failed repair Gatekeeper   Checkpoint activation (+) (-) Bax X p53 Apoptosis p21 Cell cycle arrest Tumorigenesis

  47. Features suggestive of a hereditary predisposition to breast cancer Oncologist 2004

  48. Prevalence of BRCA gene mutation • In unselected patients, BRCA 1,2 mutation: 5% ~ 7% • In the general population: 0.1% ~ 0.7% • Frequency increases among patients with - younger age of onset, - affected first-degree relatives, - family history of ovarian cancer

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