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Clinical genetics of cancer family syndromes – Polish experience

Clinical genetics of cancer family syndromes – Polish experience. J. Lubiński. INTERNATIONAL HEREDITARY CANCER CENTER POMERANIAN MEDICAL UNIVERSITY, SZCZECIN, POLAND READ-GENE SA. Sankt Petersburg 4.10.2014. Hereditary Cancer Center Szczecin. Pomeranian Medical University :

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Clinical genetics of cancer family syndromes – Polish experience

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  1. Clinicalgeneticsof cancer family syndromes– Polishexperience J. Lubiński INTERNATIONAL HEREDITARY CANCER CENTER POMERANIAN MEDICAL UNIVERSITY, SZCZECIN, POLANDREAD-GENE SA Sankt Petersburg 4.10.2014

  2. HereditaryCancer Center Szczecin • PomeranianMedicalUniversity: • Cancer Genetics OutpatientClinics • Dept Genetics Pathology • InternetionalHereditary Cancer Center (journal – Hereditary Cancer in ClinicalPractice: IF 2.1) • Oncologyclinics: • Chemotherapy • Surgery • Gynecology • Urology • Others • Read-Gene Spin-off Company

  3. Acknowledgment • Cybulski Cezary1, Byrski Tomasz1, Jakubowska Anna1, Gronwald Jacek1, Huzarski Tomasz1, Wokołorczyk Dominika1, Masojć Bartłomiej1, Dębniak Tadeusz1, Górski Bohdan1, Narod Steven A.2, Marczyk Elżbieta3, Blecharz Paweł3, Ashuryk Oleg1, Zuziak Dorota4, Wiśniowski Rafał4, Godlewski Dariusz5, Jaworska Katarzyna1*, Durda Katarzyna1, Gupta Satish1*, Muszyńska Magdalena1, Sukiennicki Grzegorz1, Grodzki Tomasz6, Waloszczyk Piotr6, Jaworowska Ewa7, Lubiński Jakub7, Kładny Józef8, Wilk Grażyna9, Górecka Barbara9, Sikorski Andrzej10, Gołąb Adam10, Tołoczko-Grabarek Aleksandra1, Lubiński Jan1: • 1Department of Genetics and Pathomorphology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin; 2Women’s College Research Institute, Toronto, Ontario, Canada; 3Regional Oncology Center, Bielsko-Biała; 4Oncology Institute, Kraków; 5Center for Epidemiology and Prevention, Poznań; 6Lung Diseases Hospital, Szczecin; 7Department of Otolaryngology and Laryngological Oncology, Pomeranian Medical University, Szczecin; 8Clinics of Surgey, Pomeranian Medical University, Szczecin; 9Department of Radiology, Pomeranian Medical University, Szczecin; 10Clinics of Urology, Pomeranian Medical University, Szczecin; *Postgraduate School of Molecular Medicine, Warsaw Medical University.

  4. Family history of cancer– strongindicationof high geneticrisk of malignancies

  5. West Pomerania 2000-2001 • 1.7 mln of inhabitants • 1.28 mln (75%) of cancer family histories collected via family doctors

  6. West Pomerania 2000-2001 • BRCA1 testing – all of females with at least one breast / ovarian cancer among relatives

  7. West Pomerania 2000-2001 • Other DNA tests – MSH2 / MLH1; VHL; RB1; APC etc. • Limited to persons pre-selected depending on pedigrees and other clinical data

  8. West Pomerania 2000-2001 • 1 CRC • HNPCC ≥ 1 cancer from the spectrum (CRC, END, SB, urinary t.) • ≥ 1 cancerdgn <50 yrs • Familialaggregation of the cancers of one-twosites i.e. colon, stomach, pancreas, breast – ovaries, etc. • Otherstrongcancerfamilialaggregations

  9. Luck!!! Poland • If genetic events present they are expressed strongly

  10. Górski B. et al. AJHG, June 2000

  11. POLISH PANEL OF BRCA1 MUTATIONS • BRCA 1 ~65% • BRCA2 ~4% Górski B. et al. Int. J. Can, 2004

  12. POLISH FAMILIES WITH STRONG AGGREGATION OF BREAST/OVARIAN CANCERS (n=200) • 5382 ins C • C 61 G • 4153 del A 90% of mutations Górski B. et al. Int. J. Can, 2004

  13. BRCA1 FOUNDER MUTATIONS IN POLAND • GÓRSKI B. ET AL. - PATENT NO P335917- MULTIPLEX PCR - 50€

  14. POPULATION SCREENINGS IN POLAND • 4% (~200) of BRCA1 carriers among 5000 relatives of women with breast cancer dgn < 50 yrs or ovarian cancer dgn at any age • Thanks to geneticists - oncologists from 20 Polish centers!

  15. BRCA1 – REGISTRY – SZCZECIN – POLAND >5000 CARRIERS THE LARGEST REGISTRY IN THE WORLD

  16. CHEK2 mutations - Poland - epidemiology a) Protein truncating mutations • 1100 delC • IS2 + 1 G  A 1,5% • del5000 b) Missense mutation • I157T 5%

  17. CHEK2 mutations - high risk of breast cancer OR > 5 • PTM + family history C. Cybulski et al. 2011 JCO • PTM + I157T C. Cybulski et al. 2009 JMG • PTM + CYP1 B1 T. Huzarski et al. 2012 in prep. • I157T + BRCA2 5972 C/T P. Serrano-Fernández Br Can Res Treat 2009

  18. Sequencing in diagnostics of high genetic risk of breast cancer Cybulski C., Scott R. Lubiński J., 2014

  19. „Exomsequencing” • 144 women with breastcancer from families with ≥ 3 BC cases • 11 BRCA1/2 foundermutations (−) • 4 CHEK2 foundermutations (−) Cybulski C. 2014

  20. Results • 12 BRCA2 mutations 17/144 11,8% • 5 BRCA1 mutations • 3 PALB2 • 2 ATM • 1 BARD1 9/144 6,3% • 1 CHEK2 • 1 XRCC2 • + candidategenes 5/144 3,5%single mutations

  21. Mutationsdetectedusing„Exomsequencing”

  22. Conclusions • Costs of sequencing • BRCA1/2 ~500 € • Gene panel ~1500 € • It is important to develop an algorithm for selection of families with breast cancers for diagnostic sequencing

  23. BRCA1/2 mutation frequency in triple negative breast cancers Scott R. 2014

  24. BRCA1/2 mutations – breastcancers 11/55 = 20% Scott R. 2014

  25. Conclusions • Assuming an acceptable cost of 10 000 zł of detection of one BRCA1/2 mutationcarrier, sequencingcosts of 2 000 zł is economically justified for patients with breast cancers: triple negative and earlyonset(<51 years of age)

  26. Purpose • To estimate the influence of the oral contraceptive use by BRCA1 carriers on risk of breast cancer with respect: - age of beginning -duration

  27. Patients and Methods • 72 participating centers (13 countries) • CASE-CONTROL STUDY: BRCA1 carriers - 2492 women affected with breast cancer vs. 2492 matched healthy controls • Data were collected from the questonnaires • Varibles between cases and controls were compared using Student’s t-test and chi-square test; conditional logistic regression was used to estimate OR and 95% CI

  28. Relationship between oral contraceptive use and breast cancer risk among BRCA1 mutation carriers

  29. Relationship between duration of oral contraceptive use prior to age 20 and breast cancer risk among BRCA1 mutation carriers

  30. Relationship between oral contraceptive use and risk of breast cancer diagnosed prior to age 40 among BRCA1 mutation carriers

  31. Conclusion • Effect of oral contraceptive is harmful for early-onset breast cancer if use is initiated prior to age 25 • Women with BRCA1 mutation should be advised to avoid oral contraceptive use before age of 25

  32. Purpose • To estimate the reduction in risk of ovarian, fallopian tube, orperitoneal cancer in BRCA1/2 carriers after oophorectomy; • To estimate the impact of prophylactic oophorectomy on all-cause mortality; • Toestimate 5-year survival associated with clinically detected ovarian, occult, and peritoneal cancersdiagnosed in the cohort.

  33. Patients and Methods • 5,783 BRCA1/2 carriers • An average follow-up period - 5.6 years • Hazard ratios (HRs) for cancer incidence and all-cause mortality associatedwith oophorectomy were evaluated

  34. 91.6% 54.4% 38.4%

  35. Conclusion • Preventive oophorectomy was associated with an 80% reduction in the risk of ovarian, fallopiantube, or peritoneal cancer in BRCA1 or BRCA2 carriers and a 77% reduction in all-cause mortality.

  36. Studies on micro- and macro- elements – summarization

  37. Retrospectivestudies • Selection of individuals with a fewtimesof increasedchance of cancer detection– CT of the lung, coloscopy, PSA and prostatebiopsies Lubiński J. 2014

  38. Prospectiveobservationalstudies • Micro- macro- elementslevelsas cancer risk factor Lubiński J. 2014

  39. Mortality – allcausesn=13887 adults, 18 yrsfollow-up, USA Risk of death (95% CI) 60 70Poland 140USA Serum seleniumconcentration (µg/l) M. Rayman, Lancet 2012

  40. Se; independantly on genotypes

  41. Fe/Zn; „S” nAA

  42. Cancer riskcan be decreased by supplementation? Clinicaltrials

  43. American study— NPC (Nutritional Prevention of Cancer) • n=1312; • mean age 63 yrs (18–80) • randomised study; • Se 200 μg/day or placebo; • observation length 6–8 yrs; • initial level of Se concentration 114 μg/l plasma

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