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SPECTRUM OF GERMLINE CANCER SUSCEPTIBILITY GENE MUTATIONS IN BREAST AND OVARIAN CANCER PATIENTS IN THE BLACK SEA REGION OF TURKEY: SINGLE CENTER EXPERIENCE

Yıl 2023, Cilt: 4 Sayı: 1, 41 - 48, 29.03.2023
https://doi.org/10.48176/esmj.2023.102

Öz

Introduction: Breast cancer consists huge amount of the cancerrelated death in population. Ovarian cancer is the second most frequent seen type of gynecological cancer and has the highest
mortality among gynecological cancers since most cases are detected late. The current study intended to determine the prevalence of oncogene mutations, especially BRCA1 and BRCA2, in high-risk patients diagnosed with ovarian and breast cancer in the Black Sea region of our country.
Material and method: Between August 2017 and January 2022, a total of 223 individuals who applied to our center and met the genetic test criteria were included in the study. Next-generation sequencing (NGS) was used to detect germ-line deleterious variants in genes included in the oncogenetic panel of patients (34 genes).
Results: Among the 223 patients analyzed within the scope of the study, 195 had breast cancer, and 28 had ovarian cancer, resulting in the detection of 15 different pathogenic variants of BRCA1 (%4,9) and BRCA2 (%6,7) genes in 26 (11.6%) patients. In the analysis of 32 oncogenes other than BRCA1 and BRCA2 genes, 26 different pathogenic (P) or likely pathogenic (LP) variants were detected in a total of 35 patients (15.7%). Based on the analysis of 223 breast/ ovarian cancer patients together, 41 different pathogenic (P) or likely pathogenic (LP) variants were found in 61 patients (27.3%). Furthermore, 65 different VUSs (Variant of Uncertain Significance) were detected in 73 patients (32.7%).
Conclusion: This is the first study to be conducted in our region in a single center located in the Black Sea region. The study was conducted in a single center within the Black Sea region and, to our knowledge, provides the first data in this region in terms of cancer genes other than BRCAs. To appreciate of the genetic susceptibility spectrum of hereditary breast and/or ovarian cancer better, it is imperative to clarify the risks associated with genes other than BRCAs, which carry a high risk for other breast and ovarian cancers, as well as BRCA1 and BRCA2. Therefore, patients in the risk group must undergo multigene panel testing in addition to routine BRCA1 and BRCA2 gene testing. We detected two novel variants in the BRCA2 gene and five novel variants other than BRCA oncogenes. Furthermore, the results of this study contributed to the development of our country's specific variant pool.

Kaynakça

  • Arbyn M, Weiderpass E, Bruni L, et al. Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. Lancet Global Health 2020;8:e191-e203.
  • Ueland FR. A perspective on ovarian cancer biomarkers: past, present and yet-to-come. Diagnostics 2017;7:14.
  • Larsen MJ, Thomassen M, Gerdes A-M, Kruse. Hereditary breast cancer: clinical, pathological and molecular characteristics. Breast Cancer 2014;8:145-55.
  • Toss A, Tomasello C, Razzaboni E, et al. Hereditary ovarian cancer: not only BRCA 1 and 2 genes. BioMed Res Int 2015;2015:341723
  • 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.
  • Wooster R, Bignell G, Lancaster J, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature 1995;378:789-92.
  • Mavaddat N, Antoniou AC, Easton DF, Garcia-Closas M. Genetic susceptibility to breast cancer. Mol Oncol 2010;4:174-91.
  • Brose MS, Rebbeck TR, Calzone KA, Stopfer JE, Nathanson KL, Weber BL. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Nat Cancer Inst 2002;94:1365-72.
  • Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Nat Cancer Inst 1999;91:1310-6.
  • Burki TK. Oophorectomy in women with BRCA1 or BRCA2 mutations. Lancet Oncol 2014;15:e156.
  • Lostumbo L, Carbine NE, Wallace J. Prophylactic mastectomy for the prevention of breast cancer. Cochrane Database Syst Rev 2010;11:CD002748.
  • Kang E, Seong M-W, Park SK, et al. The prevalence and spectrum of BRCA1 and BRCA2 mutations in Korean population: recent update of the Korean Hereditary Breast Cancer (KOHBRA) study. Breast Cancer Res Treat 2015;151:157-68.
  • Wang F, Fang Q, Ge Z, Yu N, Xu S, Fan X. Common BRCA1 and BRCA2 mutations in breast cancer families: a meta-analysis from systematic review. Mol Biol Rep 2012;39:2109-18.
  • Economopoulou P, Dimitriadis G, Psyrri A. Beyond BRCA: new hereditary breast cancer susceptibility genes. Cancer Treat Rev 2015;41:1-8.
  • Neben CL, Zimmer AD, Stedden W, et al. Multi-gene panel testing of 23,179 individuals for hereditary cancer risk identifies pathogenic variant carriers missed by current genetic testing guidelines. J Mol Diagn 2019;21:646-57.
  • Akcay IM, Celik E, Agaoglu NB, et al. Germline pathogenic variant spectrum in 25 cancer susceptibility genes in Turkish breast and colorectal cancer patients and elderly controls. Int J Cancer 2021;148:285-95.
  • LaDuca H, Stuenkel A, Dolinsky JS, et al. Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients. Genet Med 2014;16:830-7.
  • Easton DF, Pharoah PD, Antoniou AC, et al. Gene-panel sequencing and the prediction of breast-cancer risk. N Eng J Med 2015;372:2243-57.
  • LaDuca H, Polley EC, Yussuf A, et al. A clinical guide to hereditary cancer panel testing: evaluation of gene-specific cancer associations and sensitivity of genetic testing criteria in a cohort of 165,000 high-risk patients. Genet Med 2020;22:407-15.
  • Susswein LR, Marshall ML, Nusbaum R, et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med 2016;18:823-32.
  • Taşçanov MB, Çitli Ş. Akut Koroner Sendromlu Genç Hastalarda Monosit Kemoatraktan Protein-1 ve CC Kemokin Reseptörü Tip 2 Gen Polimorfizmlerinin Klinik Önemi. Harran Üniversitesi Tıp Fakültesi Dergisi 2022;19:272-6.
  • Richards S, Aziz N, Bale S, et al. 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 2015;17:405-23.
  • Bisgin A, Sag SO, Dogan ME, et al. Germline landscape of BRCAs by 7-site collaborations as a BRCA consortium in Turkey. The Breast 2022;65:15-22.
  • Bahsi T, Erdem HB. Spectrum of BRCA1/BRCA2 variants in 1419 Turkish breast and ovarian cancer patients: a single center study. Turk J Biochem 2020;45:83-90.
  • Solmaz AE, Onay H, Yeniay L, et al. BRCA1-BRCA2 mutation analysis results in 910 individuals: Mutation distribution and 8 novel mutations. Cancer Genetics 2020;241:20-4.
  • Demir S, Tozkir H, Gurkan H, et al. Genetic screening results of individuals with high risk BRCA-related breast/ovarian cancer in Trakya region of Turkey. J BUON 2020;25:1337-47.
  • Gezdirici A, İli EG, Değirmenci B, et al. Hereditary Breast-Ovarian Cancer and BRCA1/BRCA2 Variants: A Single Center Experience. Acta Oncologica Turcica 2021;54:264-72
  • Abdel-Razeq H, Abujamous L, Jadaan D. Patterns and prevalence of germline BRCA1 and BRCA2 mutations among high-risk breast cancer patients in Jordan: a study of 500 patients. J Oncology 2020; 2020: 8362179.
  • Çelebi HBG, Bolat H. BRCA and non-BRCA Variants Detected by Next Generation Sequencing in Patients with Hereditary Breast and/or Ovarian Cancer Syndrome. Acta Oncologica Turcica 2022;55:77-84
  • Yazici H, Bitisik O, Akisik E, et al. BRCA1 and BRCA2 mutations in Turkish breast/ovarian families and young breast cancer patients. Br J Cancer 2000;83:737-42.
  • Kraus C, Hoyer J, Vasileiou G, et al. Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2. Int J Cancer 2017;140:95-102.
  • Hauke J, Horvath J, Groß E, et al. Gene panel testing of 5589 BRCA 1/2‐negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer. Cancer Med 2018;7:1349-58.

KARADENİZ BÖLGESİNDEKİ MEME VE YUMURTALIK KANSERİ HASTALARINDA GERMLİNE KANSER YATKINLIK GENLERİNİN MUTASYON SPEKTRUMU: TEK MERKEZ DENEYİMİ

Yıl 2023, Cilt: 4 Sayı: 1, 41 - 48, 29.03.2023
https://doi.org/10.48176/esmj.2023.102

Öz

Giriş: Meme kanseri kadınlarda en sık görülen kanserdir ve kansere bağlı ölümlerin en sık nedenlerinden biridir. Over kanseri, jinekolojik kanserler arasında ikinci en sık kanser türüdür ve bu hastaların çoğu geç tanı aldığından dolayı mortalitesi en yüksek jinekolojik kanser olarak bilinir. Bu çalışmada ülkemiz karadeniz bölgesinde Meme ve Over kanseri tanısı almış yüksek risk grubundaki hastalarda BRCA1 ve BRCA2 başta olmak üzere sorumlu olabilecek onkogen mutasyonlarının prevalansı ve bölge populasyonumuza özgü varyantları belirlemeyi amaçladık.
Materyal ve metod: Çalışmada Ağustos 2017–0cak 2022 aralığında merkezimize başvuran ve genetik test kriterlerini karşılayan 223 hasta analiz edilmiştir. Çalışmaya alınan hastalarda onkogenetik panel (34 gen) kapsamındaki genlerde germ-line zararlı varyantları tanımlamak için (Next generation sequencing (NGS)) yeni nesil dizileme kullanıldı.
Bulgular: Çalışma kapsamında analiz edilen 195 Meme kanserli ve 28 Over kanserli olmak üzere toplam 223 hastanın BRCA1 (%4,9) ve BRCA2 (6,7) genlerinde toplam 26 (%11,6) hastada 15 farklı
Patojenik varyant saptanmıştır. BRCA1 ve BRCA2 genleri dışındaki diğer 32 onkogenin analizinde ise toplam 35 hastada (%15,7) 26 farklı Patojenik (P) veya Likely Patojenik (LP) varyant tespit edilmiştir. Analiz edilen 223 meme/over kanserli hasta beraber düşünüldüğünde ise 61 hastada (%27.3) 41 farklı Patojenik (P) veya Likely Patojenik (LP) variant tespit edilmiştir. Bunlara ek olarak Çalışmaki 73 hastada (%32.7) ise 65 farklı VUS (Variant of Uncertain Significance = Önemi Belirsiz Varyant) saptanmıştır.
Sonuç: Çalışma karadeniz bölgesindeki üçüncü basamak bir hastanede yürütülmüş olup bildiğimiz kadarıyla BRCA genleri dışındaki kanser genleri açısından bölgemize dair ilk verileri ortaya koymaktadır. Kalıtsal meme/over kanseri genetik yatkınlık spektrumunun daha fazla anlaşılması için BRCA1 ve BRCA2 genlerinin yanı sıra diğer meme/over ca açısından yüksek risk taşıyan BRCA1 ve BRCA2 genleri dışındaki kanser genlerine özgü risklerin de aydınlatılması gerekmektedir. Bundan dolayı risk grubundaki hastalara rutin BRCA1 ve BRCA2 genlerine ek olarak çoklu gen panel testine ihtiyaç vardır. Çalışmada BRCA2 geninde 2 novel variant saptanırken BRCA genleri dışındaki onkogenlerde 5 novel variant tespit edildi. Ek olarak çalışmamız sonucunda ülkemize spesifik varyant havuzuna da katkı sağlandı.

Kaynakça

  • Arbyn M, Weiderpass E, Bruni L, et al. Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. Lancet Global Health 2020;8:e191-e203.
  • Ueland FR. A perspective on ovarian cancer biomarkers: past, present and yet-to-come. Diagnostics 2017;7:14.
  • Larsen MJ, Thomassen M, Gerdes A-M, Kruse. Hereditary breast cancer: clinical, pathological and molecular characteristics. Breast Cancer 2014;8:145-55.
  • Toss A, Tomasello C, Razzaboni E, et al. Hereditary ovarian cancer: not only BRCA 1 and 2 genes. BioMed Res Int 2015;2015:341723
  • 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.
  • Wooster R, Bignell G, Lancaster J, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature 1995;378:789-92.
  • Mavaddat N, Antoniou AC, Easton DF, Garcia-Closas M. Genetic susceptibility to breast cancer. Mol Oncol 2010;4:174-91.
  • Brose MS, Rebbeck TR, Calzone KA, Stopfer JE, Nathanson KL, Weber BL. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Nat Cancer Inst 2002;94:1365-72.
  • Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Nat Cancer Inst 1999;91:1310-6.
  • Burki TK. Oophorectomy in women with BRCA1 or BRCA2 mutations. Lancet Oncol 2014;15:e156.
  • Lostumbo L, Carbine NE, Wallace J. Prophylactic mastectomy for the prevention of breast cancer. Cochrane Database Syst Rev 2010;11:CD002748.
  • Kang E, Seong M-W, Park SK, et al. The prevalence and spectrum of BRCA1 and BRCA2 mutations in Korean population: recent update of the Korean Hereditary Breast Cancer (KOHBRA) study. Breast Cancer Res Treat 2015;151:157-68.
  • Wang F, Fang Q, Ge Z, Yu N, Xu S, Fan X. Common BRCA1 and BRCA2 mutations in breast cancer families: a meta-analysis from systematic review. Mol Biol Rep 2012;39:2109-18.
  • Economopoulou P, Dimitriadis G, Psyrri A. Beyond BRCA: new hereditary breast cancer susceptibility genes. Cancer Treat Rev 2015;41:1-8.
  • Neben CL, Zimmer AD, Stedden W, et al. Multi-gene panel testing of 23,179 individuals for hereditary cancer risk identifies pathogenic variant carriers missed by current genetic testing guidelines. J Mol Diagn 2019;21:646-57.
  • Akcay IM, Celik E, Agaoglu NB, et al. Germline pathogenic variant spectrum in 25 cancer susceptibility genes in Turkish breast and colorectal cancer patients and elderly controls. Int J Cancer 2021;148:285-95.
  • LaDuca H, Stuenkel A, Dolinsky JS, et al. Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients. Genet Med 2014;16:830-7.
  • Easton DF, Pharoah PD, Antoniou AC, et al. Gene-panel sequencing and the prediction of breast-cancer risk. N Eng J Med 2015;372:2243-57.
  • LaDuca H, Polley EC, Yussuf A, et al. A clinical guide to hereditary cancer panel testing: evaluation of gene-specific cancer associations and sensitivity of genetic testing criteria in a cohort of 165,000 high-risk patients. Genet Med 2020;22:407-15.
  • Susswein LR, Marshall ML, Nusbaum R, et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med 2016;18:823-32.
  • Taşçanov MB, Çitli Ş. Akut Koroner Sendromlu Genç Hastalarda Monosit Kemoatraktan Protein-1 ve CC Kemokin Reseptörü Tip 2 Gen Polimorfizmlerinin Klinik Önemi. Harran Üniversitesi Tıp Fakültesi Dergisi 2022;19:272-6.
  • Richards S, Aziz N, Bale S, et al. 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 2015;17:405-23.
  • Bisgin A, Sag SO, Dogan ME, et al. Germline landscape of BRCAs by 7-site collaborations as a BRCA consortium in Turkey. The Breast 2022;65:15-22.
  • Bahsi T, Erdem HB. Spectrum of BRCA1/BRCA2 variants in 1419 Turkish breast and ovarian cancer patients: a single center study. Turk J Biochem 2020;45:83-90.
  • Solmaz AE, Onay H, Yeniay L, et al. BRCA1-BRCA2 mutation analysis results in 910 individuals: Mutation distribution and 8 novel mutations. Cancer Genetics 2020;241:20-4.
  • Demir S, Tozkir H, Gurkan H, et al. Genetic screening results of individuals with high risk BRCA-related breast/ovarian cancer in Trakya region of Turkey. J BUON 2020;25:1337-47.
  • Gezdirici A, İli EG, Değirmenci B, et al. Hereditary Breast-Ovarian Cancer and BRCA1/BRCA2 Variants: A Single Center Experience. Acta Oncologica Turcica 2021;54:264-72
  • Abdel-Razeq H, Abujamous L, Jadaan D. Patterns and prevalence of germline BRCA1 and BRCA2 mutations among high-risk breast cancer patients in Jordan: a study of 500 patients. J Oncology 2020; 2020: 8362179.
  • Çelebi HBG, Bolat H. BRCA and non-BRCA Variants Detected by Next Generation Sequencing in Patients with Hereditary Breast and/or Ovarian Cancer Syndrome. Acta Oncologica Turcica 2022;55:77-84
  • Yazici H, Bitisik O, Akisik E, et al. BRCA1 and BRCA2 mutations in Turkish breast/ovarian families and young breast cancer patients. Br J Cancer 2000;83:737-42.
  • Kraus C, Hoyer J, Vasileiou G, et al. Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2. Int J Cancer 2017;140:95-102.
  • Hauke J, Horvath J, Groß E, et al. Gene panel testing of 5589 BRCA 1/2‐negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer. Cancer Med 2018;7:1349-58.
Toplam 32 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Sağlık Kurumları Yönetimi
Bölüm Araştırma Makaleleri
Yazarlar

Şenol Çitli 0000-0001-6226-4712

Yelda Dağcıoğlu 0000-0001-5169-9702

Esra Aydın 0000-0003-0210-3153

Kemal Kurtçu 0000-0002-3291-5366

Yayımlanma Tarihi 29 Mart 2023
Yayımlandığı Sayı Yıl 2023 Cilt: 4 Sayı: 1

Kaynak Göster

APA Çitli, Ş., Dağcıoğlu, Y., Aydın, E., Kurtçu, K. (2023). SPECTRUM OF GERMLINE CANCER SUSCEPTIBILITY GENE MUTATIONS IN BREAST AND OVARIAN CANCER PATIENTS IN THE BLACK SEA REGION OF TURKEY: SINGLE CENTER EXPERIENCE. Eskisehir Medical Journal, 4(1), 41-48. https://doi.org/10.48176/esmj.2023.102
AMA Çitli Ş, Dağcıoğlu Y, Aydın E, Kurtçu K. SPECTRUM OF GERMLINE CANCER SUSCEPTIBILITY GENE MUTATIONS IN BREAST AND OVARIAN CANCER PATIENTS IN THE BLACK SEA REGION OF TURKEY: SINGLE CENTER EXPERIENCE. Eskisehir Med J. Mart 2023;4(1):41-48. doi:10.48176/esmj.2023.102
Chicago Çitli, Şenol, Yelda Dağcıoğlu, Esra Aydın, ve Kemal Kurtçu. “SPECTRUM OF GERMLINE CANCER SUSCEPTIBILITY GENE MUTATIONS IN BREAST AND OVARIAN CANCER PATIENTS IN THE BLACK SEA REGION OF TURKEY: SINGLE CENTER EXPERIENCE”. Eskisehir Medical Journal 4, sy. 1 (Mart 2023): 41-48. https://doi.org/10.48176/esmj.2023.102.
EndNote Çitli Ş, Dağcıoğlu Y, Aydın E, Kurtçu K (01 Mart 2023) SPECTRUM OF GERMLINE CANCER SUSCEPTIBILITY GENE MUTATIONS IN BREAST AND OVARIAN CANCER PATIENTS IN THE BLACK SEA REGION OF TURKEY: SINGLE CENTER EXPERIENCE. Eskisehir Medical Journal 4 1 41–48.
IEEE Ş. Çitli, Y. Dağcıoğlu, E. Aydın, ve K. Kurtçu, “SPECTRUM OF GERMLINE CANCER SUSCEPTIBILITY GENE MUTATIONS IN BREAST AND OVARIAN CANCER PATIENTS IN THE BLACK SEA REGION OF TURKEY: SINGLE CENTER EXPERIENCE”, Eskisehir Med J, c. 4, sy. 1, ss. 41–48, 2023, doi: 10.48176/esmj.2023.102.
ISNAD Çitli, Şenol vd. “SPECTRUM OF GERMLINE CANCER SUSCEPTIBILITY GENE MUTATIONS IN BREAST AND OVARIAN CANCER PATIENTS IN THE BLACK SEA REGION OF TURKEY: SINGLE CENTER EXPERIENCE”. Eskisehir Medical Journal 4/1 (Mart 2023), 41-48. https://doi.org/10.48176/esmj.2023.102.
JAMA Çitli Ş, Dağcıoğlu Y, Aydın E, Kurtçu K. SPECTRUM OF GERMLINE CANCER SUSCEPTIBILITY GENE MUTATIONS IN BREAST AND OVARIAN CANCER PATIENTS IN THE BLACK SEA REGION OF TURKEY: SINGLE CENTER EXPERIENCE. Eskisehir Med J. 2023;4:41–48.
MLA Çitli, Şenol vd. “SPECTRUM OF GERMLINE CANCER SUSCEPTIBILITY GENE MUTATIONS IN BREAST AND OVARIAN CANCER PATIENTS IN THE BLACK SEA REGION OF TURKEY: SINGLE CENTER EXPERIENCE”. Eskisehir Medical Journal, c. 4, sy. 1, 2023, ss. 41-48, doi:10.48176/esmj.2023.102.
Vancouver Çitli Ş, Dağcıoğlu Y, Aydın E, Kurtçu K. SPECTRUM OF GERMLINE CANCER SUSCEPTIBILITY GENE MUTATIONS IN BREAST AND OVARIAN CANCER PATIENTS IN THE BLACK SEA REGION OF TURKEY: SINGLE CENTER EXPERIENCE. Eskisehir Med J. 2023;4(1):41-8.