Mutation Profiles Detected by New Generation DNA Sequence Analysis in Gynecological Cancers: Single Centre Case Series Results

Year 2020, Volume: 46 Issue: 3, 349 - 356, 01.12.2020

H.öztürk Şahin , Kübra Özkan Burcu Albuz , Fatma Sılan

https://doi.org/10.32708/uutfd.731913

Abstract

Our objective is to investigate the mutation frequency and sequences of our patients, who underwent surgery with a diagnosis of ovarian (OC) and endometrial cancer (EC) and subsequently underwent genetic mutation analysis, regardless of age and family history. In recent years, apart from the development of preventive strategies, opportunities in treatment options and increase in genetic studies have increased the interest in hereditary cancers. The most common hereditary gynecological cancers are hereditary breast ovarian cancer (HBOC) and Lynch Syndrome (LS). The low prevalence of the disease, cost of testing, and ethical reasons make population-based screening impractical. 37 patients diagnosed with endometrial cancer and 15 patients diagnosed with ovarian cancer were included in the study, and their genetic research was conducted in our department between 01.04.2018 and 01.10.2019. A large familial panel test consisting of 25 genes including BRCA1/2 and LS genes (MLH1, MSH2, MSH6, PMS 2) was performed. Pathological mutation was found in 1 MLH1 and 1 ATM genes in 27 patients with endometrial cancer who underwent familial gene panel test (3.7% LS, 3.7% non LS). Eleven patients had a variant mutation of uncertain significance (VUS) (40.7%). No pathological mutation was found in our 20 patients with endometrial cancer who were investigated for BRCA mutation. In our 14 patients with ovarian cancer whose BRCA mutation was investigated, 3 pathological variants were identified, and all of them were in BRCA1 gene (HBOC 21.4%). Pathological mutations in 1 MSH6 and 1 ATM genes were observed in 4 patients with ovarian cancer whose familial cancer panel was evaluated. The proliferation of comprehensive familial mutation data in ovarian and endometrial cancers and their sharing in the literature will reduce VUS rates, reveal the role of genes other than BRCA and LS in gynecological cancers, and create new screening algorithms.

Keywords

Gynecologic cancers, Hereditary, Genetic counseling

Jinekolojik Kanserlerde Yeni Nesil DNA Dizi Analizi ile Saptanan Mutasyon Profilleri: Tek Merkez Vaka Serisi Sonuçlarımız

Abstract

Amacımız, yaş ve aile hikayesinden bağımsız olarak merkezimizde over (OC) ve endometriyum kanseri (EC) tanısı ile cerrahisi ve ardından genetik mutasyon analizi uygulanan hastalarımızın mutasyon sıklığını ve sekanslarını araştırmaktır. Son yıllarda önleyici stratejilerin gelişimi dışında tedavi seçeneklerindeki fırsatlar ve genetik çalışmaların artışı herediter kanserlere ilgiyi arttırmıştır. En sık görülen herediter jinekolojik kanserler; herediter meme over kanseri (HBOC) ve Lynch Sendromu (LS) dur. Hastalığın düşük prevalansı, test pahalılığı ve etik sebepler popülasyon bazlı taramayı kullanışsız hale getirmektedir. Birimimizde 01.04.2018-01.10.2019 tarihleri arasında genetik araştırması yapılan 37 EC ve 15 OC tanısı almış hastamız çalışmaya dahil edilmiştir. BRCA1/2 ve LS genlerini de içeren (MLH1, MSH2, MSH6, PMS 2) 25 genden oluşan geniş ailevi panel testi uygulanmıştır. Ailevi gen paneli testi yapılan 27 EC hastamızda, 1 MLH1 ve 1 ATM geninde patolojik mutasyon saptandı (%3.7 LS,%3.7 non LS). 11 hastada önemi belirsiz varyant mutasyon (VUS) görüldü (%40.7). BRCA mutasyon araştırması yapılan 20 EC’li hastamızda patolojik mutasyon saptanmadı. BRCA mutasyonu araştırılan 14 OC’lu hastamızda 3 patolojik varyant identifiye edildi ve hepsi BRCA1 genindeydi (HBOC %21,4). Ailevi kanser paneli değerlendirilen 4 OC’lu hastada 1 MSH6 ve 1 ATM geninde patolojik mutasyonlar izlendi. Over ve endometriyum kanserlerinde ailevi geniş mutasyon verilerinin çoğalması ve literatürde paylaşımı VUS oranlarını azaltacak, BRCA ve LS dışındaki genlerin jinekolojik kanserlerdeki rolünü ortaya çıkartacak ve yeni tarama algoritmalarını oluşturacaktır.

Keywords

Jinekolojik kanserler, Heredite, Genetik analiz

References

• 1. Harper P. Practical Genetic Counselling. Sixth Edition. London: Hodder Arnold; 2004. 331 pp.
• 2. Ferlay J, Bray F, Forman D, Mathers C, Parkin DMSHR. Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet] Lyon, France: GLOBOCAN; International Agency for Research on Cancer; 2010. 2008.
• 3. M.S. Daniels Genetic testing by cancer site: uterus Cancer J., 18 (2012), pp. 338-342.
• 4. Lamberti C, Kruse R, Ruelfs C, et al. Microsatellite instability-a useful diagnostic tool to select patients at high risk for hereditary non-polyposis colorectal cancer: a study in different groups of patients with colorectal cancer. Gut. 1999;44:839–843.
• 5. Resnick KE, Hampel H, Fishel R, Cohn DE. Current and emerging trends in Lynch syndrome identification in women with endometrial cancer. Gynecol Oncol. 2009;114:128–134.
• 6. NCCN. Clinical practice guidelines in oncology: genetic/familial high-risk assessment: colorectal. Available at https://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Accessed Oct. 11, 2016.
• 7. A.K. Tiwari, H.K. Roy, H.T. Lynch .Lynch syndrome in the 21st century: clinical perspectives QJM, 109 (2016), pp. 151-158.
• 8. H.Hampel, W. Frankel, J. Panescu, et al. Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients(published addendum appears in Cancer Res 2007;67:9603) Cancer Res., 66 (2006), pp. 7810-7817.
• 9. H.Hampel, W.L. Frankel, E. Martin ,et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer) N. Engl. J. Med., 352 (2005), pp. 1851-1856.
• 10. M.J. Berends, Y. Wu, R.H. Sijmons, et al.Toward new strategies to select young endometrial cancer patients for mis- match repair gene mutation analysis J. Clin. Oncol., 21 (2003), pp. 4364-4370.
• 11. K.H. Lu, J.O. Schorge, K.J. Rodabaugh, et al. Prospective determination of prev- alence of lynch syndrome in young women with endome- trial cancer J. Clin. Oncol., 25 (2007), pp. 5158-5164.
• 12. V. Pinol, A. Castells, M. Andreu, et al.Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolypo- sis colorectal cancer. Gastrointestinal Oncology Group of the Spanish Gastroenterological Association JAMA, 293 (2005), pp. 1986-1994.
• 13. Pål Møller, Toni Seppälä, Inge Bernstein , et al. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut. 2017;66:464–472.
• 14. K.H. Lu, M. Dinh, W. Kohlmann, et al. Gynecologic cancer as a “sentinel cancer” for women with hereditary nonpolyposis colorectal cancer syndrome Obstet. Gynecol., 105 (2005), pp. 569-574.
• 15. Cousineau I, Abaji C, Belmaaza A. BRCA1 regulates RAD51 function in response to DNA damage and suppresses spontaneous sister chromatid replication slippage: implications for sister chromatid cohesion, genome stability, and carcinogenesis. Cancer Res. 2005 Dec 15;65(24):11384-91.
• 16. T. Walsh, S. Casadei, M.K. Lee, et al., Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing Proc Natl Acad Sci, 108 (2011), pp. 18032-18037.
• 17. Z.K. Stadler, E. Salo-Mullen, S.M. Patil, et al. Prevalence of BRCA1 and BRCA2 mutations in Ashkenazi Jewish families with breast and pancreatic cancer Cancer, 118 (2012), pp. 493-499.
• 18. J.Mersch, M.A. Jackson, M. Park, et al.Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian Cancer, 121 (2015), pp. 269-275.
• 19. C.A. Shu, M.C. Pike, A.R. Jotwani, et al. Uterine cancer after risk-reducing salpingo-oophorectomy without hysterectomy in women with BRCA mutations JAMA Oncol, 2 (2016), pp. 1434-1440.
• 20. Lakhani SR, Manek S, Penault-Llorca F, et al. Pathology of ovarian cancers in BRCA1 and BRCA2 carriers. Clin Cancer Res. 2004;10(7):2473–81.
• 21. Risch HA, McLaughlin JR, Cole DE, et al.Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet. 2001;68(3):700–10.
• 22. Ferla R, Calo V, Cascio S, et al. Founder mutations in BRCA1 and BRCA2 genes. Ann Oncol. 2007;18 (Suppl 6):vi93-8.
• 23. Shanmughapriya S, Nachiappan V, Natarajaseenivasan K. BRCA1 and BRCA2 mutations in the ovarian cancer population across race and ethnicity: special reference to Asia. Oncology. 2013;84(4):226–32.
• 24. D.Ford, D.F.Easton, M.Stratton, et al.Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families Am J Hum Genet, 62 (1998), pp. 676-689.
• 25. A.Antoniou, P.D.P. Pharoah, S. Narod, et al.Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies Am J Hum Genet, 72 (2003), pp. 1117-1130.
• 26. King MC, Marks JH, Mandell JB; New York Breast Cancer Study Group. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003 Oct 24;302(5645):643-6.
• 27. Biron-Shental T, Drucker L, Altaras M, Bernheim J, Fishman A. High incidence of BRCA1-2 germline mutations, previous breast cancer and familial cancer history in Jewish patients with uterine serous papillary carcinoma. Eur J Surg Oncol. 2006;32:1097–100.
• 28. Lavie O, Ben-Arie A, Segev Y, et al. BRCA germline mutations in women with uterine serous carcinoma--still a debate. Int J Gynecol Cancer. Official journal of the International Gynecological Cancer Society. 2010;20:1531–4.
• 29. Goshen R, Chu W, Elit L, et al. Is uterine papillary serous adenocarcinoma a manifestation of the hereditary breast-ovarian cancer syndrome? Gynecologic oncology. 2000;79:477–81.
• 30. J.M. Lancaster, C.B. Powell, L.M. Chen, D.L. Richardson SGO Clinical Practice Committee. Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositionsGynecol. Oncol., 136 (1) (2015 Jan), pp. 3-7.
• 31. Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL; Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015;17:70–87.
• 32. Myriad Genetic Laboratories.Mutation prevalance table for HNPCC.[Retrieved October 2005];Available at:myriadtests.com/provider/mutprevhnpcc.htm.
• 33. Trainer AH, Meiser B, Watts K, Mitchell G, Tucker K, Friedlander M. Moving toward personalized medicine: Treatment-focused genetic testing of women newly diagnosed with ovarian cancer. Int J Gynecol Cancer. 2010;(5):704–16.
• 34. M.B. Daly, R. Pilarski, J.E. Axilbund,et al. Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2015 J. Natl. Compr. Cancer Netw., 14 (2) (2016 Feb), pp. 153-162.
• 35. K.H. Lu, M.E. Wood, M. Daniels, et al. American Society of Clinical Oncology. American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providersJ. Clin. Oncol., 32 (8) (2014 Mar 10), pp. 833-840.
• 36. K.P. Pennington, E.M. Swisher Hereditary ovarian cancer: beyond the usual suspects Gynecol. Oncol., 124 (2) (2012), pp. 347-353.
• 37. B.Kaufman, R. Shapira-Frommer, R.K. Schmutzler, et al.Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation J. Clin. Oncol., 33 (3) (2015 Jan 20), pp. 244-250.
• 38. Dung T. Le, Jennifer N. Uram, Hao Wang, et al.PD-1 blockade in tumors with mismatch repair deficiency J. Clin. Oncol., 33 (2015).
• 39. Richards S., Aziz N., Bale S.,et al. (2015). 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. Genetics in medicine, 17(5), 405-423.
• 40. Eccles DM, Balmaña J, Clune J ,et al. Selecting Patients with Ovarian Cancer for Germline BRCA Mutation Testing: Findings from Guidelines and a Systematic Literature Review. Adv Ther. 2016 Feb;33(2):129-50.
• 41. Cancer Genome Atlas Research Network Integrated genomic analyses of ovarian carcinoma Nature, 474 (7353) (2011), pp. 609-615.
• 42. Maistro S, Teixeira N, Encinas G, et al. Germline mutations in BRCA1 and BRCA2 in epithelial ovarian cancer patients in Brazil. BMC Cancer. 2016 Dec 3;16(1):934.
• 43. George A, Riddell D, Seal S, et al. Implementing rapid, robust, cost-effective, patient-centred, routine genetic testing in ovarian cancer patients. Sci Rep. 2016 Jul 13;6:29506.
• 44. Alhuqail AJ, Alzahrani A, Almubarak H, et al.High prevalence of deleterious BRCA1 and BRCA2 germline mutations in arab breast and ovarian cancer patients. Breast Cancer Res Treat. 2018 Apr;168(3):695-702.
• 45. Li A, Xie R, Zhi Q,et al. BRCA germline mutations in an unselected nationwide cohort of Chinese patients with ovarian cancer and healthy controls. Gynecol Oncol. 2018 Oct;151(1):145-152.
• 46. Yazıcı H, Kılıç S, Akdeniz D,et al. Frequency of Rearrangements Versus Small Indels Mutations in BRCA1 and BRCA2 Genes in Turkish Patients with High Risk Breast and Ovarian Cancer. Eur J Breast Health. 2018 Apr 1;14(2):93-99.
• 47. Laitman Y, Michaelson-Cohen R, Levi E, et al. Israeli Consortium of Hereditary Breast Cancer. Uterine cancer in Jewish Israeli BRCA1/2 mutation carriers. Cancer. 2019 Mar 1;125(5):698-703.
• 48. Segev Y, Iqbal J, Lubinski J, et al. The incidence of endometrial cancer in women with BRCA1 and BRCA2 mutations: an international prospective cohort study. Gynecol Oncol. 2013;130:127–31.
• 49. Tan David SP, Rothermundt C, Thomas K,et al. “BRCAness” syndrome in ovarian cancer: a case–control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(34):5530–6.
• 50. Quinn JE, James CR, Stewart GE, et al. BRCA1 mRNA expression levels predict for overall survival in ovarian cancer after chemotherapy. Clin Cancer Res. 2007;13(24):7413–20.
• 51. Cuppone F, Bria E, Carlini P, et al. Taxanes as primary chemotherapy for early breast cancer: meta-analysis of randomized trials. Cancer. 2008;113(2):238–46.
• 52. Chen Y, Zhang L, Hao Q. Olaparib: a promising PARP inhibitor in ovarian cancer therapy. Arch Gynecol Obstet. 2013;288(2):367–74.
• 53. Lee J, Ledermann JA, Kohn EC. PARP inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies. Ann Oncol. 2014;25(1):32–40.
• 54. C.H.M. Leenen, M.G.F. van Lier, H.C. van Doorn, et al.Prospective evaluation of molecular screening for Lynch syndrome in patients with endometrial cancer ≤70 years Gynecol Oncol, 125 (2012), pp. 414-420.
• 55. F.J. Backes, D.E. Cohn Lynch syndrome Clin Obstet Gynecol, 54 (2011), pp. 199-214.
• 56. M.-H. Tan, J.L. Mester, J. Ngeow,et al. Cancer risks in individuals with germline PTEN mutations Clin Cancer Res, 18 (2012), pp. 400-407.
• 57. E. Barrow, J. Hill, D.G. Evans Cancer risk in Lynch syndrome Fam Cancer, 12 (2013), pp. 229-240.
• 58. Özdemir TR, Alan M, Sancı M, Koç A. Targeted Next-Generation Sequencing of MLH1, MSH2, and MSH6 Genes in Patients with Endometrial Carcinoma under 50 Years of Age. Balkan Med J. 2019 Jan 1;36(1):37-42.
• 59. M.H. Chui, C.B. Gilks, K. Cooper, B.A. Clarke Identifying Lynch syndrome in patients with ovarian carcinoma: the significance of tumor subtype Adv Anat Pathol, 20 (2013), pp. 378-386.
• 60. M.H. Chui, P. Ryan, J. Radigan,et al. The histomorphology of Lynch syndrome–associated ovarian carcinomas: toward a subtype-specific screening strategy Am J Surg Pathol, 38 (2014), pp. 1173-1181.
• 61. C.Loveday, C. Turnbull, E. Ruark,et al. Germline RAD51C mutations confer susceptibility to ovarian cancer Nat Genet, 44 (2012), pp. 475-476.
• 62. C. Loveday, C. Turnbull, E. Ramsay, et al.Germline mutations in RAD51D confer susceptibility to ovarian cancer Nat Genet, 43 (2011), pp. 879-882.
• 63. H.T. Lynch, M.J. Casey, C.L. Snyder, et al.Hereditary ovarian carcinoma: heterogeneity, molecular genetics, pathology, and management Mol Oncol, 3 (2009), pp. 97-137.
• 64. NCCN. Guidelines, genetic/familial high-risk assessment: breast and ovarian. Version 1. 2017 2016. Available at: https://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Accessed January 31, 2017.
• 65. C. Palles, J.-B. Cazier, K.M. Howarth,et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas Nat Genet, 45 (2013), pp. 136-144.
• 66. T.J. McGarrity, H.E. Kulin, R.J. Zaino Peutz-Jeghers syndrome Am J Gastroenterol, 95 (2000), pp. 596-604.
• 67. Hans F A Vasen, Ignacio Blanco, Katja Aktan-Collan,et al. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts (the Mallorca group) Gut. 2013 Jun; 62(6): 812–823.
• 68. Nielsen SM, Eccles DM, Romero IL, Al-Mulla F, et al. Genetic Testing and Clinical Management Practices for Variants in Non-BRCA1/2 Breast (and Breast/Ovarian)Cancer Susceptibility Genes: An International Survey by the Evidence-BasedNetwork for the Interpretation of Germline Mutant Alleles (ENIGMA) ClinicalWorking Group. JCO Precis Oncol. 2018;2.
• 69. Kurian AW. BRCA1 and BRCA2 mutations across race and ethnicity: distribution and clinical implications. Curr Opin Obstet Gynecol. 2010 Feb;22(1):72-8.
• 70. Eccles DM, Mitchell G, Monteiro AN, et al. ENIGMA Clinical Working Group. BRCA1 and BRCA2 genetic testing-pitfalls and recommendations for managing variants of uncertain clinical significance. Ann Oncol. 2015 Oct;26(10):2057-65.
• 71. J.M. Eggington, K.R. Bowles, K. Moyes, et al. A comprehensive laboratory-based program for classification of variants of uncertain significance in hereditary cancer genes Clin. Genet., 86 (2014), pp. 229-237.
• 72. Frey MK, Kim SH, Bassett RY, et al. Rescreening for genetic mutations using multi-gene panel testing in patients who previously underwent non-informative genetic screening. Gynecol Oncol. 2015 Nov;139(2):211-5.
• 73. Ahmed M, Rahman N. ATM and breast cancer susceptibility. Oncogene. 2006 Sep 25;25(43):5906-11. Review.
• 74. Gatti R,Perlman S.(Adam MP,Ardinger HH,Pagon RA,et al.,editors) GeneReviews.University of Washington ,Seattle.Last update:October 27,2016. Available at: https://www.ncbi.nlm.nih.gov/books/NBK26468/
• 75.ClinVar aggregates information about genomic variation and its relationship to human health . Available at: http://www.ncbi.nlm.nih.gov/clinvar/
• 76. Southey MC, Goldgar DE, Winqvist R, et al.PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. J Med Genet. 2016 Dec;53(12):800-811.