BRCA1/2 normal meme kanserli kadınlarda genotip-fenotip ilişkisinin araştırılması: Türkiye'den tek merkez deneyimi

Yıl 2021, Cilt: 12 Sayı: 3, 349 - 356, 29.09.2021

Neslihan Duzkale , Aysun Gökce , Tülay Eren , Gökşen İnanç İmamoğlu , Mustafa Altınbaş

https://doi.org/10.18663/tjcl.948240

Öz

Amaç: Meme kanserlerinin yaklaşık %10'unun kalıtsal olduğu ve bunların yaklaşık %20'sinden BRCA1/2 genlerinin sorumlu olduğu bilinmektedir. Yapılan araştırmalar, meme kanserinde BRCA1/2 dışındaki birçok genin mutasyonlarının da yatkınlığa neden olduğunu göstermiştir. Bu çalışmada meme kanserli Türk kadınlarda diğer kanser yatkınlık genlerinin araştırılması amaçlanmıştır.
Gereç ve Yöntemler: Bu retrospektif çalışmaya Ankara Dışkapı Yıldırım Beyazıt Eğitim ve Araştırma Hastanesi Genetik Bölümü'nde 2016-2021 yılları arasında değerlendirilen 66 kadın hasta dahil edildi. Hastaların kansere yatkınlık genleri, yeni nesil dizileme tekniği (NGS) kullanılarak incelendi.
Bulgular: Hastaların ortalama tanı yaşı 43 ± 8.0 idi. Genetik analiz ile 66 hastanın 9'unda (%13,63) nedensel gen tespit edildi. Bu genler ATM (%13), CHEK2 (%36), FANCC (%13), MUTYH (%13) ve PALB2'dir (%25). Nedensel varyantı olan hastalar ve diğerleri gruplandırılarak tanı yaşı, tümör lokalizasyonu, tümörün histopatolojik tipi, östrojen/progesteron reseptör durumu, cerbb2, evre, tanı anındaki metastaz ve kanserli akraba sayısı gibi parametreler açısından karşılaştırıldı. Gruplar arasında istatistiksel bir ilişki bulunamadı.
Sonuç: Bu çalışmada meme kanserli Türk kadınlarında BRCA1/2 dışındaki kansere yatkınlık genlerinin nedensel varyantlarının saptanma oranı %13,63 olarak belirlendi. Kanserli bireylerde NGS ile çoklu gen testlerinin yapılması, taşıyıcı bireylerin doğru tanı ve uygun tedavi almalarını ve gerekli taramalara yönlendirilmelerini sağlayacaktır.

Anahtar Kelimeler

Meme kanseri, BRCA1/2, kalıtsal kanser yatkınlık genleri, yeni nesil dizileme, çoklu gen paneli

Investigation of genotype-phenotype relationship in women with BRCA1/2 normal breast cancer: A single-center experience from Turkey

Öz

Aim: It is known that approximately 10% of breast cancers are hereditary, and BRCA1/2 genes are responsible for
approximately 20% of these. Studies have shown that mutations of many genes other than BRCA1/2 in breast cancer also
cause this predisposition. In this study, it was aimed to investigate other causative cancer susceptibility genes in women
with breast cancer.
Material and Methods: In this retrospective study, 66 female patients who were evaluated in Ankara Dışkapı Yıldırım
Beyazıt Training and Research Hospital Genetics Department between 2016-2020 were included. Cancer susceptibility
genes of the patients were examined using next-generation sequencing technique (NGS).
Results: Mean age at diagnosis of the patients was 43 ± 8.0. By genetic analysis, causative genes were identified in 9
(13.63%) of 66 patients. These genes are ATM (%11), BRIP1 (%11), CHEK2 (%34), FANCC (%11), MUTYH (%11) and PALB2
(%22). Patients with a causal variant and others were grouped, and compared in terms of parameters such as age at
diagnosis, tumor localization, histopathological type of tumor, estrogen/progesterone receptor status, c-erbB2, stage,
metastasis at diagnosis, and number of relatives with cancer. No statistical relationship was found between the groups.
Conclusion: This study determined the rate of detection of causal variants of cancer susceptibility genes other than
BRCA1/2 in women with breast cancer who applied to the medical genetics department as 13.63%. Performing multiple
gene tests with the NGS in cancer individuals will allow carrier individuals to receive correct diagnosis and appropriate
treatment and to be directed to necessary screenings.

Anahtar Kelimeler

Breast cancer, BRCA1/2, hereditary cancer susceptibility genes, next generation sequencing, multi-gene panel

Kaynakça

• 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61: 69-90.
• 2. Broca P. Traité des tumeurs. Vols. 1 and 2. Paris: Asselin; 1866–9
• 3. Honrado E, Benítez J, Palacios J. The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications. Mod Pathol 2005; 18: 1305–20
• 4. Stratton MR, Rahman N. The emerging landscape of breast cancer susceptibility. Nat Genet 2008; 40: 17-22.
• 5. Vargas AC, Reis-Filho JS, Lakhani SR. Phenotype-genotype correlation in familial breast cancer. J Mammary Gland Biol Neoplasia 2011; 16: 27–40.
• 6. Beck AC, Yuan H, Liao J et al. Rate of BRCA mutation in patients tested under NCCN genetic testing criteria. Am J Surg 2020; 219: 145-9.
• 7. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 1991; 19: 403-10.
• 8. 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: 405-24.
• 9. Thompson D, Easton D. The genetic epidemiology of breast cancer genes. J Mammary Gland Biol Neoplasia 2004; 9: 221–36.
• 10. Peto J, Mack TM. High constant incidence in twins and other relatives of women with breast cancer. Nat Genet 2000; 26: 411-4.
• 11. Gerdes AM, Cruger DG, Thomassen M, Kruse TA. Evaluation of two different models to predict BRCA1 and BRCA2 mutations in a cohort of Danish hereditary breast and/or ovarian cancer families. Clin Genet 2006; 69: 171-8.
• 12. Roy R, Chun J, Powell SN. BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer 2011; 12: 68-78.
• 13. Easton DF, Pooley KA, Dunning AM et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 2007; 447: 1087-93.
• 14. Cox A, Dunning AM, Garcia-Closas M et al. A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet 2007; 39: 352-8.
• 15. Nevanlinna H, Bartek J. The CHEK2 gene and inherited breast cancer susceptibility. Oncogene 2006; 25: 5912-9.
• 16. Rainville I, Hatcher S, Rosenthal E et al. High risk of breast cancer in women with biallelic pathogenic variants in CHEK2. Breast Cancer Res Treat. 2020; 180: 503-9.
• 17. NCCN clinical practice guidelines in oncology, genetic/familial high-risk assessment: breast and ovarian (version 3. 2019). https://www.nccn.org/professionals/physician_gls/pdf/ genetics_bop.pdf. (5 Haziran 2021).
• 18. Antoniou AC, Casadei S, Heikkinen T et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med 2014; 371: 497-506.
• 19. Zhou J, Wang H, Fu F et al. Spectrum of PALB2 germline mutations and characteristics of PALB2-related breast cancer: Screening of 16,501 unselected patients with breast cancer and 5890 controls by next-generation sequencing. Cancer 2020; 126: 3202-8.
• 20. Antoniou AC, Casadei S, Heikkinen T et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med 2014; 371: 497-506.
• 21. Janatová M, Borecká M, Soukupová J et al. PALB2 jako další kandidátní gen pro genetické testování u pa-cientů s hereditárním karcinomem prsu v České republice [PALB2 as Another Candidate Gene for Genetic Testing in Patients with Hereditary Breast Cancer in Czech Republic]. Klin Onkol 2016; 29: 31-4.
• 22. Weber-Lassalle N, Hauke J, Ramser J et al. BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer. Breast Cancer Res 2018; 20: 7.
• 23. Mazouzi A, Battistini F, Moser SC et al. Repair of UV-Induced DNA Damage Independent of Nucleotide Excision Repair Is Masked by MUTYH. Mol Cell 2017; 68: 797-807.
• 24. Rennert G, Lejbkowicz F, Cohen I, Pinchev M, Rennert HS, Barnett-Griness O. MutYH mutation carriers have increased breast cancer risk. Cancer 2012; 118: 1989-93.
• 25. Jerzak KJ, Mancuso T, Eisen A. Ataxia-telangiectasia gene (ATM) mutation heterozygosity in breast cancer: a narrative review. Curr Oncol 2018; 25: 176-80