.: ORİJİNAL ARAŞTIRMA
Herediter Meme Kanseri Tanılı ve Riskli Bireylerde BRCA1/BRCA2 Sonuçlarının Değerlendirilmesi: Varyant Frekansı, Dağılımı ve Dört Yeni Varyant (Retrospektif Kohort Çalışması)
Evaluation of BRCA1/BRCA2 Results in Individuals Diagnosed with and at Risk for Hereditary Breast Cancer: Variant Frequency, Distribution and Four Novel Variants (Retrospective Cohort Study)
Turkiye Klinikleri J Med Sci. 2024;44(1):35-42
doi: 10.5336/medsci.2023-99225
Makale Dili: TR
Tam Metin
ÖZET
Amaç: Bu çalışmanın amacı, herediter meme kanseri tanısı ve herediter meme ve/veya over kanseri [hereditary breast and over cancer (HBOC)] riski ile başvuran bireylerin BRCA1/2 genlerindeki germline varyant sıklığının, dağılımının ve yeni varyantların değerlendirilmesidir. Gereç ve Yöntemler: Çalışma retrospektif bir çalışma olup, Ulusal Kapsamlı Kanser Ağı kılavuzlarına göre genetik analiz yapılması önerilen aralarında akrabalık bulunmayan 147 meme kanserli birey ve 41 sağlıklı birey dâhil edilmiştir. BRCA1/2 genlerindeki tek nükleotid değişimi, küçük delesyon/duplikasyon tespiti için yeni nesil dizileme yapılmıştır. Büyük delesyon/duplikasyonlar ve kopya sayısı değişiklikleri için multipleks ligasyona bağlı prob amplifikasyonu yöntemi kullanılmıştır. Bulgular: Kanserli olguların 20'sinde (%13,6), sağlıklı olguların ise 8'inde (%19,5) olmak üzere, çalışmaya dâhil edilen toplam 188 olgunun 28'inde (%14,89) BRCA1 ve/veya BRCA2 geninde heterozigot varyant [patojenik (P), muhtemel patojenik (likely pathogenic ''LP''), klinik önemi belirsiz (variants of uncertain significance ''VUS''), kopya sayısı değişikliği (copy number variation ''CNV'')] tespit edildi. Tüm olguların 20'si (%10,64), BRCA1 (n=12, %7,95) veya BRCA2 (n=8, %4,24) geninde P/LP/CNV varyant taşırken 8 olguda (%4,25) VUS varyant vardı. Olgularda en sık görülen varyant BRCA1 genindeki c.5266dupC idi. BRCA1 geninde bir yeni varyant (p.Pro1575Ala), BRCA2 geninde 3 yeni varyant (p.Lys2950ArgfsTer26, p.Ser973AspfsTer41, p.Gly1700Leu) tespit edildi. Sonuç: Çalışmamızda BRCA1/2 genlerinde %14,89 olarak bulunan germline varyant sıklığı Türkiye'de yapılan önceki çalışmalara benzerdi. Tespit edilen 4 yeni varyant, genetik spektrumun genişletilmesine katkı sağladı. HBOC'li ya da riskli bireylerde BRCA1/2 gen analizi tanı konulmuş hastalarda tedavi yönetiminin planlanması, yüksek riskli sağlıklı bireylerde ise kanser gelişimine karşı riski azaltıcı önlemlerin alınması, bu bireylere erken tanı konulması ve genetik danışmanlık verilmesi açısından oldukça önemlidir.
Anahtar Kelimeler: Ailesel meme kanseri; BRCA1; BRCA2; germline varyant
Amaç: Bu çalışmanın amacı, herediter meme kanseri tanısı ve herediter meme ve/veya over kanseri [hereditary breast and over cancer (HBOC)] riski ile başvuran bireylerin BRCA1/2 genlerindeki germline varyant sıklığının, dağılımının ve yeni varyantların değerlendirilmesidir. Gereç ve Yöntemler: Çalışma retrospektif bir çalışma olup, Ulusal Kapsamlı Kanser Ağı kılavuzlarına göre genetik analiz yapılması önerilen aralarında akrabalık bulunmayan 147 meme kanserli birey ve 41 sağlıklı birey dâhil edilmiştir. BRCA1/2 genlerindeki tek nükleotid değişimi, küçük delesyon/duplikasyon tespiti için yeni nesil dizileme yapılmıştır. Büyük delesyon/duplikasyonlar ve kopya sayısı değişiklikleri için multipleks ligasyona bağlı prob amplifikasyonu yöntemi kullanılmıştır. Bulgular: Kanserli olguların 20'sinde (%13,6), sağlıklı olguların ise 8'inde (%19,5) olmak üzere, çalışmaya dâhil edilen toplam 188 olgunun 28'inde (%14,89) BRCA1 ve/veya BRCA2 geninde heterozigot varyant [patojenik (P), muhtemel patojenik (likely pathogenic ''LP''), klinik önemi belirsiz (variants of uncertain significance ''VUS''), kopya sayısı değişikliği (copy number variation ''CNV'')] tespit edildi. Tüm olguların 20'si (%10,64), BRCA1 (n=12, %7,95) veya BRCA2 (n=8, %4,24) geninde P/LP/CNV varyant taşırken 8 olguda (%4,25) VUS varyant vardı. Olgularda en sık görülen varyant BRCA1 genindeki c.5266dupC idi. BRCA1 geninde bir yeni varyant (p.Pro1575Ala), BRCA2 geninde 3 yeni varyant (p.Lys2950ArgfsTer26, p.Ser973AspfsTer41, p.Gly1700Leu) tespit edildi. Sonuç: Çalışmamızda BRCA1/2 genlerinde %14,89 olarak bulunan germline varyant sıklığı Türkiye'de yapılan önceki çalışmalara benzerdi. Tespit edilen 4 yeni varyant, genetik spektrumun genişletilmesine katkı sağladı. HBOC'li ya da riskli bireylerde BRCA1/2 gen analizi tanı konulmuş hastalarda tedavi yönetiminin planlanması, yüksek riskli sağlıklı bireylerde ise kanser gelişimine karşı riski azaltıcı önlemlerin alınması, bu bireylere erken tanı konulması ve genetik danışmanlık verilmesi açısından oldukça önemlidir.
Anahtar Kelimeler: Ailesel meme kanseri; BRCA1; BRCA2; germline varyant
ABSTRACT
Objective: The aim of this study is to evaluate the frequency and distribution of germline variants and novel variants in the BRCA1 and BRCA2 genes of individuals presenting with the diagnosis of hereditary breast cancer and hereditary breast and over cancer (HBOC) risk. Material and Methods: A total of 147 unrelated cancer individuals and 41 healthy individuals, whose genetic analysis was recommended according to the National Comprehensive Cancer Network guidelines, were included in the study. Next generation sequencing was performed to detect single nucleotide change, small deletion/duplication in BRCA1 and BRCA2 genes. The multiplex ligation-dependent probe amplification method was used for large deletions/duplications and copy number changes. Results: Heterozygous variant [pathogenic (P), likely pathogenic (LP), variants of uncertain significance (VUS), copy number variation (CNV)] was detected in BRCA1 and/or BRCA2 genes in 28 (14.89%) of 188 patients included in the study, 20 (13.6%) of cancer patients and 8 (19.5%) of healthy patients. Twenty of all cases (10.64%) carried P/LP/CNV variant in BRCA1 (n=12, 7.95%) or BRCA2 (n=8, 4.24%) gene, while VUS was found in 8 cases (4.25%). The most common variant in the cases was c.5266dupC in the BRCA1 gene. One novel variant (p.Pro1575Ala) was detected in the BRCA1 gene and 3 novel variants (p.Lys2950ArgfsTer26, p.Ser973AspfsTer41, p.Gly1700Leu) in the BRCA2 gene. Conclusion: The frequency of germline variants in BRCA1 and BRCA2 genes in our study was 14.89% that similar to previous studies conducted in Türkiye. The 4 novel variants contributed to expanding the genetic spectrum. BRCA1 and BRCA2 gene analysis in individuals with HBOC or risky individuals is very important in terms of planning the treatment management in patients with diagnosed, taking measures to reduce the risk of cancer development in healthy individuals with high risk, early diagnosis and providing genetic counseling to these individuals.
Keywords: Hereditary breast cancer; BRCA1; BRCA2; germline variant
Objective: The aim of this study is to evaluate the frequency and distribution of germline variants and novel variants in the BRCA1 and BRCA2 genes of individuals presenting with the diagnosis of hereditary breast cancer and hereditary breast and over cancer (HBOC) risk. Material and Methods: A total of 147 unrelated cancer individuals and 41 healthy individuals, whose genetic analysis was recommended according to the National Comprehensive Cancer Network guidelines, were included in the study. Next generation sequencing was performed to detect single nucleotide change, small deletion/duplication in BRCA1 and BRCA2 genes. The multiplex ligation-dependent probe amplification method was used for large deletions/duplications and copy number changes. Results: Heterozygous variant [pathogenic (P), likely pathogenic (LP), variants of uncertain significance (VUS), copy number variation (CNV)] was detected in BRCA1 and/or BRCA2 genes in 28 (14.89%) of 188 patients included in the study, 20 (13.6%) of cancer patients and 8 (19.5%) of healthy patients. Twenty of all cases (10.64%) carried P/LP/CNV variant in BRCA1 (n=12, 7.95%) or BRCA2 (n=8, 4.24%) gene, while VUS was found in 8 cases (4.25%). The most common variant in the cases was c.5266dupC in the BRCA1 gene. One novel variant (p.Pro1575Ala) was detected in the BRCA1 gene and 3 novel variants (p.Lys2950ArgfsTer26, p.Ser973AspfsTer41, p.Gly1700Leu) in the BRCA2 gene. Conclusion: The frequency of germline variants in BRCA1 and BRCA2 genes in our study was 14.89% that similar to previous studies conducted in Türkiye. The 4 novel variants contributed to expanding the genetic spectrum. BRCA1 and BRCA2 gene analysis in individuals with HBOC or risky individuals is very important in terms of planning the treatment management in patients with diagnosed, taking measures to reduce the risk of cancer development in healthy individuals with high risk, early diagnosis and providing genetic counseling to these individuals.
Keywords: Hereditary breast cancer; BRCA1; BRCA2; germline variant
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