Pathogenicity assessment of breast cancer associated BRCA1/2 variants using explainable machine learning approach

Öz

Breast cancer is the most common type of cancer in women worldwide and represents a heterogeneous group of diseases resulting from the interaction of genetic and environmental factors. Pathogenic mutations in the BRCA1/2 genes significantly increase lifetime breast cancer risk, highlighting the critical role of genetic testing in early diagnosis and preventive strategies. This study aimed to evaluate the pathogenicity of BRCA1/2 variants using machine learning algorithms. During model development, a comprehensive dataset comprising 32,719 BRCA1/2 variants was obtained from the ClinVar database. The dataset was systematically collected, preprocessed and analyzed within a multi-class classification framework (benign, likely benign, variant of uncertain significance, likely pathogenic, pathogenic). Seven different supervised classification algorithms were applied, and the best-performing model, Extreme Gradient Boosting (XGBoost), was trained using Bayesian optimization under 10-fold stratified cross-validation. The XGBoost model achieved the highest performance, with an accuracy of 96.12% and a weighted-F1 score of 95.67%. Furthermore, analyses with explainable artificial intelligence methods demonstrated which features the model relied on for classification decisions and highlighted the criteria with the greatest contribution. These findings suggest that machine learning–based approaches can serve as scalable and clinically meaningful tools for the interpretation of BRCA1/2 variants.

Anahtar Kelimeler

• Machine learning
• Bayesian optimization
• Explainable Artificial Intelligence
• Breast cancer
• BRCA1/2 variants
• Pathogenicity classification

Destekleyen Kurum

TÜBİTAK TEYDEB, Project Number: 7241058

Proje Numarası

7241058

Etik Beyan

There is no conflict of interest declared in this study.

Teşekkür

This research was supported by the TÜBİTAK TEYDEB program under Project Number 7241058.

Açıklanabilir makine öğrenimi yaklaşımı kullanılarak meme kanseriyle ilişkili BRCA1/2 varyantlarının patojenite değerlendirmesi

Öz

Meme kanseri, dünya genelinde kadınlarda en sık görülen kanser türüdür ve genetik ile çevresel faktörlerin etkileşimi sonucu ortaya çıkan heterojen bir hastalık grubunu temsil etmektedir. BRCA1/2 genlerindeki patojenik mutasyonlar, yaşam boyu meme kanseri riskini önemli ölçüde artırmakta ve bu durum, erken tanı ile önleyici stratejilerde genetik testlerin kritik rolünü vurgulamaktadır. Bu çalışmada, BRCA1/2 varyantlarının patojenitesinin makine öğrenimi algoritmaları kullanılarak değerlendirilmesi amaçlanmıştır. Model geliştirme sürecinde, BRCA1/2 genlerine ait 32.719 varyant içeren kapsamlı bir veri seti ClinVar veritabanından elde edilmiştir. Veri seti sistematik olarak hazırlanmış, ön işleme uygulanmış ve çoklu sınıflandırma (iyi huylu, muhtemel iyi huylu, belirsiz öneme sahip varyant, muhtemel patojenik, patojenik) çerçevesinde analiz edilmiştir. Yedi farklı denetimli sınıflandırma algoritması uygulanmış, en iyi performansı gösteren Aşırı Gradyan Artırma (AGA) modeli ise 10-katlı tabakalı çapraz doğrulama altında Bayes optimizasyonu ile çalıştırılmıştır. AGA modeli %96,12 doğruluk ve %95,67 ağırlıklı-F1 skoru ile en yüksek başarıyı elde etmiştir. Açıklanabilir yapay zekâ yöntemiyle yapılan analizler, modelin sınıflandırma kararlarını hangi özelliklere dayandırdığını ve en yüksek katkıyı sunan kriterlerin öne çıktığını göstermektedir. Bulgular, makine öğrenimi tabanlı yaklaşımların BRCA1/2 varyant yorumlamasında ölçeklenebilir ve klinik açıdan anlamlı araçlar olarak kullanılabileceğini göstermektedir.

Anahtar Kelimeler

• Makine öğrenimi
• Bayes optimizasyonu
• Açıklanabilir Yapay Zeka
• Meme kanseri
• BRCA1/2 varyantları
• Patojenite sınıflandırması

Destekleyen Kurum

TÜBİTAK TEYDEB, Proje No: 7241058

Proje Numarası

7241058

Etik Beyan

Bu çalışma kapsamında herhangi bir çıkar çatışması bulunmamaktadır.

Teşekkür

Bu araştırma, TÜBİTAK TEYDEB programı tarafından desteklenmiştir.

Kaynakça

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